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Background: The increasing number of semi-invasive pain therapies in knee osteoarthritis poses challenges in decision-making. This review aimed to simultaneously compare established intra-articular therapies with newer peri-articular therapies and explore effect modifiers., Methods: Randomized controlled trials were searched from five electronic databases without date or language restrictions. Study selection and data extraction of reports, retrieved up to May 2024, were performed independently by paired assessors. The primary outcome was 6-month pain score. Nine treatments were included. The effect size (ES) for each treatment, relative to placebo, was estimated using standardized means difference and expressed with 95% confidence intervals (CI). The rigor of results was evaluated with subgroup/sensitivity analyses., Results: A total of 111 studies (14,695 participants) were included, with intra-articular hyaluronic acid having the greatest number of participants. Neuroablation demonstrated the greatest ES (1.08, 95% CI: 0.07, 2.10). While platelet-rich plasma (PRP) ranked second (ES: 0.75, 95% CI: 0.28, 1.22), it was the only intervention demonstrating statistically significant effect at 3, 6, and 12 months. However, this statistical significance was lost in some sensitivity analyses. Larger estimates for biologics and PRP compared with prolotherapy, steroid, and hyaluronic acid injections were consistently observed across different timepoints and in multiple sensitivity analyses. Generally, no statistically significant difference was found between the nine types of therapies., Conclusion: Although there is robust evidence suggesting greater efficacy of PRP, potentially including biologics, over other interventions, future research is needed to identify the phenotype or patient subgroup that would benefit most from PRP., (© 2024 World Institute of Pain.)

While breakthroughs with organoids have emerged as next-generation in vitro tools, standardization for drug discovery remains a challenge. This work introduces human airway organoids with reversed biopolarity (AORBs), cultured and analyzed in a high-throughput, single-organoid-per-well format, enabling milestones towards standardization. AORBs exhibit a spatio-temporally stable apical-out morphology, facilitating high-yield direct intact-organoid virus infection. Single-cell RNA sequencing and immunohistochemistry confirm the physiologically relevant recapitulation of differentiated human airway epithelia. The cellular tropism of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains along with host response differences between Delta, Washington, and Omicron variants, as observed in transcriptomic profiles, also suggest clinical relevance. Dose-response analysis of three well-studied SARS-CoV-2 antiviral compounds (remdesivir, bemnifosbuvir, and nirmatrelvir) demonstrates that AORBs efficiently predict human efficacy, comparable to gold-standard air-liquid interface cultures, but with higher throughput (~10-fold) and fewer cells (~100-fold). This combination of throughput and relevance allows AORBs to robustly detect false negative results in efficacy, preventing irretrievable loss of promising lead compounds. While this work leverages the SARS-CoV-2 study as a proof-of-concept application, the standardization capacity of AORB holds broader implications in line with regulatory efforts to push alternatives to animal studies., Competing Interests: Competing Interests Lee, Parigoris, and Takayama are inventors on US20230194506A1, filed on May 21, 2021, related to this work.

Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits HIV-1 at multiple stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for the treatment of HIV-1. Here, we characterized ISL and LEN in vitro to assess combinatorial antiviral activity, cytotoxicity, and the potential for interactions between the two compounds. Bliss analysis revealed ISL with LEN demonstrated additive inhibition of HIV-1 replication, with no evidence of antagonism across the range of concentrations tested. ISL exhibited potent antiviral activity against variants encoding known LEN resistance-associated mutations (RAMs) with or without the presence of M184V, an ISL RAM in reverse transcriptase (RT) . Static resistance selection experiments were conducted with ISL and LEN alone and in combination, initiating with either wild-type virus or virus containing the M184I RAM in RT to further assess their barrier to the emergence of resistance. The combination of ISL with LEN more effectively suppressed viral breakthrough at lower multiples of the compounds' IC 50 (half-maximal inhibitory concentration) values and fewer mutations emerged with the combination compared to either compound on its own. The known pathways for development of resistance with ISL and LEN were not altered, and no novel single mutations emerged that substantially reduced susceptibility to either compound. The lack of antagonism and cross-resistance between ISL and LEN support the ongoing evaluation of the combination for treatment of HIV-1., Competing Interests: T.L.D., S.L.G., W.N., S.R., M.X. (former), D.J.K., J.A.G. (former), and E.A.A. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), who may own stock and/or hold stock options in MSD.

