Category Archives: Molecular Medicine

Liquid biopsy is a non-invasive method of sampling and analysing non-solid biological tissue using biomarkers circulating within bodily fluids, such as blood. A compelling application for this technology lies within oncology, in areas such as early routine diagnosis of cancer, as well as long-term monitoring of tumours and associated mutations.

The technique works by examining either circulating tumour cells (CTCs) or circulating tumour DNA (ctDNA) within a patients blood sample. When tumour cells die, ctDNA is released into the blood, where it is further broken down by enzymatic pathways. (1) This results in the presence of small fragments of ctDNA within the patients blood, molecular fingerprints which can be analysed using next-generation sequencing (NGS) technology.

There is significant potential for liquid biopsy to transform cancer diagnosis as well as free up laboratory capacity. A promising area for liquid biopsy can be seen in population screening for earlier detection of tumours. (2) The World Health Organization (WHO) estimates that this could have an impact on preventing 30-50% of cancers through earlier diagnosis and subsequent treatment. (3)

One of the challenges in making liquid biopsy a standard clinical tool lies in reducing the error of the analysis such as false positive/negative results. Whilst sequencing has indeed become cheaper and cheaper, it has also to some extent become noisier. Sequencing noise contributes towards diagnostic errors by making it more difficult to distinguish the signal (tumour origin) from the noise. As well as this, improving the cost-effectiveness of liquid biopsy remains a challenge that must be overcome.

A major driver of these challenges lies in the very nature of oncology liquid biopsy ctDNA contributes only a small percentage of the total DNA within the patients blood sample. This means that the sequencing signal is weak, and the noise is too much. A way to overcome these challenges is to enrich the sample a method known as size selection to concentrate the fraction originating from the tumour. This helps to reduce the sample noise, as well as improve cost-effectiveness by sequencing more ctDNA and less DNA from healthy cells.

Yourgenes LightBench with Ranger Technology helps scientists and clinicians to realise the potential of liquid biopsy in oncology screening by allowing you to isolate the short fraction of cfDNA originating from the tumour, in a highly reproducible manner. Enriching the ctDNA with automated gel electrophoresis allows you to push down the error and lower the cost of sequencing. Unlike with traditional manual processes (such as polyacrylamide gel electrophoresis), the LightBench allows you to scale-up your process. Simply load a cassette and let the machine do the work.

Pantel K, Alix-Panabires C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010;16(9):398-406. doi:10.1016/j.molmed.2010.07.001 (https://pubmed.ncbi.nlm.nih.gov/20667783/)Hunter Underhill, Liquid Biopsy: Current Status and Future Directions, Front Line Genomics, p31 https://www.who.int/activities/promoting-cancer-early-diagnosis

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Precision medicine: From bench to clinic clinic, lightbench - Open Access Government

CAMBRIDGE, Mass., June 29, 2021 /PRNewswire/ --nference, the AI-driven health technology company, today announced publication of two peer-reviewed studies in Med that analyzed the largest, context-rich electronic health record (EHR) and clinical notes platform with nference real-time artificial intelligence (AI) software, confirming the safety and efficacy of the two messenger RNA (mRNA) COVID-19 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech), that are FDA-authorized for emergency use. Med is a monthly journal from Cell Press that publishes rigorously vetted original research across the translational and clinical continuum.

In the first study, "Real-time analysis of a mass vaccination effort confirms the safety of FDA-authorized mRNA COVID-19 vaccines," the authors analyzed over 1.2 million EHR notes in the Mayo Clinic health system and compared rates of post-vaccination clinical follow-up and adverse effects between 68,266 vaccinated individuals (51,795 who received BNT162b2 and 16,471 who received mRNA-1273) and 68,266 matched unvaccinated individuals. Their results show that vaccinated individuals are likely to experience muscle and joint soreness, but they are not more likely to seek out emergent clinical care or to experience any severe medical events than unvaccinated individuals.

In the second study, "FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system," the authors analyzed the same cohorts to assess the real-world effectiveness of BNT162b2 and mRNA-1273 vaccines. By comparing rates of positive PCR testing, hospitalization, and ICU admission between the vaccinated and matched unvaccinated individuals, they found that both vaccines protect against SARS-CoV-2 infection and severe COVID-19. Specifically, the estimated effectiveness in preventing infections was 86% for BNT162b2 and 93% for mRNA-1273, and no individuals receiving either vaccine were admitted to the ICU for COVID-19.

Since multiple CDC-recognized variants of concern, including the UK variant, were circulating significantly during the time period of this study, this research validates the real-world effectiveness of the two messenger mRNA vaccines against this variant of concern. Furthermore, beyond symptomatic COVID-19 diagnosis studied in clinical trials, this study is the first to demonstrate that the COVID-19 mRNA vaccines significantly mitigate even asymptomatic human-to-human transmission of the SARS-CoV-2 pathogen.

"These studies provide critical, independent real-world insights that should assuage those who are vaccine-hesitant because the evidence is undeniable. These vaccines are extremely safe and effective, including to mitigate asymptomatic viral transmission and against some of the prominent variants of concern," said Venky Soundararajan, PhD, co-founder and chief scientific officer of nference.

In the process of conducting these studies, nference employed its leading-edge augmented intelligence software platform, nferX, which uses proprietary natural language processing, molecular analytics, and clinical institutional wisdom synthesis technologies to rapidly process and triangulate vast amounts of biomedical insights from disparate sources in previously incompatible formats.

"The application of augmented curation technology over the Mayo Clinic institution-wide clinical data analytics platform provides compelling, timely evidence that vaccinations are indeed the key to conquering the COVID-19 pandemic," said Andrew Badley, MD, co-author of the study enterprise chair of the department of molecular medicine and enterprise chair of COVID-19 task force at the Mayo Clinic.

The innovative and powerful augmented intelligence technology implemented by nference during the COVID-19 pandemic has enabled scientific discoveries with a wide range of implications that contribute to a greater understanding of the virus, which are ultimately advancing patient care and informing important policy decisions at the vanguard of protecting global public health.

About nferenceThrough its powerful augmented intelligence software nferX, nference is transforming health care by making biomedical knowledge computable. The platform partnership with Mayo Clinic has given nference an opportunity to synthesize more than 100 years of institutional wisdom, producing real-world evidence in real time by converting large amounts of knowledge into deep insights that advance discovery and development of diagnostics and therapeutics. nference is headquartered in Cambridge, Massachusetts and has operations in Rochester, Minnesota; Toronto, Canada; and Bangalore, India. Follow nference on LinkedIn and Twitter. Visit us at nference.ai.

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nference and Mayo Clinic Studies Confirm Safety and Effectiveness of FDA-authorized mRNA Vaccines for COVID-19 - PRNewswire

The number of daily new cases of COVID-19 has surged over the past week in the United States, as the government eliminates all remaining restrictions on the spread of the disease even as the dangerous Delta variant becomes prevalent.

In the United States, where the Delta variant has been detected in all 50 states, daily cases have turned upwards, having risen 14.8 percent compared to the previous week.

In Europe, COVID-19 cases have surged 29 percent higher than the previous week.

There will be a new wave in the WHO European region unless we remain disciplined, warned WHO Regional Director for Europe Hans Kluge.

The Delta variant of the coronavirus (B.1.617.2), which ravaged India in May, has now rapidly swept across more than 85 countries, frustrating many countries that had planned to lift restrictions and reopen their economies before the summer tourist season. Only in South America has the Gamma variant, also known as P.1, remained dominant and is ravaging the continent.

Presently, according to Worldometer, there have been over 183 million cases of COVID-19 worldwide. The death count is fast approaching 4 million. However, this is known to be a gross underestimation, with modeling studies suggesting the death toll could be a magnitude of three times higher.

Despite the weeks of declines beginning in the early part of April, the global incidence of cases is again rising. Yesterday, the seven-day average stood at 378,000 COVID-19 cases. The seven-day moving average for deaths continues to remain high at over 8,000 per day. Though deaths continue to decline, they lag the trends in COVID cases and are expected to follow in step in the next week or two.

In the United States, increases have been most prominent in Southern and Western states, where vaccination rates are below the national averages, according to the Center for Infectious Disease Research and Policy.

Dr. Anthony Fauci said this week: Im very concerned about the stark disparity between places with low and high vaccination rates. When you have such a low level of vaccination superimposed upon a variant that has a high degree of efficiency of spread, what you are going to see among under-vaccinated regionsbe those states, cities or countiesyoure going to see these individual types of blips. Its almost like its going to be two Americas.

The highest case rates were in Nevada and Arkansas, with a 55 percent increase over the past seven days. Missouri and Wyoming saw almost a 20 percent rise over a week. In all, the United States reported more than 14,000 new cases and 249 deaths yesterday. There have been more than 34.5 million COVID-19 cases and over 620,000 deaths during the pandemic.

Indeed, the Independence Day weekend will add fuel to the fire. The holiday is expected to be the busiest travel period since the pandemic. Approximately 48 million people are planning to travel, primarily by car. AAA (American Automobile Association) forecasted that 3.5 million people would be flying, bringing airlines back to 90 percent of pre-pandemic traffic.

Eric Topol, professor of molecular medicine at the Scripps Research Institute, said of the Delta variant: It is the most hyper-transmissible, contagious version of the virus weve seen to date, for sureits a superspreader strain if there ever was one. Also, recent studies indicate that the Delta variant may produce more severe disease. A recent study published in The Lancet on June 14, noted that hospitalization rates of patients with the Delta strain were about 85 percent higher than those that were infected with the Alpha variant.

Despite the Centers for Disease Control and Preventions (CDC) recommendation that vaccinated individuals need not wear masks, health officials in Los Angeles strongly encouraged everyone, regardless of their vaccine status, to wear them indoors due to the threat posed by the highly transmissible strain of the coronavirus. During their last press briefing on COVID-19, the World Health Organization also recommended that all people wear masks indoors, including fully vaccinated people.

The United States vaccination campaign has stalled, remaining precariously at around 1 million vaccinations per day. Only 46.7 percent of the population has been fully vaccinated, with 54.4 percent having received at least a single dose. The current projections place August 2 as the estimated date when at least 70 percent of all adults in the US will have received at least one dose of the COVID vaccines, far behind the White Houses estimations.