Objective: To explore regional differences (i.e. Europe, Asia and others) in the well-being of para-athletes and its potential psychosocial determinants, including the Athletic Identity Measure Scale (AIMS), the Brief Resilience Scale (BRS) and the Satisfaction with Life Scale (SWLS)., Methods: The study was a cross-sectional survey using data from multinational badminton federations. The study participants were athletes registered in the Para Badminton Classification Master List of the Badminton World Federation (BWF). The main study outcome is the WHO Quality of Life-Disability Questionnaire (WHOQOL-DIS)., Results: There were 1,385 (aged 36 years old, IQR 18 years old) registrants on the master list. Respondents totaled 170. Only 137 (65% were males) were included in the analysis after excluding those with missing data (Europe 40%, Asia 30%, others 30%). Following the results of factor analysis, the original Athletic Identity Measure Scale (AIMS) was separated into self-identity (SI) and AIMS-modified. SI, AIMS-modified, the BRS and the Satisfaction with Life Scale (SWLS) were all scored above average. The AIMS-modified scores of Europeans were significantly lower than those of other non-Asians (U = 757.000, P < 0.05). BRS was statistically higher among those with acquired disabilities (median: 3.33) compared to those with congenital disabilities (median: 3.0) (U = 1,717.000, Z = - 2.711, P < 0.05) and among Europeans (median: 3.3) compared to Asians (median: 3.0) (U = 704.500, P < 0.05). The regression model explained 32% of the variability in quality of life (QOL) with five significant predictors. The SWLS ( β = 0.307, P = 0.01), BRS ( β = 0.269, P = 0.01), full-time employment ( β = 0.191, P = 0.05) and being female ( β = 0.162, P = 0.05) all had a positive effect on QOL, but not the AIMS ( - 0.228, P = 0.05)., Conclusion: The results show that the athletes' resilience, satisfaction with life and identity vary across regions. Furthermore, satisfaction with life, employment and gender were found to be significant predictors of athletes' QOL., Competing Interests: Conflict of Interest: None., (© Penerbit Universiti Sains Malaysia, 2024.)

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC 50 , CC 50 ) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (C max )/EC 50 , were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC 50 was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound C max /EC 50 ≥ 6.8 in Calu-3 or Caco-2 cells. EC 50 of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials.