The situation in Russia is growing direr by the day as deaths have surpassed the winter highs. Yesterday, 672 had succumbed to the infection, with 124 deaths in Moscow and 110 in St. Petersburg. Still, thousands of supporters were permitted to view the games as the quarter-final matches between Spain and Switzerland were given the go-ahead as planned. Meanwhile, Moscows Mayor Sergei Sobyanin confirmed that nearly 2,000 people are being hospitalized daily.

Sixty-five percent of the population have received at least one dose of the COVID vaccines in the UK. Still, there has been a 67 percent increase in cases of COVID-19 from a week before. The Delta variant now accounts for 97 percent of all COVID cases. Yesterday, they reported close to 28,000 new infections in contrast to just 3,165 on June 1. The epidemiological curves are rising exponentially.

Hans Kluge, Europes regional director for the WHO, has blamed these reversals in trends in relaxing restrictions and increased travel as the tourist season gets underway. Additionally, the Euro 2020 soccer tournament has drawn huge crowds of spectators from numerous countries mixing in crowded surroundings. Restaurants, pubs and bars are filled with patrons. Public transportation is brimming with fans and spectators. Reuters reported that this week almost 2,000 people from Scotland traveled to London for their game against England while infected with COVID-19.

I am not here to pour cold water on any EURO 2020 fan of anyones holidays, Kluge said. But before we watch our players, and before we all pack and go for some well-deserved rest near home or far away, it is my imperative to give [some]messages. If you decide to travel and gather, assess the risks and do it safely, keeping all life-saving reflexes of masks and self-protection, especially indoors and in crowds. He warned that Europe would be Delta dominant by August. He also noted that vaccination rates remain too slow.

Germanys Interior Minister Horst Seehofer had more choice words for the Union of European Football Associations (UEFA), calling them absolutely irresponsible for allowing 40,000 fans to watch the match between Germany and England at Wembley Stadium on Tuesday. I have the suspicion that this is about commerce again, he said. And commerce must not outshine the protection of the population against infection.

Dr. Eric Feigl-Ding, who has been prominent in educating the public on the pandemic and the science behind the SARS-CoV-2 virus, tweeted: Anyone who doubts the delta variant wave is coming only needs to look at Israel and the UKtwo of the most heavily vaccinated countries in the world.

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World Health Organization warns of new pandemic wave as cases surge in Europe and US - WSWS

Why is the Development of Disease-Modifying Osteoarthritis Drugs (DMOADs) Required?Disease Burden

Osteoarthritis (OA) is the most prevalent arthritis globally and represents a major challenge for twenty-first century health care systems.1,2 The Global Burden of Disease 2020 report showed an increase of 9.3% and 8.2% in the age-standardized OA point prevalence and annual incidence rate from 1990 to 2017.3 The prevalence rises with increasing age; in the USA (United States of America), OA was found in 13.9% of adults aged 25 years and 33.6% for those aged 65 years respectively in 2005.4 The lifetime risk of having symptomatic knee OA is about 40% in men and 47% in women, and the risk increases to 60.5% among obese persons.5 By the year 2040, an estimated 25.9% of the total adult population will have doctor-diagnosed arthritis in the USA.6

Globally, 80% of patients with OA suffer from limitations in movement, and 25% from difficulty in performing their major daily activities of life; representing a significant impact of OA on functional impairment and disability.7 In terms of economic burden, mean per-person earnings losses caused by OA were, on average, 7548 US$ per year from 2008 to 2011.8 The mean all-cause health care utilization of working-age patients with OA is $14,521 US$ per year.9 The socio-economic costs of OA were reported to range between 0.25% and 0.50% of a countrys GDP.10 In an individual patient data meta-analysis, the pooled estimate for premature mortality revealed a 23% increased risk (95% CI 1.07, 1.42) in patients with knee OA and a 20% increased risk (95% CI 1.04, 1.37) in hip OA.11

Current OA treatment options are focused on symptomatic improvement in pain and joint function and include paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, and intra-articular medications such as steroids and hyaluronic acids.14 Surgical treatments are typically indicated only for patients with end-stage OA, as a last resort. Recently, paracetamol and opioids are only conditionally or not recommended by several scientific organisations,12,13 highlighting the importance of finding new effective treatments for OA. In addition, outcomes for patients with OA are usually suboptimal and patients remain vulnerable to the clinical consequences of the disease on pain and physical function.14

OA was previously regarded as a degenerative disorder resulting from cartilage damage;15 however, the development and utilization of modern imaging methods revealed that it results from the failure of the joint organ with a heterogeneous involvement of the whole joint structures, including cartilage damage, subchondral bone remodeling, synovial inflammation and osteophyte development.16 Therefore, OA can be defined as a complex heterogeneous syndrome with multiple joint tissue involvement of varying severity. In part as a consequence, it is a huge challenge to develop a single one size fits all therapy that may be suitable and effective for all patients with OA.17

The central hallmark in the pathologic process of OA disease is the progressive deterioration in the biological, structural and mechanical properties and function of the joint tissues, and an effective medical treatment should possess the ability to delay these processes or ideally even halt them completely. Such pharmaceutical agents that will alter the natural history of disease progression by arresting joint structural change and ameliorating symptoms, either by reducing pain or improving physical function are termed as DMOADs.18

Currently, regulatory bodies such as US Food and Drug Administration (FDA)19 and the European Medicines Agency (EMA)20 have not approved any drug as an effective DMOAD, as the approval guide requires a potential DMOAD to demonstrate a slowing in the loss of knee or hip joint space width (JSW) on x-ray with associated symptomatic improvement.17 Therefore, current OA trials for DMOAD development pipeline need to meet both clinically meaningful symptom improvement with concomitant structural benefits according to US FDAs published draft industry guidance on structural endpoints for OA published in 2018.18

Because OA is characterised by its extraordinary inter-patient variability in clinical and structural manifestations, identification of patient/disease subtypes appropriate for targeted therapy is probably one of the promising ways forward in drug development research.21,22 In addition, structural changes in OA result from complex interactions among different pathobiological pathways, which implicate a variety of catabolic factors and cytokines in the different joint tissues (molecular cross-talk).23 Therefore, a new model of classifying OA based on pathophysiological disease subtypes is needed.

These subtypes can be clinical phenotypes or molecular/mechanistic endotypes.24 A clinical phenotype can be defined as a group of observable traits (ie aetiologic factors, risk factors) that can identify and characterize a subtype in a defined population.25,26 In other words, these subgroups of patients have similar clinically observable characteristics for better identifying individuals who are at higher risk of progression (prognostic) or who are more likely to respond to a specific intervention (prescriptive).27,28

An endotype is a disease subtype defined by distinct pathophysiologic mechanisms, including cellular, molecular and biomechanical signalling pathways.29 Therefore, the endotype is distinct from a phenotype, and indicates the presence of a well-defined molecular mechanism. A given clinical phenotype of OA may comprise overlapping molecular endotypes (ie, different mechanisms giving rise to the same manifestation at varying degrees during different phases of the disease).24

From the point of view of targeted drug discovery, where identifying and directing the right pathobiological mechanism and structural manifestations of disease is key for success, drug development in OA should be based on the endotypes as the basis of the main drivers of OA disease.30 In this review, we will, therefore, focus on currently ongoing phase 2 and 3 clinical trials of active drug development (Figure 1) related to three main molecular/mechanistic endotypes: 1) Cartilage-driven endotype, 2) Bone-driven endotype, 3) Inflammation-driven endotype. While each drug has been assigned to and is discussed under one endotype based on its predominant activity, a particular therapeutic may have broader endotype-effects and where present, these are duly noted.

Figure 1 Active drugs related to the three main molecular or mechanistic OA endotypes (phase 2 and 3).

One author (WMO) conducted electronic and manual searches on the https://clinicaltrials.gov/ for identifying ongoing phase 2/3 clinical trials in active drug development pipelines, as well as electronic database searches in the PubMed and Embase via Ovid for published reports of phase-2/3 clinical trials results from the inception of these databases to 31st March 2021 using the following MESH or keywords: osteoarthritis OR osteoarthrosis AND DMOAD/ OR structure modification OR disease-modifying osteoarthritis drugs/.

Cartilage damage is considered as a central part of OA disease process, which involves a variety of catabolic and reparative mechanisms at the molecular level. The pharmaceutical drugs in phase 2 and 3 stages of development for cartilage-driven endotype are summarized in Table 1.

Matrix-degrading enzymes in the joint such as collagenases and aggrecanases are responsible for proteolysis of extracellular matrix components such as type II collagen and aggrecan, which is the most abundant proteoglycan in cartilage.31 Proteinases such as matrix metalloproteinase 13 (MMP13) and ADAMTS5 (a Disintegrin And Metalloproteinase with ThromboSpondin-motif-5) are involved in cartilage destruction and progression of cartilage damage in OA pre-clinical models.32,33 The potential benefits of MMP inhibitors in preserving the OA joint have been investigated. However, in patients with knee OA, broad-spectrum MMP inhibitors such as PG-116800 showed reversible musculoskeletal toxicities in a dose-dependent manner without clinical benefits, leading to the termination of further development of this drug.34

S201086/GLPG1972 is a potent and highly selective active site inhibitor of ADAMTS5. It possesses an excellent selectivity profile in animal models and high stability in dog and human liver microsomes and hepatocytes.35 Phase-1 clinical studies revealed favorable pharmacokinetics as well as a strong and consistent target engagement in both healthy subjects and OA patients (n=171).36 In a phase-2 study (Roccella study) which investigated the efficacy and safety profile of three different once-daily oral doses of GLPG1972/S201086 (n=932), the change in cartilage thickness [in mm (SD)] of central medial tibiofemoral compartment of the target knee via quantitative MRI was 0.116 (0.27) for the placebo group and 0.068 (0.20), 0.097 (0.27) and 0.085 (0.22), for the low, medium and high dose, respectively. There was no statistically significant difference versus placebo in both MRI and clinical outcome measures.37 Another ADAMTS5-targeting agent, M6495 an anti-ADAMTS5 Nanobody (Ablynx), showed an acceptable safety profile and dose-dependent effects in a phase-1 study.38

Sprifermin is a recombinant human fibroblast growth factor 18 (FGF18) which binds to fibroblast growth factor receptor-3 (FGFR-3) in cartilage.39 It stimulates the proliferation of articular chondrocytes and induces hyaline extracellular matrix synthesis in rat OA models.40 At the cellular level, intermittent administration may transiently promote an anabolic effect, while continuous administration may stimulate other signalling pathways, leading to a weaker effect.41

Lohmander et al reported in 2014 that intra-articular (IA) sprifermin administration did not improve medial tibiofemoral cartilage-thickness over 12 months quantified by MRI (n=168) possibly as follow-ups were too short for detection of the full disease-modifying effect of treatment.39 However, a significant dose-dependent response was detected in total and lateral tibiofemoral cartilage-thickness and radiographic JSW over 12 months. The authors speculated that the dynamic loading implicated in predominantly medial tibiofemoral involvement seems to impede attempts to prevent cartilage loss or regenerate cartilage tissue. Sprifermin had no major local or systemic adverse events compared with placebo. Conference abstracts published in 2015 and 2016 reported the structure-modifying effects on cartilage thickness and bone marrow lesions (BMLs) on MRI on 12-month follow-up, using post-hoc analyses of the same study.42,43

In another clinical trial in which Sprifermin was administered up to 300 g for advanced knee OA, it was reported in 2016 that no significant benefits were detected for cartilage outcomes on histology, synovitis, effusion, BMLs on MRI and JSW on X-ray. However, the study was underpowered as MRI was only available in 30 out of 52 patients and the follow-up period was only 24 weeks, which may be too short for capturing the structure-modifying effects.44

In a 5-year, phase 2 dose-finding, multicenter randomized clinical trial [FGF18 Osteoarthritis Randomized Trial with administration of Repeated Doses (FORWARD) study], the effects of Sprifermin on changes in total femorotibial joint cartilage thickness (n=549) on MRI was evaluated at 2-year follow-up (NCT01919164). Hochberg et al reported in 2019 that three once-weekly IA injection of 100 g sprifermin provided a significant improvement in total femorotibial joint cartilage thickness [0.05 mm (95% CI, 0.03 to 0.07 mm)] for participants administered every 6 months and [0.04 mm (95% CI, 0.02 to 0.06 mm)] for participants administered every 12 months, compared with the placebo saline injection provided every 6 months (0.02 mm).45 No significant improvement in total WOMAC scores was detected, compared with placebo. The most frequently reported treatment-emergent adverse event was arthralgia and showed no difference from the placebo group (43%). An exploratory analysis of the same study at 3 year-follow-up (n=442) reveals significant differences (0.05 mm [95% CI, 0.030.07 mm]) in total femorotibial joint cartilage thickness over MRI between Sprifermin (100 g of Sprifermin every 6 months) and placebo (saline every 6 months).45 However, the clinical significance of a 0.05-mm increase of cartilage thickness in this study remains unclear in terms of reducing risk for knee replacement, delaying time towards knee replacement, or both.46 No significant change in total WOMAC scores in this study may be attributed to using intra-articular saline injections as a control since the IA saline injection may act as an active placebo,47 masking symptomatic benefits. In addition, a large number of patients with low baseline pain and/or high baseline cartilage thickness may result in a potential floor effect on symptoms as 32% of this study had <40/100 points on WOMAC pain score at baseline and 50% had medial minimum joint space width (mJSW) >4.0 mm on baseline X-rays. Therefore, analysis of a more selective subgroup, featuring baseline characteristics associated with rapid structural and symptomatic OA progression should be investigated. In a 2019 ACR conference abstract, it was reported that in a subgroup at risk (n=161) of structural and symptomatic progression with a baseline medial or lateral mJSW between 1.5 and 3.5 mm and WOMAC pain score of 4090 out of 100, WOMAC pain was significantly improved on 3 year follow-up [8.8 (22.4, 4.9)] in the group administered with the 100 g Sprifermin (n=34) compared with the placebo (n=33)48 suggesting that, in this subgroup, the drug effect reaches the absolute minimal clinically important improvement for the WOMAC pain subscore which ranges 69.49

In a recent 2020 paper using a post-hoc analysis of the same data from the FORWARD study, thinning/thickening scores and ordered values of femorotibial cartilage thickness change on MRI over 24 months were analyzed by applying location-independent (ie not region-specific) analysis methodology in the knee joint.50 With administration of 100g Sprifermin every 6 months cartilage thickening is more than double [856m (717 to 996) vs 356m (313 to 398)] and cartilage thinning almost reduced to [432m (521 to 343) vs 335m (381 to 288)] that in healthy reference subjects from the Osteoarthritis Initiative dataset (n=82). The authors concluded that the finding supported the evidence of substantial structure-protective action of Sprifermin. However, as this is a post-hoc analysis, further study will be required to confirm its structure-modifying effect.

At a molecular level, the regulation of Wnt signalling determines osteoblast and chondrocyte lineage specification and their homeostasis.51 Increased Wnt signaling predisposes MSCs to an osteogenic lineage fate and induces generation of metalloproteinases which can cause cartilage degradation in OA.52 Increased expression and activation of the Wnt pathway in articular cartilage chondrocytes in OA similarly promotes cartilage degradation, while elevated Wnt signalling in subchondral bone enhances bone formation and sclerosis.5355 Therefore, pharmacological modulation of Wnt signaling might have potential benefits in repairing osteochondral dysregulation detected in OA disease process. Moreover, increased Wnt signaling in the synovium may potently lead to the OA progression via increased production of MMPs as well as activation of osteoclast differentiation and enhanced subchondral bone turnover.56,57

Lorecivivint (SM04690) is a small-molecule CLK/DYRK1A inhibitor that blocks Wnt signalling at the transcriptional level.58 It showed induction of chondrogenesis and reduction in cartilage degradation in preclinical studies.5860 In a 52-week, multicenter, phase-2 trial (n=455) (NCT02536833), the primary end point, a significant improvement in the WOMAC pain score compared with placebo at week 13, was not met, compared with IA placebo saline injection, However, at 52-week follow-up, intra-articular administration of 0.07 mg demonstrated a significant benefit in pain and functional scores [between-group difference versus placebo, 8.73, 95% CI (17.44, 0.03) and 10.26, 95% CI (19.82, 0.69)], as well as improvement in mJSW on X-rays [between-group difference versus placebo, +0.39 mm, 95% CI (0.06, 0.72)] in patients with unilateral knee OA. Serious adverse events were reported in 17 (3.7%) patients.61 The most common SAEs included infections and cardiac disorders and were deemed unrelated to the study drug by the investigators.62

Another phase-2 trial evaluated in 700 patients for 24 weeks was completed (NCT03122860) where the 0.07 mg lorecivivint treatment group demonstrated more favorable reductions in both WOMAC indices as compared with placebo.63 Recently, the investigators reported the safety data after the combined analysis of the two trials, which included 848 Lorecivivint-treated and 360 control subjects in total. The incidence of adverse effects or serious adverse effects was similar in treatment (41.3% and 2.4%) and control groups (38.3% and 1.1%), respectively. The most commonly reported AE in both groups was arthralgia (7.6% vs 7.2%).64 Two small phase-2 (NCT03727022, NCT03706521) and three phase-3 (NCT03928184, NCT04385303, NCT04520607) trials are still active.

Transforming growth factor- (TGF-) induces extracellular matrix protein synthesis and modulates cartilage development. A variety of TGF- signalling pathways are crucial for early cartilage growth, maintaining cartilage homeostasis in later life and may also possess anti-inflammatory and immunosuppressive properties.65 Impaired TGF- function in cartilage might be related to an increased susceptibility to OA.66 However, the biological effect of TGF- is under complex control, and may switch from being protective in normal joints to detrimental in OA as a result of changes in the predominant cell-surface receptors and intra-cellular signalling pathways in various joint tissues (cartilage, bone, synovium).67 In addition, osteocyte TGF- signaling could regulate the osteogenic and osteoclastic activity of mesenchymal stem cells and may be associated with the remodeling of subchondral bone in advanced OA.68

TissueGene-C (TG-C) uses a cell-mediated cytokine gene therapy approach and includes non-irradiated allogeneic human chondrocytes and irradiated allogeneic human GP2-293 cells in a ratio of 3:1, retrovirally transduced to promote TGF-beta1 transcription (hChonJb#7 cells).6971 A recent study reported as a possible mechanism of action that TG-C induced an M2 macrophage-dominant pro-anabolic micro-environment in a rat model, thereby providing a beneficial effect on cartilage regeneration.72 At one-year follow-up after a single IA administration, there were significant improvements in pain, sports activities and quality of life but structure-modifying effects on the cartilage were insignificant (n=156).73 In a phase-2 trial (NCT01221441) including 57 patients in the treatment group and 29 patients in the placebo group, the TG-C administration caused less progression (47.9% vs 34.6%; adjusted RR 0.7, 95% CI 0.51.1) of cartilage damage than placebo over 12-months.69 In a phase-3 trial (NCT02072070) which included 163 patients, symptomatic benefit was detected.74

The two pivotal phase-3 trials (NCT03203330, NCT03291470) had been on hold in April 2019 while the regulators were investigating chemistry, manufacturing, and control issues related with the potential mislabeling of ingredients.75 This clinical hold was lifted in April 2020, and trial enrollments have been reinitiated later in 2020.76 Recently, analysis of the safety data from an observational long-term safety follow-up trial showed that there is no evidence to suggest that injection of TG-C was associated with increased risk of cancer nor generated any long-term safety concerns over an average 10 years.71

Senescence is characterized mainly by altered responses to cellular stress and proliferation arrest of cells.77 Senescent cells (SnCs) are a newly implicated factor in the OA pathogenic process78 by promoting pathological age-related deterioration via the production of proinflammatory cytokines, chemokines, extracellular proteases, and growth factors (termed the senescence-associated secretory phenotype (SASP))79 and altering the function of neighbouring cells (termed secondary or paracrine senescence).80 Therefore, senotherapeutics which are directed at SnCs are an emerging therapy for treating diseases related to ageing. Senotherapeutics can be classified into of 3 types: 1) senolytics which kill and destroy SnCs selectively; 2) senomorphics which modulate or even reverse the phenotype of SnCs to those of young cells by blocking SASP; 3) senoinflammation, the immune system-mediated clearance of SnCs.81 Several senolytic pharmaceutical drugs such as Fisetin and UBX0101 are emerging.