Background: Blood transfusion in the perioperative cardiothoracic setting has accepted risks including deep sternal wound infection, increased intensive care unit length of stay, lung injury, and cost. It has an immunomodulatory effect which may cause allo-immunisation. This may influence long-term survival through immune-mediated factors. Targeting coagulation defects to reduce unnecessary or inappropriate transfusions may reduce these complications., Methods: In 2012, an institution-wide patient blood management evidence-based algorithmic bleeding management protocol was implemented at The Prince Charles Hospital, Brisbane, Australia. The benefit of this has been previously reported in our lung transplant and cardiac surgery (excluding transplants) cohorts. This study aimed to investigate the effect of this on our orthotopic heart transplant recipients., Results: After the implementation of the protocol, despite no difference in preoperative haemoglobin levels and higher risk patients (EuroSCORE 20 vs 26; p=0.013), the use of packed red blood cells (13.0 U vs 4.4 U; p=0.046) was significantly lower postoperatively and fresh frozen plasma was significantly lower both intra- and postoperatively (7.4 U vs 0.6 U; p<0.001, and 3.3 U vs 0.6 U; p=0.011 respectively). Concurrently, the use of prothrombin complex concentrate (33% vs 78%; p<0.001) and desmopressin (5% vs 22%; p=0.0028) was significantly higher in the post-protocol group, while there was less use of recombinant factor VIIa (15% vs 4%; p=0.058). Intraoperative units of cryoprecipitate also rose from 0.9 to 2.0 (p=0.006)., Conclusions: We have demonstrated that a targeted patient blood management protocol with point-of-care testing for heart transplant recipients is correlated with fewer blood products used postoperatively, with some increase in haemostatic products and no evidence of increased adverse events., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: People with disabilities are marginalised in mainstream culture and they also experience increased restrictions in a variety of areas, such as sport. The barriers they encounter may adversely affect their life satisfaction, especially if they have a low perceived sense of autonomy and resilience. The purpose of this study was to investigate the relationship between autonomy, resilience and life satisfaction in para-badminton athletes and the mediating role of resilience in the relationship between autonomy and life satisfaction., Methods: Data were collected from 137 para-badminton athletes (male: 65.0% and female: 35.0%). Self-reported measures were used to assess the participants' autonomy, resilience and life satisfaction levels., Results: A structural equation model analysis was performed; the model had sufficient fit indices (comparative fit index [CFI] = 0.94, root mean square error of approximation [RMSEA] = 0.06, standardised root mean square residual [SRMR] = 0.07). The findings showed that autonomy had a significant effect on resilience ( β = 0.32, P = 0.001). Further, resilience had a significant effect on life satisfaction ( β = 0.19, P = 0.011) and significantly mediated the effect of autonomy on life satisfaction ( β = 021, P = 0.033)., Conclusion: This study revealed that autonomy fosters resilience among athletes, in turn allowing them to achieve greater life satisfaction. Therefore, society and sport communities should actively seek ways to improve the autonomy and resilience levels of athletes with disabilities., Competing Interests: Conflict of Interest: None., (© Penerbit Universiti Sains Malaysia, 2024.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and related variants, are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 main protease (Mpro) plays a central role in the replication of the virus and represents an attractive drug target. Herein, we report the discovery of novel SARS-CoV-2 Mpro covalent inhibitors, including highly effective compound NIP-22c which displays high potency against several key variants and clinically relevant nirmatrelvir Mpro E166V mutants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Raymond Schinazi reports financial support was provided by National Institutes of Health. Ladislau Kovari reports financial support was provided by National Institutes of Health. Ladislau Kovari reports financial support was provided National Institutes of Health and by Richard Barber Interdisciplinary Program grant. Stefan Sarafianos reports financial support was provided National Institutes of Health and by Nahmias-Schinazi Distinguished Research Chair. R. Schinazi, K. Zandi, F. Amblard has patent Peptidomimetics for the treatment of coronavirus and picornavirus infections issued to Emory university. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Introduction: A higher prevalence of knee pain in Southeast Asian countries, compared with non-Asian countries, is an established fact. This article hypothesizes that this fact, combined with personal, cultural, and environmental factors, may influence attitudes toward illness and treatment-seeking behavior and adherence., Objective: This study aimed to determine current attitudes, stigma, and barriers of women to the management of chronic knee pain and treatment in two Southeast Asian countries., Methods: Fourteen semi-structured interviews explored female lived perceptions of chronic knee pain in Southeast Asia. Using a phenomenological reduction process, open-ended questions allowed participants to voice their perceptions of their experience of this knee condition. Particular foci were potential stigma associated with the perceptions of others, health-seeking attitudes, and attitudes toward exercise., Results: The shared experiences of managing chronic knee pain revealed the impact of their condition on participants' normality of life and their struggles with pain, limitations, and fear for the future. Key individual, interpersonal, organizational and community barriers and facilitators impacted the health seeking attitudes and engagement with conservative rehabilitation programmes., Conclusion: Improved socio-cultural competency and consideration for an individuals' intersectional identity and interpersonal relationships are key to designing rehabilitation and conservative management solutions. Co-creating alternative pathways for rehabilitation for individuals that are more distant from health facilities may help reduce socio-cultural barriers at a community level.