Fisetin is a polyphenol extracted from fruits and vegetables and shows potential senolytic and anti-inflammatory activities.82 Fisetin inhibited IL-1-induced MMP13 and ADAMTS5 expression in human OA chondrocytes in vitro, and reduced cartilage damage along with subchondral bone thickening and synovitis in a mouse OA model induced by destabilization of the medial meniscus (DMM).83 Two phase-2 clinical trials (NCT 04210986, NCT04815902) are under investigation in patients with knee OA and estimated to be completed in 2022 and 2025, respectively.

UBX0101 is a small molecule inhibitor of the MDM2/p53 protein interaction, which possesses a potent senolytic candidate. In a preclinical study, UBX0101 improved chondrogenesis in human OA tissue in vitro, and in an anterior cruciate ligament transection (ACLT) OA model in mice UBX0101 attenuated SnCs by stimulating apoptosis, and reduced cartilage damage and joint pain.84 The amount SnCs in human OA synovial tissues positively correlated with knee pain, disease severity and synovitis severity.85 A phase-1 study (n=48) revealed that a single intra-articular injection of UBX0101 at different doses up to 4 mg had a favorable safety profile and dose-dependent, clinically meaningful improvements in pain on Numeric Rating Scale (010) [3.95 (95% CI, 4.74, 3.16)] and WOMAC function [1.05 (95% CI, 1.36,-0.74)] compared with placebo injection. Recently, UNITY Biotechnology announced 12-week data from UBX0101 Phase-2 Clinical Study (NCT04129944) which did not detect a significant change in pain and function in 183 patients with painful knee OA.86 A follow-up observational study of the previous trial (NCT04349956) was terminated in November 2020 due to failure to meet the trial outcomes.

Subchondral change in OA involves an uncoupled remodelling process, which is characterized by both increased osteoblast activation and bone formation but simultaneously macrophage infiltration and osteoclast formation.87 Activation of osteoclasts can result in pain genesis through developing acidic conditions at the osteochondral junction, thereby activating acid-sensing receptors of sensory neurons.88,89 Subchondral bone also undergoes remarkable alterations in both composition and structural organization, leading to adverse effects on the overlying articular cartilage.90 Therefore, targeting the pathways that modify subchondral bone turnover is an attractive option for DMOAD research.89 The pharmaceutical drugs in phase 2 and 3 stages of development for bone-driven endotype are summarized in Table 2.

Table 2 The Registered Phase 2/3 Clinical Trials on Compounds with Potential Disease-Modifying Effects on Subchondral Bone

Cathepsin K is a cysteine protease which induces bone resorption and cartilage damage through the breakdown of key bone matrix proteins.91,92 Cathepsin K knock out mice had attenuated cartilage damage in OA induced by DMM, and inhibition of Cathepsin K in rabbits by daily oral dosing with L-006235 reduced cartilage damage and subchondral bone remodelling in an ACLT model of OA.93,94

MIV-711 is a selective cathepsin K inhibitor, and in a 6-month phase 2 clinical trial (NCT02705625) (n=244), significantly reduced femoral bone disease progression and reduced cartilage loss, although there was no improvement in pain outcome.95 Infrequent musculoskeletal symptoms, infections and rashes were reported. A further 6-month open-level extension study showed the maintenance of structural benefit with symptomatic improvement (n=50).96 However, as most of the participants in the extension sub-study were selected because their symptoms did not worsen, a treatment benefit may be due to positive selection bias.95

Recombinant human PTH, teriparatide, is a 134 amino-acid fragment acquired from human PTH). Its anabolic action on bone production is used for osteoporosis management. In OA, it exhibits the ability to maintain articular cartilage health,97 stimulate the synthesis of extracellular matrix and induce chondrocyte proliferation in pre-clinical injury-induced OA models.98 PTH can increase subchondral bone mineral density, which could exert a negative effect on OA progression. In this sense, PTH could be an excellent drug in OA patients with osteoporosis and low subchondral sclerosis.99 Additionally, intermittent parathyroid hormone treatment attenuates OA pain in a DMM model, in association with inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration.100 A phase-2 study is currently ongoing to evaluate the efficacy of PTH in knee OA participants (NCT03072147).

TPX-100 is a novel 23-amino-acid peptide derived from MEPE, a member of the Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) protein family, involved in subchondral bone remodeling.101 TPX-100 provided symptomatic improvements in patellofemoral OA knees administered with 4 weekly 200 mg injections compared with placebo injection in the contralateral knees (n=93), but only 14% of knees showed changes in cartilage thickness/volume measured on MRI over 12 months with no evidence of structural modification. No drug-related SAEs occurred in this study.102 Another 2020 OARSI conference abstract reported a statistically significant decrease in pathologic bone shape change in the femur at both 6 and 12 months using 3D femoral bone shape change.103

Antiresorptive drugs have shown reduction in bone remodeling and improvement in trabecular microarchitecture and bone mineralization. In clinical trials investigating the structure-modifying effects of bisphosphonates (alendronate, risedronate, zoledronic acid), the results are inconsistent across the studies and their outcomes presented a great heterogeneity.17,104 In a recent systematic review including preclinical studies (n=26) over the past two decades (20002020), these drugs showed better chondroprotective effects at high doses with a dose-dependent manner as well as depending on the timing of treatment initiation in relation to OA stage (time-dependency).105 Therefore, these agents may still be of potential benefits in certain OA endotypes with high rates of subchondral bone turnover. This phenotype-dependency has been demonstrated in pre-clinical research, where bisphosphonates are differentially effective in reducing pain and not only bone but also cartilage pathology in OA models with high versus low bone turnover.106109 Recently, clodronate (n=74)110 and neridronate (n=64)111 have been successfully used for the treatment of knee and hand OA, with an interesting efficacy on BMLs, although the sample sizes are small. An individual patient data meta-analysis for examining their efficacy in specific knee OA subtypes is still ongoing.112

In a multicentre, randomised controlled trial involving knee OA patients with significant knee pain and MRI-detected BMLs (n = 223), 2 annual infusions with 5 mg of zoledronic acid (the most potent of all bisphosphonates) did not significantly reduce cartilage volume loss, knee pain or BML size although the study was designed for detecting effects on the bone-driven subgroup with BMLs which may likely have potential benefits from this therapy.113 It was noted that more knee replacement procedures were performed in the zoledronic acid group compared with the placebo group (9% vs 2%) in contrast with other population-based studies.114,115

Another study involving Osteoarthritis Initiative (OAI) female participants (n=346) showed that bisphosphonate therapy may be protective of radiographic knee OA progression in nonoverweight patients with earlystage OA.116 Currently, a Phase 3 study (NCT04303026) to examine its effects in hip OA is ongoing. A phase 2 study examining the effects of another anti-resorptive, denosumab, in hand OA is expected to finish in 2021 (NCT02771860).

Vitamin D has a direct impact on cartilage by inducing proteoglycan synthesis in mature chondrocytes,117 and enhances chondrocyte viability and reduces their inflammatory cytokine synthesis through activating AMPK/mTOR and autophagy.118 Active vitamin D administration reduced cartilage degradation and inflammation in models of OA in mice and rats induced by meniscal injury/meniscectomy and ACLT.118120 Out of two recently published systematic reviews, one review showed the association of vitamin D deficiency with knee OA in patients but inconsistent evidence for its role in the prevention of incidence and progression of radiographic OA,121 while the other argued that inconsistent results may be attributed to factors such as severity of knee OA, baseline level of serum vitamin D, duration of treatment, and vitamin D dosages.122 There is a need for multicentric and well-conducted randomized studies using larger samples to determine its efficacy. A small Phase 4 clinical trial is currently active (NCT04739592).

Synovial inflammation (synovitis) is an important contributing factor to the OA pathogenesis through increased local production of pro-inflammatory cytokines, chemokines, and mediators of joint tissue damage123,124 which may be amenable to a range of anti-inflammatory drugs commonly used in inflammatory rheumatic diseases. The pharmaceutical drugs in phase 2 and 3 stages of development for inflammation-driven endotype are summarized in Table 3.

Diacerein is a purified anthraquinone derivative. It involves an inhibitory action on IL-1 and its signalling pathway, possesses an anticatabolic effect on OA tissues and reduces generation of metalloproteases.125 In animal models of OA (sheep meniscectomy, canine ACLT, rabbit ACLT and partial meniscectomy) diacerein has generally shown limited long-term effect on cartilage composition or pathology, but some evidence of reducing synovitis.126129 In a 2014 Cochrane review, the authors concluded that diacerein demonstrated only a minimal symptomatic improvement in patients with unclear benefits in JSW on X-rays, compared with placebo. Diarrhoea was the main adverse event with an absolute difference of 26%.130

The EMAs Pharmacovigilance Risk Assessment Committee suspended diacerein across Europe in 2013 due to its harms overweighing benefits,131 and then re-evaluated the drug in 2014, suggesting that it remain available with restrictions to limit risks of severe diarrhoea and hepatotoxicity.132 In 2016, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) reported that diacerein had efficacy similar to that of NSAIDs with slower onset of action, suggesting that it might have some benefits for patients with contraindication to NSAID.133

Recently, results of a phase-3 clinical trial (NCT02688400) were reported where the authors explored the comparative efficacy and safety of diacerein vs celecoxib in patients with moderate and severe knee OA using a non-inferiority trial design [(6-months of diacerein 50 mg once daily for 1 month and twice daily thereafter (n = 187), or celecoxib 200 mg once daily (n = 193)]. Diacerein was non-inferior to celecoxib in reducing pain, stiffness, or functional limitations. The diacerein group had a higher number of emergent AEs (26.3%) compared with the celecoxib group (17.4%), mainly due to higher diarrhoea events (10.2% vs 3.7%). One patient in the diacerein group had three SAEs (abdominal pain, elevated transaminase and gamma-glutamyl transferase, collectively suggestive of hepatitis) which resolved spontaneously following drug withdrawal.134

In in vitro and in vivo preclinical studies, interleukin-1 (IL-1), tumor necrosis factor- (TNF-), IL-6, IL-15, IL-17, and IL-18 exhibit pro-inflammatory actions, leading to the initiation and progression of cartilage damage and joint inflammation. So far, IL-1 and TNF- have been the most extensively studied cytokines in pre-clinical research.135,136 Despite this favorable evidence in animal OA models, most clinical trials investigating the disease-modifying effects demonstrated by inhibitors of IL-1 and TNF- in OA patients failed to meet the primary and secondary endpoints such as in cases of Gevokizumab (XOMA-052),137 AMG108,138 Lutikizumab (ABT-981),139,140 anakinra,141 adalimumab142144 and etanercept.145 In a meta-analysis evaluating the efficacy of disease-modifying anti-rheumatic drugs in OA, neither IL1-inhibitors nor TNF-inhibitors possess symptomatic benefits irrespective of the joint site affected or the inflammatory phenotype (erosive or non-erosive OA).146

These failed trial results may suggest the implication of a more complicated interaction among various cytokines in the OA pathogenic process. One of the reasons for failure may be that the clinical trials were designed to detect an effect on symptoms rather than on joint structure, which is conversely the main outcome evaluated in preclinical studies, or that they are underpowered or have not followed participants for long enough to find meaningful structural effects such as proposed in the recent CANTOS trial.147 In a recent exploratory analysis of the CANTOS trial involving patients with elevated high-sensitivity C-reactive protein (hs-CRP) levels 2 mg/L and a history of myocardial infarction (n=10061), IL-1 inhibition using canakinumab may render a substantial reduction of THR/TKR rates as well as OA-related symptoms on an averaged 3.7 years follow-up.147 Although the study had some positives such as a large sample size and long-term follow-up, it was not primarily designed to investigate the DMOAD efficacy of canakinumab and many relevant OA outcomes were missing, necessitating further confirmatory studies.