Background: Despite the existence of evidence-based rehabilitation strategies that address biomechanical deficits, the persistence of recurrent ankle problems in 70% of patients with acute ankle sprains highlights the unresolved nature of this issue. Artificial intelligence (AI) emerges as a promising tool to identify definitive predictors for ankle sprains. This paper aims to summarize the use of AI in investigating the ankle biomechanics of healthy and subjects with ankle sprains., Methods: Articles published between 2010 and 2023 were searched from five electronic databases. 59 papers were included for analysis with regards to: i). types of motion tested (functional vs. purposeful ankle movement); ii) types of biomechanical parameters measured (kinetic vs kinematic); iii) types of sensor systems used (lab-based vs field-based); and, iv) AI techniques used., Findings: Most studies (83.1%) examined biomechanics during functional motion. Single kinematic parameter, specifically ankle range of motion, could obtain accuracy up to 100% in identifying injury status. Wearable sensor exhibited high reliability for use in both laboratory and on-field/clinical settings. AI algorithms primarily utilized electromyography and joint angle information as input data. Support vector machine was the most used supervised learning algorithm (18.64%), while artificial neural network demonstrated the highest accuracy in eight studies., Interpretations: The potential for remote patient monitoring is evident with the adoption of field-based devices. Nevertheless, AI-based sensors are underutilized in detecting ankle motions at risk of sprain. We identify three key challenges: sensor designs, the controllability of AI models, and the integration of AI-sensor models, providing valuable insights for future research., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Molnupiravir, an oral prodrug of N-hydroxycytidine (NHC), previously demonstrated broad in vitro antiviral activity against multiple RNA viruses and has shown a high barrier to the development of resistance. Here, we present the antiviral activity of NHC against recent SARS-CoV-2 variants and the results of resistance selection studies to better understand the potential for viral resistance to NHC. NHC activity against SARS-CoV-2 variants omicron (BA.1, BA.1.1, BA.2, BA.4, BA.4.6, BA.5, BQ.1.1, XBB.1, and XBB.1.5), alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), lambda (C.37), and mu (B.1.621) was evaluated in Vero E6 cells using cytopathic effect assays. Resistance selection studies were performed by passaging SARS-CoV-2 (WA1) in the presence of NHC or a 3C-like protease inhibitor (MRK-A) in Vero E6 cells. Supernatants from cultures exhibiting a cytopathic effect score of ≥2 were re-passaged, and IC 50 values were estimated. Whole-genome deep sequencing was performed on viral RNA isolated at each passage. NHC demonstrated similar potency against all SARS-CoV-2 variants evaluated. No evidence of SARS-CoV-2 phenotypic or genotypic resistance to NHC was observed following 30 passages. A random pattern of nucleotide changes was observed in NHC cultures, consistent with the drug's mechanism of action. In contrast, resistance was readily selected in all three MRK-A control cultures with the selection of a T21I substitution in the 3C-like protease. In conclusion, molnupiravir maintains antiviral activity across all major SARS-CoV-2 variants. Furthermore, no evidence of viral resistance to NHC was observed, supporting previous reports that NHC has a high barrier to developing resistance., Competing Interests: J.S., J.M.G., N.M., J.H., B.H., K.C.K., P.M., and S.L.G. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA.

Objective: This overview of systematic reviews aimed to appraise evidence regarding self-management strategies on health-related quality of life, self-efficacy, medication compliance, seizure status and psychosocial outcomes compared to usual care for people with epilepsy., Methods: Databases were searched until September 2022 using MeSH terms included OVID Medline, Embase and Cochrane. Following application of eligibility criteria, data were extracted and quality of articles was assessed using the AMSTAR2 checklist. A narrative synthesis of evidence included certainty of evidence evaluated using a Grading of Recommendations, Assessment, Development and Evaluation approach., Results: The 12 selected reviews contained three meta-analyses and 91 unique primary studies. One review considered only epilepsy with intellectual disability and three considered paediatrics. Interventions included technologically-based interventions, small group discussion, or counselling and educational programs. There was high certainty evidence to suggest self-management is associated with improvement in health-related quality of life and moderate certainty evidence to suggest improvement in depression symptoms. There was low certainty evidence to suggest a modest reduction in negative health events and a minimal increase in the satisfaction with life. There was no evidence of benefit favouring self-management on measures of adherence epilepsy self-management, perception of self-efficacy, medication adherence or seizure status., Significance: Despite high certainty evidence to suggest that self-management strategies for people with epilepsy improve health-related quality of life, benefits have not been demonstrated for outcomes that would be expected to be associated with these improvements, such as seizure status. These results provide support for self-management strategies to supplement usual care for people with epilepsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Knee osteoarthritis (OA) is a debilitating musculoskeletal disorder that causes functional disability. Automatic knee OA diagnosis has great potential of enabling timely and early intervention, that can potentially reverse the degenerative process of knee OA. Yet, it is a tedious task, concerning the heterogeneity of the disorder. Most of the proposed techniques demonstrated single OA diagnostic task widely based on Kellgren Lawrence (KL) standard, a composite score of only a few imaging features (i.e. osteophytes, joint space narrowing and subchondral bone changes). However, only one key disease pattern was tackled. The KL standard fails to represent disease pattern of individual OA features, particularly osteophytes, joint-space narrowing, and pain intensity that play a fundamental role in OA manifestation. In this study, we aim to develop a multitask model using convolutional neural network (CNN) feature extractors and machine learning classifiers to detect nine important OA features: KL grade, knee osteophytes (both knee, medial fibular: OSFM, medial tibial: OSTM, lateral fibular: OSFL, and lateral tibial: OSTL), joint-space narrowing (medial: JSM, and lateral: JSL), and patient-reported pain intensity from plain radiography., Methods: We proposed a new feature extraction method by replacing fully-connected layer with global average pooling (GAP) layer. A comparative analysis was conducted to compare the efficacy of 16 different convolutional neural network (CNN) feature extractors and three machine learning classifiers., Results: Experimental results revealed the potential of CNN feature extractors in conducting multitask diagnosis. Optimal model consisted of VGG16-GAP feature extractor and KNN classifier. This model not only outperformed the other tested models, it also outperformed the state-of-art methods with higher balanced accuracy, higher Cohen's kappa, higher F1, and lower mean squared error (MSE) in seven OA features prediction., Conclusions: The proposed model demonstrates pain prediction on plain radiographs, as well as eight OA-related bony features. Future work should focus on exploring additional potential radiological manifestations of OA and their relation to therapeutic interventions., Competing Interests: Declaration of Competing Interest We confirm that this work is original, has not been published elsewhere, and is not currently being considered for publication elsewhere. The consent of all authors of this paper has been obtained for submitting the paper and all authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Given the deficits in allergists and testing capacity, the diagnosis of drug allergy is largely dependent on the clinician's and pharmacist's judgment. The ability to recognize drug allergies and respond appropriately is crucial to patient safety. Currently, there is a void in the evidence that limits the ability to recommend comprehensive and swift improvements on this front., Objective: This study thus aimed to evaluate the knowledge, attitude, and practice toward drug allergy among doctors and pharmacists working in public healthcare facilities in Sabah, Malaysia., Methods: This cross-sectional study was conducted in 24 hospitals and 11 clinics in Sabah. A validated Drug Allergy Knowledge, Attitude, and Practice Questionnaire was adapted from a published study and developed on an online survey platform. The questionnaire