IL-6 can increase the risk of radiographic OA and associated with knee cartilage damage,148 suggesting the potential role of low-level inflammation in the pathogenesis of OA. IL-6R blockage with tocilizumab contributes to cartilage preservation and increases bone volume in a mouse model of ischemic osteonecrosis,149 and reduced cartilage lesions, osteophyte formation and synovitis in DMM-induced OA in mice.150 However, male IL-6 knock out mice have increased cartilage damage and age-related OA.151 In local joint tissues, IL-6 classic signaling produces structure-protective effects, while trans-signaling leads to catabolic effects.152 This finding might suggest that selective inhibition of IL-6 trans-signaling could be a superior treatment strategy as this may inhibit deleterious IL-6 effects in OA, while maintaining protective IL-6 signaling via the classic pathway.153 Recently, in a phase-3 trial evaluating the efficacy of tocilizumab in hand OA for 12 weeks (n=104), it revealed no more effectiveness than placebo for pain relief (7.9 vs 9.9 on VAS score in the tocilizumab and placebo groups).154

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. It also possesses chondroprotective effects, via reduced production of matrix metalloproteases155 as well as inhibition of chondrocyte apoptosis.156 Therefore, IL-10 could have potential benefits in OA management, both for pain improvement and suppression of the cartilage-damaging processes. Currently, there is a phase-2 clinical trial evaluating the safety and efficacy of a single injection of XT-150 (a plasmid DNA with a variant of human IL-10 transgene) in patients with knee OA (NCT04124042), and it is estimated to be complete in 2022.

In this section, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers (Figure 2).

Figure 2 Reasons for DMOAD trial failures.

The drug will be required to demonstrate symptomatic benefits (pain and/or function) coupled with structural modifications to meet regulatory requirements as a disease-modifying agent.19,20 To date, no agent has been approved by the regulatory agencies.17 Some argue that the improvements in structural change (in the absence of any meaningful symptomatic benefits) should be a meaningful target for approval, in and of itself. However, this is unlikely to meet consumers needs as their primary reason for clinical presentation relates to symptomatic complaints.30

On the other hand, OA is a slowly progressive disease and only 14% of patients with incident OA have measurable disease progression over a 1-year period (Figure 2).157 Therefore, structure-modifying effects using targeted therapy would be optimal to delay or even avoid disease worsening and joint replacement. In OA, symptom-structure discordance is often described.158 Analysis of data from the Osteoarthritis Initiative revealed that changes in bone structure over 2 years do not translate into pain worsening until 4 years,159 suggesting that a structure-modifying drug may need longer follow-up to detect symptomatic benefit. In addition, a variety of disease outcomes using different OA subtypes (genotypes, phenotypes and endotypes) are needed to demonstrate the ability of a structure-modifying drug to directly predict for symptomatic benefits to overcome the regulatory hurdles.18

In addition, FDAs formal recognition of OA as a serious disease paves the way for using surrogate outcome measures for regulatory approval of DMOADs under accelerated approval regulations. However, two challenges need to be addressed: 1) selection/qualification of appropriate surrogate outcome measures, and 2) appropriate designs for post-marketing confirmatory studies. To overcome the first challenge, the Foundation for NIH (FNIH) OA Biomarkers Consortium initiative was established.160 For addressing the second challenge, Kraus et al proposed two major study design scenarios: 1) prospective trial continuation which continue all patients on initial drug allocation into the post-marketing approval trial until a failure threshold is achieved; and 2) separate post-marketing approval study which use different study population administered with active treatment only.161

The imaging standard in OA clinical trials has been radiographically measured mJSW which is notoriously unresponsive to change as well as possessing several other drawbacks such as issues with alignment, positioning and assuming JSW as the composite contribution of changes in other structures in this heterogeneous OA with multiple-tissue involvement.162,163 Therefore, utilization of this insensitive-to-change measure may limit our opportunity to detect any modification in what oftentimes is a slow-moving disease.

In 2015 OARSI published recommendations related to the applications of knee imaging in knee OA trials to set standards and improve quality assurance.164 Although a range of different MRI approaches have been developed to evaluate changes in overall joint structure,165167 further validation studies and evaluation of their clinimetrics are required to gain acceptance by regulatory authorities as a suitable surrogate endpoint which is the focus of the FNIH OA Biomarkers Consortium.160

In addition, the emergence of approved surrogate outcomes would allow pharmaceutical companies to examine the efficacy of the DMOADs in a shorter duration of clinical trials and reduce drug development costs. In this way, there is a possibility of instituting accelerated approval based on surrogate imaging endpoints and post-marketing approval studies to prove the longitudinal benefit-to-harm profile and the durability of the potential new therapies.161

In the study design for post-marketing approval which uses observational outcomes such as time-to-event of joint replacement surgery, considerable barriers exist in terms of need for large sample sizes due to low annual incidence rates (1.611.9%),14 long study follow-ups (>5 years at least),46 and the impact of non-disease and other subjective factors on the outcome (ie, comorbidities and/or age of the patient, costs, insurance cover, etc.).168,169 There is a lack of universal consensus criteria for guiding patient recommendations regarding joint replacement surgery, leading to differences even among treatment centres within the same region. These issues need to be adequately addressed by study design.161 There is a need for developing a criteria set to define appropriateness for total knee replacement or a virtual total knee replacement.170

Instead of utilizing the systemic route of administration which may produce undesirable systemic toxicity and off-target effects, many of the agents in the development pipeline are focused on an intra-articular route for drug delivery. This can also potentially enhance the local bioavailability, thereby maximizing therapeutic effects locally in the joint with a higher safety profile compared to systemic exposure.171 On the other hand, the marked placebo effect generated by local intraarticular administration is well-documented in the literature,172 making the assessment of symptom efficacy more challenging.30

Another issue related with the intra-articular therapy is that drugs have a short residence time within the joint.171,173 To overcome this barrier, a variety of drug delivery systems were proposed to prolong drug residence time while providing a stable concentration within the therapeutic window, leading to a reduction of side effects and better patient compliance.174 It remains unclear how long particular drugs have to remain in the joint for a meaningful symptomatic relief and/or structure-modification after an intra-articular administration. An ideal drug delivery system should comply with adequate disease modification, biocompatibility, and biodegradability while responding to its physiological environment.175

In the randomized clinical trials for IA drugs, saline is commonly used as the placebo in the control group. A recent meta-analysis examining the effects of IA saline in 50 clinical trials (n=4076) revealed significant improvement of pain severity on 0100 VAS up to 6 months [13.4 (21.7/5.1)] and WOMAC function sub-score [10.1 (12.2,-8.0)]. The pooled responder rate after saline injections using the OMERACT-OARSI criteria is 48% at 3 months and 56% at 6 months,47 challenging the concept of saline being a mere placebo.176 However, there is no evidence supporting hypotheses advocating the disease-modifying role of saline injection. Future scientifically robust studies which examined the effects of sham injections compared with saline injections are required to shed new light on this issue.

The IA therapies show a considerably larger therapeutic effect after the adjustment for the effects of IA saline, suggesting an inappropriate underestimating of the true effect of the active medication.177 Further research is required to determine the underlying mechanisms and the factors influencing the placebo response and ways to overcome it. In addition, the mechanisms of pain genesis in OA are poorly understood and thought to involve a complex interaction among local pathological processes in the OA joint and neuronal mechanisms and alterations of pain processing (ie central sensitization, especially in advanced OA).178 Further studies should focus on the effects of these interactions on the outcomes in the placebo-controlled clinical trials. It is also necessary to strictly report in each clinical trial what placebo has been used as well as the presence or absence of any additional blinded clinical evaluator, even more, if considering clinical trials with intra-articular therapies.

As OA is a heterogeneous disease with a combination of different endotypes in varying degree at different stages of the disease process, a one size fits all approach using a single therapeutic agent targeting a single target within a single endotype may be unlikely to succeed in the management of OA.179 Therefore, as in the oncology therapeutic area, combinations of drugs targeting different hallmarks of OA pathogenic process should be considered. Further research examining the potential synergistic action of combining anabolic therapies with those that downregulate catabolic factors will be required.

OA is well known for marked variations of disease expression,180 involves a variety of tissue pathologies as a whole joint disease16 and presents with different pathobiological manifestations,181 suggesting the potential value of personalised and precision medicine from the treatment perspective. Personalized medicine is used for treatment focusing on the patient based on their individual clinical characterization, considering the diversity of symptoms, severity, and genetic traits.182 In precision medicine, the molecular information maximizes the accuracy with which the patients are categorized and treated, typically applying large amounts of data for identification of patient subtypes which possess sharing specific relevant characteristics to predict diagnosis, progression, or treatment response, and to utilize appropriate therapeutic targets.183 The use of precision medicine in OA remains limited.

The implementation of private/ public initiatives, such as the Osteoarthritis Initiative, the FNIH biomarkers consortium, the European APPROACH ((Applied Public-Private Research enabling OsteoArthritis Clinical Headway)) project have contributed greatly to moving the field forward. Clinical phenotypes, endotypes, and molecular and imaging biomarkers are being identified, but the exact interplay among them and underlying mechanisms of each remain to be elucidated.24 While these biomarkers may have potential benefits in detecting those patients with the greatest risk for structural progression, their use still needs to be translated into more efficient clinical trial design and widespread clinical application.184

There remains an immense unmet need for effective and safe targeted interventions to inhibit both pain and disease progression. The complex overlapping interplay among the pathobiological OA processes and heterogeneity of clinical presentations of patients with OA, call for a universally accepted classification of phenotypes and endotypes for developing targeted disease-modifying therapy and providing the appropriate treatment in clinical setting. Although challenges exist towards the eventual management of OA by applying the concepts of personalized and precision medicine, the lessons learned through failed clinical trials, the ongoing developments of more advanced imaging and sophisticated biomarkers tools and effective drug delivery systems are leading to substantial progress in our field.

WMO is supported by the Presidential Scholarship of Myanmar for his PhD course. DJH is supported by the NHMRC Investigator Grant. VD is supported by a University of Sydney Postgraduate Award scholarship.

DJH provides consulting advice on scientific advisory boards for Pfizer, Lilly, TLCBio, Novartis, Tissuegene, Biobone. CL has provided consulting advice for Merck Serono and Galapagos Pharmaceuticals, and receives research funding from numerous pharmaceutical companies (Fidia Farmaceutici, Inter-K Peptide Therapeutics Ltd, Taisho Pharmaceutical Co. Ltd, Concentric Analgesics Inc, Cynata Therapeutics, CEVA Animal Health, Regeneus) through specific services/testing contract research agreements between and managed by The University of Sydney or the NSLHD. The authors report no other conflicts of interest in this work.

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Disease-modifying therapies for osteoarthritis | DDDT - Dove Medical Press

Telemedicine has shown immense promise during COVID-19 in terms of access to consultation at home.

By Vaibhav Tewari,

The Government of India launched the Digital India campaign in 2015 in a bid to transform the country into a knowledge economy, with on-the-go access to information, governance and services. Since then, we have become the second-fastest adopter of digital services. With about half a billion internet users, the potential to unlock an additional economic value of $1 trillion dollars through inclusive growth is immense. This is also true of the healthcare sector wherein blending the digital approach can help tackle the issues of access, affordability and quality. Such a health system also fits in with the idea of an all-in-all digital nation supported by missions like the Ayushman Bharat and Make in India.

On 15th August 2020, Honble Prime Minister Shri Narendra Modi announced the launch of the National Digital Health Mission as a part of his Independence Day address. This unprecedented digital initiative is being seen as the first major step towards Universal Health Coverage in India. The move augurs well since healthcare record management in India is as inefficient and disconnected as the sector itself. There are also vast technological and procedural variations across private and public sector facilities.

Currently, a standard government hospital or local healthcare facility is unable to uniformly document all records for services. Although such facilities exist to certain extent in urban area hospitals, there is a great lack of uniform standards of record keeping. This creates issues such as requirement of repeated diagnostic tests and consultations, delayed treatments, concealment or ignorance of medical history etc. All these can often lead to wrong diagnosis and treatment as well as increased costs of treatment. Even in hospitals where digital records are maintained, there is no provision of electronic transfer of patient records from one service provider to another. This lack of access leads to either the patient carrying the medical records in paper format or not having access to them at all. Through the National Digital Health Mission (NDHM), the government is endeavouring to leverage the existing digital infrastructure such as the frameworks related to Aadhar, UPI and the pan India coverage of internet-enabled smartphones to create a cohesive digital system. This is expected to be rolled out soon. However, there are also other components that must be integrated into this ecosystem to make it all-inclusive.

Technology for better access

Digital health solutions are powered by technologies such as artificial intelligence (AI) and machine learning (ML). Adopting these with prevention, diagnosis and cure can help India run closer to the goal of digital health for all. This is because health-tech is an integral component of the Fourth Industrial Revolution, and of a society where lifespans are increasing, as is the population of the elderly. Unlike space tech where India already holds a prime place, health-tech is still at a nascent stage. For actionable impact, a digital health ecosystem must comprise digital technologies and access to the same as well. Various healthcare startups are already making a headway in this direction by providing patient-centric care at the comfort of their homes with the help of technology. It is now not only possible to monitor a persons condition at home but also provide treatment therein. This augurs well for the rising elderly population since they can stay away from hospital-acquired infections. Digital technology is also enabling remote monitoring in extreme situations like the current pandemic.

Telemedicine

This is one of the original components of digital health and Indias National Health Policy.Although there is adoption, the need of the hour is to nurture this component better. Telemedicine has shown immense promise during COVID-19 in terms of access to consultation at home. What is needed in this domain is proper regulation and bringing it under policy deliberation. This will enable access to specialized medical consultation services throughout India and solve the issue of doctor shortage as well as reduce the burden on tertiary-care hospitals in remote areas. There is also a need for more investment in telemedicine especially from the private sector but a clear policy and legislation can resolve this.

Digital therapeutics and diagnostics

These have disrupted the format of health products and services. Digital therapeutics and diagnostics include components such as

Deep tech in human biology (including an understanding of how diseases occur and progress)

Genetic engineering and molecular medicine

ICT services such as cloud computing and 3D printing which enable seamless continuum of care and apps that help in tracking health parameters in real time

Predictive Analytics which make healthcare decision-making more robust and allow for doctor-patient interactions to become more empathic and care-based as opposed to hurried and transactional.

There is thus a need for a concerted action that operates at different levels of healthcare to resolve problems. A digital decision support system in healthcare will reduce the possibility of errors and improve decision making. A national health policy that puts in place definite guidelines and regulatory framework covering different aspects of digital health will lead the way for better public-private partnerships, indigenous start-ups, and path breaking ideas and therefore, attract more investment in healthcare and health-tech. All this will ensure that Indias dream of a digital health ecosystem appears not as an uphill task but a dream that all sectors are working in a consolidated manner to realize.

(The author is Co-Founder and COO, Portea Medical. Views expressed are personal and do not reflect the official position or policy of the Financial Express Online.)

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Indias journey towards a digital healthcare ecosystem: taking the leap of faith - The Financial Express

Newswise The most practical solution for drug delivery to the eyeball is topical, i.e. eye drops. However, a naturally occurring substance in tears actually can interact with the drug delivery system (DDS), hindering absorption of the drug and preventing it from getting into the cells it needs to target. Mucin, or MUC, is usually there to protect your eye, but when MUC is exposed to a molecule such as a lipoplex, a common form of DDS already used in ophthalmological drugs, it will bind to it and reduce absorption into the targeted tissue. So, scientists asked, is there some way to sneak the lipoplex past the MUC?

Through the use of an engineered, artificial protein corona (PC), researchers were able to dress the lipoplexes up as something that MUC would ignore. They found that a protein called Fibronectin (FBN), and a tripeptide of the amino acids Valine, Glycine, and Aspartate (VGA), were both effective at concealing the lipoplex, avoiding being coated in MUC, and binding to the corneal epithelial cells for better absorption of the DDS.

Because MUC binds to the lipoplex surface, it alters both their size and the positive or negative surface charge, explains Carlo Astarita, Ph.D. candidate studying at the Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, College of Science and Technology, Temple University. This reduces absorption of the medicine by the primary corneal epithelial cells. So, how do we prevent MUC from interfering? We give the liposome a new coating that is recognized by receptors expressed on the ocular surface, circumventing the problem, and delivering the molecule more directly to the targeted tissue.

The researchers are part of a multi-institutional, international collaboration between the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University, the University of Pennsylvanias Scheie Eye Institute, and co-authors at several universities in Italy.

As a dry eye specialist I see a myriad of patients with various surface disease issues, says Giacomina Massaro, M.D., of the Scheie Eye Institute, Department of Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania, and in order to achieve an effective treatment, drugs need to reach the target tissue (i.e. the corneal epithelial cells). In many situations the drugs are blocked by a complex mix of mucous, lipids, proteins and fluids which bathe the ocular surface. It is imperative that drugs have the ability to break through this barrier.

This study is a quintessential example of our researchers using precision medicine to innovate, says Antonio Giordano, M.D., Ph.D., Founder and Director of the Sbarro Health Research Organization (SHRO) and the Sbarro Institute at Temple University, as well as a joint research program with the University of Siena, Italy. We identify a problem which inhibits the efficacy of certain types of treatments, and then we ask, what does the body provide in this case as its own solution? In this case, the answer is right there on the surface of the cells: we make the medicine so that it binds with the targeted tissue. In this way, precision medicine opens the door to increased effectiveness to treat a wide range of ocular conditions and disease.

About the Sbarro Health Research Organization (SHRO)

The Sbarro Health Research Organization is a non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and related chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism (www.shro.org)

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The Medicine in Eye Drops Needs a Disguise to Sneak Past Your Tears - Newswise

New studies of the molecular action of tarantula venom on sodium channels may suggest ideas for the structural design of better drugs to treat chronic pain. The venom plunges a biochemical stinger into a voltage sensor on the channel that traps it in its resting position, keeping the channel from activating and from producing electrical signals. Credit: Alice C. Gray

Venom immobilizes prey by interfering with sodium channels that generate electrical signals in the animals nerve cells.

Oversized, hairy tarantulas may be unsightly and venomous, but surprisingly their hunter toxin may hold answers to better control of chronic pain.

A bird-catching Chinese tarantula bite contains a stinger-like poison that plunges into a molecular target in the electrical signaling system of their preys nerve cells.

A new high-resolution cryo-electron microscopy study shows how the stinger quickly locks the voltage sensors on sodium channels, the tiny pores on cell membranes that create electrical currents and generate signals to operate nerves and muscles. Trapped in their resting position, the voltage sensors are unable to activate.

The findings are published in Molecular Cell, a journal of Cell Press.

The action of the toxin has to be immediate because the tarantula has to immobilize its prey before it takes off, said William Catterall, professor of pharmacology at the University of Washington School of Medicine. He was the senior researcher, along with pharmacology professor and Howard Hughes Medical Institute investigator, Ning Zheng, on the study of the molecular damage inflicted by tarantula venom.