was distributed to all listed eligible respondents via email and personal messenger service., Results: A total of 549 doctors and pharmacists responded, with an overall response rate of 18.2%. The total mean knowledge, attitude, and practice scores were 8.3 (SD, 1.98), 18.9 (SD, 2.55), and 17.3 (SD, 4.4), respectively. It was found that pharmacists performed significantly poorer than both medical officers (mean score difference = -0.5; P = 0.006) and specialists (mean score difference = -0.9; P = 0.020) in the knowledge domain. As the time in service doubles, the knowledge score increases significantly by 0.3 ( P = 0.015)., Conclusion: Knowledge, attitude, and practice on drug allergy among doctors and pharmacists in Sabah were poor. It is thus timely for advanced educational programs on drug allergy to be formalized and implemented., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2023. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Objective: Clinical guidelines recommend exercise as a core treatment for knee or hip osteoarthritis (OA). However, how its analgesic effect compares to analgesics, for example, oral non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol-the most commonly used analgesics for OA, remains unknown., Design: Network meta-analysis., Data Sources: PubMed, Embase, Scopus, Cochrane Library and Web of Science from database inception to January 2022., Eligibility Criteria for Selecting Studies: Randomised controlled trials (RCTs) comparing exercise therapy with oral NSAIDs and paracetamol directly or indirectly in knee or hip OA., Results: A total of n=152 RCTs (17 431 participants) were included. For pain relief, there was no difference between exercise and oral NSAIDs and paracetamol at or nearest to 4 (standardised mean difference (SMD)=-0.12, 95% credibility interval (CrI) -1.74 to 1.50; n=47 RCTs), 8 (SMD=0.22, 95% CrI -0.05 to 0.49; n=2 RCTs) and 24 weeks (SMD=0.17, 95% CrI -0.77 to 1.12; n=9 RCTs). Similarly, there was no difference between exercise and oral NSAIDs and paracetamol in functional improvement at or nearest to 4 (SMD=0.09, 95% CrI -1.69 to 1.85; n=40 RCTs), 8 (SMD=0.06, 95% CrI -0.20 to 0.33; n=2 RCTs) and 24 weeks (SMD=0.05, 95% CrI -1.15 to 1.24; n=9 RCTs)., Conclusions: Exercise has similar effects on pain and function to that of oral NSAIDs and paracetamol. Given its excellent safety profile, exercise should be given more prominence in clinical care, especially in older people with comorbidity or at higher risk of adverse events related to NSAIDs and paracetamol.CRD42019135166., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. The human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process. HIV-1 capsid (CA), the chief structural component of the viral core, is a critical determinant in nuclear transport of the virus. HIV-1 interactions with NPCs are dependent on CA, which makes direct contact with nucleoporins (Nups). Here we identify Nup35, Nup153, and POM121 to coordinately support HIV-1 nuclear entry. For Nup35 and POM121, this dependence was dependent cyclophilin A (CypA) interaction with CA. Mutation of CA or removal of soluble host factors changed the interaction with the NPC. Nup35 and POM121 make direct interactions with HIV-1 CA via regions containing phenylalanine glycine motifs (FG-motifs). Collectively, these findings provide additional evidence that the HIV-1 CA core functions as a macromolecular nuclear transport receptor (NTR) that exploits soluble host factors to modulate NPC requirements during nuclear invasion., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Knee osteoarthritis is one of the most common musculoskeletal diseases and is usually diagnosed with medical imaging techniques. Conventionally, case identification using plain radiography is practiced. However, we acknowledge that knee osteoarthritis is a 3D complexity; hence, magnetic resonance imaging will be the ideal modality to reveal the hidden osteoarthritis features from a three-dimensional view. In this work, the feasibility of well-known convolutional neural network (CNN) structures (ResNet, DenseNet, VGG, and AlexNet) to distinguish knees with and without osteoarthritis (OA) is investigated. Using 3D convolutional layers, we demonstrated the potential of 3D convolutional neural networks of 13 different architectures in knee osteoarthritis diagnosis. We used transfer learning by transforming 2D pre-trained weights into 3D as initial weights for the training of the 3D models. The performance of the models was compared and evaluated based on the performance metrics [balanced accuracy, precision, F1 score, and area under receiver operating characteristic (AUC) curve]. This study suggested that transfer learning indeed enhanced the performance of the models, especially for ResNet and DenseNet models. Transfer learning-based models presented promising results, with ResNet34 achieving the best overall accuracy of 0.875 and an F1 score of 0.871. The results also showed that shallow networks yielded better performance than deeper neural networks, demonstrated by ResNet18, DenseNet121, and VGG11 with AUC values of 0.945, 0.914, and 0.928, respectively. This encourages the application of clinical diagnostic aid for knee osteoarthritis using 3DCNN even in limited hardware conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yeoh, Lai, Goh, Hasikin, Wu and Li.)

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1 + cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 + T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin-angiotensin-aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin-angiotensin-aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04-0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05-60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11-7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42-10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86-5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57-6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin-angiotensin-aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Throughout the SARS-CoV-2 pandemic, the use of botanical dietary supplements in the United States has increased, yet their safety and efficacy against COVID-19 remains underexplored. The Quave Natural Product Library is a phylogenetically diverse collection of botanical and fungal natural product extracts including popular supplement ingredients. Evaluation of 1867 extracts and 18 compounds for virus spike protein binding to host cell ACE2 receptors in a SARS-CoV-2 pseudotyped virus system identified 310 extracts derived from 188 species across 76 families (3 fungi, 73 plants) that exhibited ≥ 50% viral entry inhibition activity at 20 µg/mL. Extracts exhibiting mammalian cytotoxicity > 15% and those containing cardiotoxic cardiac glycosides were eliminated. Three extracts were selected for further testing against four pseudotyped variants and infectious SARS-CoV-2 and were then further chemically characterized, revealing the potent (EC 50  < 5 µg/mL) antiviral activity of Solidago altissima L. (Asteraceae) flowers and Pteridium aquilinum (L.) Kuhn (Dennstaedtiaceae) rhizomes., (© 2023. The Author(s).)

The validity and reliability of the Lafayette stability platform are well-established for double leg testing. However, no evaluation of single leg (SL) stance on the platform was discovered yet. Therefore, this study aimed to investigate the reliability of conducting the SL stance on the Lafayette platform. Thirty-six healthy and active university students (age 23.2 ± 3.2 years; BMI 21.1 ± 3.1 kg/m2) were tested twice, one week apart (week 1; W1, week 2; W2). They stood on their dominant leg with eyes-open (EO) and eyes-closed (EC) in random order. Three successful trials of 20 seconds each were recorded. The duration during which the platform was maintained within 0° of tilt was referred to as time in balance (TIB). At all-time points, TIB was consistently longer in EO (EOW1: 17.02 ± 1.04s; EOW2: 17.32 ± 1.03s) compared to EC (ECW1: 11.55 ± 1.73s; ECW2: 13.08 ± 1.82s). A ±10 seconds difference was demonstrated in the Bland-Altman analysis in both EO and EC. Lower standard error of measurement (SEM) and coefficient of variation (CV) indicated consistent output. High intraclass correlation coefficient (ICC) values were seen between weeks (EO = 0.74; EC = 0.76) and within weeks (EOW1 = 0.79; EOW2 = 0.86; ECW1 = 0.71; ECW2 = 0.71). Although statistical measures (i.e., SEM, CV, and ICC) indicated good reliability of Lafayette for SL tasks, the wide agreement interval is yet to be clinically meaningful. Factors underlying the wide variation need to be identified before Lafayette is used for TIB assessment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zaghlul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We present a case of a small bowel obstruction secondary to a rare plastic bezoar. A man in their early 20s with autism and an intellectual disability presented with symptoms of small bowel obstruction. CT revealed very subtle signs and, despite passage of gastrografin, ongoing clinical suspicion led to operative management which confirmed the diagnoses of plastic bezoar., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Yellow fever virus (YFV) is a potentially lethal, zoonotic, blood-borne flavivirus transmitted to humans and non-human primates by mosquitoes. Owing to multiple deadly epidemics, the WHO classifies YFV as a "high impact, high threat disease" with resurgent epidemic potential. At present, there are no approved antiviral therapies to combat YFV infection. Herein we report on 2'-halogen-modified nucleoside analogs as potential anti-YFV agents. Of 11 compounds evaluated, three showed great promise with low toxicity, high intracellular metabolism into the active nucleoside triphosphate form, and sub-micromolar anti-YFV activity. Notably, we investigated a 2'-fluoro,2'-bromouridine phosphate prodrug (C9), a known anti-HCV agent with good stability in human blood and favorable metabolism. Predictive modeling revealed that C9 could readily bind the active site of the YFV RdRp, conferring its anti-YFV activity. C9 displayed potent anti-YFV activity in primary human macrophages, 3D hepatocyte spheroids, and in mice. In an A129 murine model, shortly after infection, C9 significantly reduced YFV replication and protected against YFV-induced liver inflammation and pathology with no adverse effects. Collectively, this work identifies a potent new anti-YFV agent with strong therapeutic promise.

Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 (" i nducer of ce ll d eath-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.

Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N 4 -hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early SARS-CoV-2 infections. Herein, we report the synthesis and evaluation of a series of novel NHC analogs.

Abstract: Fibromyalgia is a highly heterogeneous condition, but the most common symptoms are widespread pain, fatigue, poor sleep, and low mood. Nonpharmacological interventions are recommended as first-line treatment of fibromyalgia. However which interventions are effective for the different symptoms is not well understood. The objective of this study was to assess the efficacy of nonpharmacological interventions on symptoms and disease-specific quality of life. Seven databases were searched from their inception until June 1, 2020. Randomised controlled trials comparing any nonpharmacological intervention to usual care, waiting list, or placebo in people with fibromyalgia aged >16 years were included without language restriction. Fibromyalgia Impact Questionnaire (FIQ) was the primary outcome measure. Standardised mean difference and 95% confidence interval were calculated using random effects model. The risk of bias was evaluated using the modified Cochrane tool. Of the 16,251 studies identified, 167 randomised controlled trials (n = 11,012) assessing 22 nonpharmacological interventions were included. Exercise, psychological treatments, multidisciplinary modality, balneotherapy, and massage improved FIQ. Subgroup analysis of different exercise interventions found that all forms of exercise improved pain (effect size [ES] -0.72 to -0.96) and depression (ES -0.35 to -1.22) except for flexibility exercise. Mind-body and strengthening exercises improved fatigue (ES -0.77 to -1.00), whereas aerobic and strengthening exercises improved sleep (ES -0.74 to -1.33). Psychological treatments including cognitive behavioural therapy and mindfulness improved FIQ, pain, sleep, and depression (ES -0.35 to -0.55) but not fatigue. The findings of this study suggest that nonpharmacological interventions for fibromyalgia should be individualised according to the predominant symptom., (Copyright © 2021 International Association for the Study of Pain.)