This graphic abstract for a Nov. 23 Molecular Cell paper shows how a tarantula nerve toxin acts on a chimera of a voltage-gated sodium channel. The chimeric sodium channel contains part of a human channel crucial for pain transmission that has been imported onto a model ancestral sodium channel from a bacterium. The tarantula toxin has a lysine stinger that traps the voltage sensor on the sodium channel and keeps it from activating. The toxin thus immobilizes the tarantulas prey. Its action on sodium channels also holds ideas for designs for better pain-control drugs. Credit: Catterall and Zheng labs/UW Medicine

While some might dismiss those tarantulas as ugly, tough and mean, medical scientists are actually interested in their venoms ability to trap the resting state of the voltage sensor on voltage-gated sodium channels and shut them down. Such studies of toxins from these big, nasty dudes, as Catterall describes them, could point to new approaches to structurally designing drugs that might treat chronic pain by blocking sensory nerve signals.

Catterall explained that chronic pain is a difficult-to-treat disorder. Efforts to seek relief can sometimes be a gateway to opiate overdose, addiction, prolonged withdrawal, and even death. The development of safer, more effective, non-addictive drugs for pain management is a vital need.

However, because it has been hard to capture the functional form of the tarantula toxin-ion channel chemical complex, reconstructing the toxins blocking method in a small molecule has so far eluded molecular biologists and pharmacologists seeking new ideas for better pain drug designs.

Researchers overcame this obstacle by engineering a chimeric model sodium channel. Like mythical centaurs, chimeras are composed of parts of two or more species. The researchers took the toxin-binding region from a specific type of human sodium channel that is crucial for pain transmission and imported it into their model ancestral sodium channel from a bacterium. They were then able to obtain a clear molecular view of configuration of the potent toxin from tarantula venom as it binds tightly to its receptor site on the sodium channel.

This achievement revealed the structural basis for voltage sensor trapping of the resting state of the sodium channel by this toxin.

Remarkably, the toxin plunges a stinger lysine residue into a cluster of negative charges in the voltage sensor to lock it in place and prevent its function, Catterall said. Related toxins from a wide range of spiders and other arthropod species use this molecular mechanism to immobilize and kill their prey.

Catterall explained the medical research importance of this discovery. The human sodium channel placed into the chimeric model is called the Nav1.7 channel. It plays an essential role, he noted, in transmission of pain information from the peripheral nervous system to the spinal cord and brain and is therefore a prime target for pain therapeutics.

Our structure of this potent tarantula toxin trapping the voltage sensor of Nav1.7 in the resting state, Catterall noted, provides a molecular template for future structure-based drug design of next-generation pain therapeutics that would block function of Nav1.7 sodium channels.

Reference: Structural Basis for High-Affinity Trapping of the NaV1.7 Channel in Its Resting State by Tarantula Toxin by Goragot Wisedchaisri, Lige Tonggu, Tamer M. Gamal El-Din, Eedann McCord, Ning Zheng and William A. Catterall, 23 November 2020, Molecular Cell.DOI: 10.1016/j.molcel.2020.10.039

The lead authors on the study were Goragot George Wisedchaisri and Lige Tonggu, both of the UW School of Medicine Department of Pharmacology. Tamer M. Gamal El-Din, also of Pharmacology, and Eedann McCord, now with the Department of Physiology and Biophysics at the UW medical school, contributed to the research.

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Tarantula Toxin Attacks With Molecular Stinger May Hold Answers to Better Control of Chronic Pain - SciTechDaily

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Combination therapies appear to prevent emergence of drug resistance

MD/PhD student Rita Chen (left) and Brett Case, PhD, a postdoctoral researcher, prepare to work with SARS-CoV-2, the virus that causes COVID-19, under strict biosafety conditions. Chen, Case and MD/PhD student Emma Winkler co-led a study with virologist and immunologist Michael S. Diamond, MD, PhD, at Washington University School of Medicine in St. Louis, to assess how well antibody-based drugs for COVID-19 perform against a range of virus variants.

COVID-19 therapies made from antibodies often are given to patients who are at high risk of severe illness and hospitalization. However, there have been nagging questions about whether such antibody therapies retain their effectiveness as worrisome new virus variants arise.

New research at Washington University School of Medicine in St. Louis suggests that many, but not all, therapies made from combinations of two antibodies are effective against a wide range of variants of the virus. Further, combination therapies appear to prevent the emergence of drug resistance.

The study, in mice and hamsters, tested all single and combination antibody-based therapies authorized for emergency use by the Food and Drug Administration (FDA), or that are being evaluated in late-stage clinical trials, against a panel of emerging international and U.S. variants of SARS-CoV-2, the virus that causes COVID-19.

The findings, published June 21 in the journal Nature, suggest that COVID-19 drugs made of two antibodies often retain potency as a therapy against variants even when in vitro studies experiments conducted in a dish indicate that one of the two antibodies has lost some or all ability to neutralize the variant.

We knew how these antibodies were behaving in vitro, but we dont give people drugs based solely on cell culture data, said senior authorMichael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. When we looked in animals, there were some surprises. Some of the combinations performed better than we thought they would, based on in vitro data. And there was no drug resistance to combinations whatsoever, across all of the different variants. Were going to have to continue to monitor the effectiveness of antibody therapy as more variants arise, but combination therapy is likely needed for treating infections with this virus as more variants emerge.

So-called monoclonal antibodies mimic those generated by the body to fight off the virus that causes COVID-19. Administration of antibody therapies bypasses the bodys slower and sometimes less effective process of making its own antibodies. At the time this study began, there were two dual-antibody combination therapies and a single antibody therapy authorized by the FDA for emergency use. The FDA withdrew authorization for the single antibody therapy, bamlanivimab, in April on the grounds that it was not effective against the variants circulating at that time. In May, the FDA authorized the single antibody sotrovimab as a treatment for COVID-19.

In all, the researchers evaluated antibodies corresponding to the FDA-authorized ones made by Eli Lilly and Co., Regeneron and Vir Biotechnology/GlaxoSmithKline, as well as the antibodies currently under development by AbbVie, Vir and AstraZeneca that are in clinical trials.

The researchers led by co-first authors Rita E. Chen, an MD/PhD student, Emma S. Winkler, an MD/PhD student, and Brett Case, PhD, a postdoctoral researcher tested the antibodies against a panel of virus variants containing key mutations in their spike genes. The SARS-CoV-2 virus uses spike protein to invade cells. All monoclonal antibody-based COVID-19 therapies work by interfering with the interaction between spike protein and cells.

The panel included mutations found in three of the four variants that have been designated variants of concern by the World Health Organization Alpha (first identified in the United Kingdom), Beta (South Africa) and Gamma (Brazil) as well as an emerging variant from India similar to the Delta variant of concern. They also tested variants from New York and California. The researchers used a mix of virus samples originally obtained from people with COVID-19 and laboratory strains genetically engineered to contain key mutations.

The researchers evaluated the antibodies in hamsters and two strains of mice. The researchers first gave the animals antibodies singly or in the same combinations in which they are given to treat patients a day before infecting them with one of the virus variants. The researchers monitored the animals weight for six days and then measured the amount of virus in their noses, lungs and other parts of the body.

Although some single antibodies showed reduced or no ability to neutralize virus variants in a dish, low doses of most of the antibody combinations protected against disease caused by many of the variants. The researchers sequenced viral samples from the animals and found no evidence of drug resistance in viruses from any of the animals that had been treated with combination therapies.

Dual therapy seemed to prevent the emergence of resistant viruses, said co-author Jacco Boon, PhD, an associate professor of medicine, of molecular microbiology and of pathology & immunology. Resistance arose with some of the monotherapies, but never with combination therapy.

Since antibody-based COVID-19 therapies primarily are used to treat people who already are infected, the researchers also evaluated how well the antibody combinations performed when given after infection with the Beta variant. The Beta variant was chosen because it has been shown to be most likely to escape neutralization in laboratory-based experiments and has the most resistance to COVID-19 vaccines. The antibody cocktails corresponding to those from AstraZeneca, Regeneron and Vir were all effective at reducing disease caused by the Gamma variant; the one from AbbVie only was partially protective, and the one from Lilly showed no efficacy at all.

Its going to be useful going forward to understand how these monoclonal antibodies are going to behave as variants continue to emerge, said Diamond, who also is a professor of molecular microbiology and of pathology & immunology. We need to think about and generate combinations of antibodies to preserve our ability to treat this disease. And well need to monitor for resistance although, in my opinion, the use of specific combinations will make this less of an issue.

Chen RE, Winkler ES, Case JB, Aziati ID, Bricker TL, Joshi A, Darling T, Ying B, Errico JM, Shrihari S, VanBlargan LA, Xie X, Gilchuk P, Zost SJ, Droit L, Liu Z, Stumpf S, Wang D, Handley SA, Stine WB, Shi P-Y, Davis-Gardner ME, Suthar MS, Knight MG, Andino R, Chiu CY, Ellebedy AH, Fremont DH, Whelan SPJ, Crowe JE, Purcell L, Corti D, Boon ACM, Diamond MS. In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains. Nature. June 21, 2021. DOI: 10.1038/s41586-021-03720-y

This study was supported by the National Institutes of Health (NIH), grant and contract numbers R01 AI157155, U01 AI151810, U01 AI141990, R01 AI118938, 75N93019C00051, HHSN272201400006C, HHSN272201400008C, and HHSN75N93019C00074; the Childrens Discovery Institute, grant number PDII2018702; the Defense Advanced Research Project Agency, grant number HR0011-18-2-0001; the Dolly Parton COVID-19 Research Fund at Vanderbilt University; Fast Grants; the Mercatus Center at George Mason University; and the Future Insight Prize from Merck KGaA.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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COVID-19 dual-antibody therapies effective against variants in animal study Washington University School of Medicine in St. Louis - Washington...

The GW4 Alliance (Bath, Bristol, Cardiff and Exeter universities GW4) formally launched their new One Health antimicrobial resistance research consortium this week [Wednesday 16 June]. The World Health Organisation cites antimicrobial resistance (AMR) as one of the most significant risks facing the world. AMR threatens global health and development as it impacts on human, animal and plant health and also our environment, water safety and food security.

The GW4 AMR Alliancehas been established to tackle this global challenge and become the UKs leading interdisciplinary One Health AMR research consortium, recognised worldwide.

A launch event showcasing GW4s cross-disciplinary AMR research collaborations and some of the One Health AMR projects and programmes being undertaken by GW4 teams and their collaborators took place on Wednesday [16 June] and included talks from University of Bristol researchers who discussed some of their latest findings from AMR research projects.

Antimicrobial resistance where bacterial, fungal, viral and parasitic infections become resistant to existing antimicrobial drugs is an increasing global societal threat, as there is no matching increase in new antibiotics or new therapies to help treat patients infections.

The COVID-19 pandemic has brought the pandemic of AMR into sharper focus. Antimicrobial use, which drives the emergence of AMR, increased in many intensive care units around the world, as clinicians mitigated the development of secondary bacterial and fungal infections in acutely ill hospitalised patients. AMR is a slower moving, silent pandemic but requires urgent action now to stop resistance expanding and find drugs to treat these infections.

The GW4 AMR Alliance builds on and enhances the GW4 universities strong and diverse portfolio of AMR research. Its vision is to tackle AMR using a One Health approach and to be the partner of choice for future AMR research consortia funding to help mitigate the urgent threat of AMR.

During the launch, Dr Kristen Reyher, leader of BristolsAMR Forceresearch group at Bristol Vet School, Matthew Avison, Professor of Molecular Bacteriology from Bristols School of Cellular and Molecular Medicine, and Helen Lambert, Professor of Medical Anthropology at Bristol Medical School, addressed AMR known unknowns as well as the link between climate change and AMR, and presented their latest research findings from projects in Thailand, Argentina and China.

Professor Avison, lead PI of the One Health Drivers of AMR in Thailand (OH-DART)project, discussed the key levers that could be pulled to help mitigate the threat of AMR in the country which, in 2010 was estimated to have caused 38,000 deaths and an economic loss of 1.2 billion US$ per year. This is mostly due to antibacterial resistance (ABR) which is common in bacteria isolated from humans, animals and the environment. He also discussed a recent paper modelling the impacts of antimicrobial usage changes in farming and human medicine.

Dr Reyher presented the latest findings from the Bristol-led One Health Selection and Transmission of Antimicrobial Resistance (OH-STAR) study and their implications for surveillance of AMR on farms, including advice about sampling from the same sites on farms, controlling for temperature in sampling and using a consistent sampling technique.

Professor Lambert, lead PI of the UK-China AMR Partnership Hub STAR-CHINA, discussed the social and cultural drivers which underpin the threat of AMR such as antibiotic prescribing and environmental exposure via water use practices, highlighting the need for interventions that alter AMR transmission pathways to take patterns of human behaviour into account.

Dr Timothy Jinks, Head of the Drug-Resistant Infections Programme at theWellcome Trust, who is delivering the keynote lecture, said: Containing and controlling AMR requires collaborative, long-term, interdisciplinary and sustainable research taking a global One Health approach. It is great news that the GW4 AMR Alliance is launching to increase understanding, development and implementation of effective interventions.

GW4s proven academic excellence in AMR research across disciplines and across institutions is demonstrated by a portfolio of AMR relevant research funding in excess of 40m.

Dr Joanna Jenkinson, GW4 Alliance Director, commented: Our strategic initiative is in total accord with the G7 Health Ministers recent communique (on 4 June) which outlined the need to act on the growing pandemic of AMR with clear leadership, bold science-based actions and a One Health approach, recognising and understanding that the health of humans, animals, plants and their shared environment are inextricably interlinked. The GW4 has fostered collaborative AMR projects at scale to achieve more than our institutions can individually. We are also proud to support our early career researchers (ECR) through our Crucible programme on Interdisciplinary Approaches to AMR and opportunities to apply for seed funding. We are delighted that one new ECR AMR community, further supported by our GW4 Generator Award funding scheme, is contributing a presentation at the launch today on their project to find new antibiotic leads.

AMR disproportionately affects low-and-middle income countries and the research being showcased today demonstrates our global reach with collaborative GW4 projects taking place in Thailand, China, Bangladesh, Argentina, India and here in the UK. GW4 researchers are exploring what drives the emergence of AMR in different settings e.g. the environment (particularly in aquatic systems from industrial and domestic waste), livestock farming, aquaculture and healthcare.

Identifying the drivers of AMR will help to help modify them by informing policy and implementing interventions to mitigate this rising threat. In the UK alone, there was a nine per cent increase in deaths caused by drug-resistant infections between 2017 and 2018.

Chair of the GW4 AMR Alliance, Prof Eshwar Mahenthiralingam (Cardiff University), said: This is a very exciting and timely consortium bringing the considerable AMR research strengths across the GW4 universities together to work as one cohesive unit to drive forward our understanding of, and to develop new interventions for containing and controlling AMR.

About the GW4 AMR Alliance

The GW4 Alliance Bath, Bristol, Cardiff and Exeter universities (GW4) are developing initiatives at scale that recognise the combined research strengths of the Alliance. The new GW4 AMR Alliance joins a number of global challenge research programmes (including climate) designed to foster new regional, national and global research partnerships to tackle major global challenges at scale.

The AMR Alliance is taking a One Health approach to tackle the growing threat of AMR. A 12-strong Steering Group draws together key members from the GW4s AMR research community to drive the programme forward, using cross-institutional, synergistic, interdisciplinary research that maximises engagement, translation and impact. The University of Bristol is represented by Professor Matthew Avison (School of Cellular and Molecular Medicine and Bristol AMR lead), Professor Helen Lambert (Bristol Medical School and UKRI Challenge Leader for Global Health) and Dr Kristen Reyher (Bristol Veterinary School).

About Bristol AMR

TheBristol AMRinterdisciplinary research network is led by a cross-faculty management committee comprising AMR research investigators from all six faculties.

Since 2015, the Bristol AMR research community has received 17.2 million of AMR research funding including grants awarded from the UKRI 'Tackling AMR A Cross-Council AMR initiative'. Funded projects include EPSRC BristolBridge, ESRC AMR Research Champion (Prof Helen Lambert) and three large consortium awards for AMR Themes 2 (BBSRC-led), 3 (NERC-led) and 4 (ESRC-led).

Bristol AMR investigators work across all disciplines to help tackle AMR, including the discovery of new antibiotics, the development of novel antimicrobial materials to prevent infection, rapid diagnostics for AMR, understanding behaviours to promote the responsible use of antimicrobials in healthcare and veterinary medicine, using data linkage to improve the use of antibiotics in healthcare and understanding how different regulatory systems in human and animal healthcare drive global AMR.

Bristol AMR investigators take a global One Health approach and work with collaborators across the UK and in low-and-middle income countries. Projects include an MRC/DoHSC 'AMR in a Global Context' award to study the drivers of AMR in Thailand; two MRC/Newton Fund UK-China Partnership Programmes to identify the key determinants of antimicrobial use and strategies to reduce the burden of AMR in China; a DoHSC GAMRIF/CONICET UK-Argentina awardlooking at future-proofing antibacterial resistance risk management surveillance and stewardship in the Argentinian farming environment; an MRC South Africa-UK Drug Discovery Partnership Hub to find new antibiotics from biodiverse-rich habitats and an EPSRC GCRF funded project to help develop nanoparticle based rapid diagnostics for tuberculosis with collaborators in Kenya.

Bristol also leads the 4 million Medical Research Foundation National PhD Training Programme in AMR Research to train next generation of AMR researchers through its multidisciplinary AMR studentships its national training cohort of 150 PhD students studying AMR across the UK.

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June: gw4amr-launch | News and features - University of Bristol

Bio-IT World Conference & Expo, September 20-22, 2021

NEEDHAM, Mass. (PRWEB) June 22, 2021

Bio-IT World Conference & Expo has just released the final agenda for the 20th anniversary eventtaking place virtually and in-person on September 20-22, 2021 in Boston, Mass.featuring a comprehensive list of 180+ biopharma executives along with other industry experts.

Bio-IT World Conference & Expo will return this year to Boston, Mass., once again bringing a diverse lineup of speakers and an expo with leading solution providers to its new venue, the Sheraton Boston. The hybrid format also features a virtual platform that provides an option for biopharma leaders from around the world to engage with their peers and expert thought leaders safely and conveniently.

Bio-IT World continues taking a leadership role to keep our life science community connected. We are investing in technology to ensure you stay connected with others whether you attend in-person or virtually. We are grateful for the support of our community during the past year as we pivoted from an in-person meeting in 2019, to a 100% virtual meeting in 2020, and now to a hybrid format for 2021. We are excited to see you at our new venue in Boston and look forward to hearing the latest research, science, and solutions, said Bio-IT World Executive Event Director, Cindy Crowninshield.

Biopharma executives who will be sharing their thought leadership this September include:

Attend Bio-IT World Conference & Expo this September 20-22, 2021, at the Sheraton Boston in Boston, Mass. In-person space is limited this year. Register today to secure your spot: bio-itworldexpo.com.

About Bio-IT World Conference & ExpoFor 20 years, the Bio-IT World Conference & Expo has been the worlds premier event showcasing technologies and analytic approaches that solve problems, accelerate science, and drive the future of precision medicine. Bio-IT World unites a community of leading life sciences, pharmaceutical, clinical, healthcare, informatics and technology experts in the field of biomedical research, drug discovery & development, and healthcare from around the world.

For sponsorship opportunities contact Angela Parsons, VP, Business Development at aparsons@healthtech.com.

To register to attend Bio-IT World Conference & Expo, click here.

About Cambridge Healthtech InstituteCambridge Healthtech Institute (CHI), a division of Cambridge Innovation Institute, is the preeminent life science network for leading researchers and business experts from top pharmaceutical, biotech, CROs, academia, and niche service providers. CHI is renowned for its vast conference portfolio held worldwide including PepTalk, Molecular Medicine Tri-Conference, SCOPE Summit, Bio-IT World Conference & Expo, PEGS Summit, Drug Discovery Chemistry, World Pharma Week, The Bioprocessing Summit, Next Generation Dx Summit, Immuno-Oncology Summit, and Discovery on Target. CHI's portfolio of products includes Cambridge Healthtech Institute Conferences, Barnett International, Insight Pharma Reports, Bio-IT World, Clinical Research News and Diagnostics World. For more information visit healthtech.com.

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Bio-IT World Conference & Expo to Bring Together Top Biopharma Executives for its Hybrid Return - PR Web