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits human immunodeficiency virus (HIV) reverse transcription by blocking reverse transcriptase (RT) translocation on the primer:template. ISL is being developed for the treatment of HIV-1 infection. To expand our knowledge of viral variants that may confer reduced susceptibility to ISL, resistance selection studies were conducted with wild-type (WT) subtype A, B, and C viruses. RT mutations encoding M184I and M184V were the most frequently observed changes. Selection studies were also initiated with virus containing a single known resistance-associated mutation in RT (K65R, L74I, V90I, M184I, or M184V), and no additional mutations were observed. Antiviral activity assays were performed on variants that emerged in selection studies to determine their impact. M184I and M184V were the only single-codon substitutions that reduced susceptibility >2-fold compared to WT. A114S was an emergent substitution that when combined with other substitutions further reduced susceptibility >2-fold. Viruses containing A114S in combination with M184V did not replicate in primary blood mononuclear cells (PBMCs), consistent with the rare occurrence of the combination in clinical samples. While A114S conferred reduced susceptibility to ISL, it increased susceptibility to approved nucleoside reverse transcriptase inhibitors (NRTIs). This differential impact of A114S on ISL, an NRTTI, compared to NRTIs likely results from the different mechanisms of action. Altogether, the results demonstrate that ISL has a high barrier to resistance and a differentiated mechanism compared to approved NRTIs.

SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target., Competing Interests: Declaration of interests R.F.S. is the inventor of the use of baricitinib for coronavirus infections and receives royalties from Eli Lilly. His conflict of interest has been reviewed and approved by Emory University. All other authors have declared that no conflict of interest exists. Contents within this manuscript are included in patent USPTO 10670594., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Early Th 17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th 17 polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th 17 responses. However, the molecular mechanisms that contributed to Th 17 polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th 17 polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th 17 responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th 17 polarization in vitro and in vivo . In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th 17 responses and identify the CD40-DLL4 pathways as targets for developing new Th 17 -inducing vaccines and adjuvants for tuberculosis., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

The lack of antiviral innate immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is characterized by limited production of interferons (IFNs). One protein associated with Aicardi-Goutières syndrome, SAMHD1, has been shown to negatively regulate the IFN-1 signaling pathway. However, it is unclear whether elevated IFN signaling associated with genetic loss of SAMHD1 would affect SARS-CoV-2 replication. In this study, we established in vitro tissue culture model systems for SARS-CoV-2 and human coronavirus OC43 infections in which SAMHD1 protein expression was absent as a result of CRISPR-Cas9 gene KO or lentiviral viral protein X-mediated proteosomal degradation. We show that both SARS-CoV-2 and human coronavirus OC43 replications were suppressed in SAMHD1 KO 293T and differentiated THP-1 macrophage cell lines. Similarly, when SAMHD1 was degraded by virus-like particles in primary monocyte-derived macrophages, we observed lower levels of SARS-CoV-2 RNA. The loss of SAMHD1 in 293T and differentiated THP-1 cells resulted in upregulated gene expression of IFNs and innate immunity signaling proteins from several pathways, with STAT1 mRNA being the most prominently elevated ones. Furthermore, SARS-CoV-2 replication was significantly increased in both SAMHD1 WT and KO cells when expression and phosphorylation of STAT1 were downregulated by JAK inhibitor baricitinib, which over-rode the activated antiviral innate immunity in the KO cells. This further validates baricitinib as a treatment of SARS-CoV-2-infected patients primarily at the postviral clearance stage. Overall, our tissue culture model systems demonstrated that the elevated innate immune response and IFN activation upon genetic loss of SAMHD1 effectively suppresses SARS-CoV-2 replication., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Knee osteoarthritis (OA) is a deliberating joint disorder characterized by cartilage loss that can be captured by imaging modalities and translated into imaging features. Observing imaging features is a well-known objective assessment for knee OA disorder. However, the variety of imaging features is rarely discussed. This study reviews knee OA imaging features with respect to different imaging modalities for traditional OA diagnosis and updates recent image-based machine learning approaches for knee OA diagnosis and prognosis. Although most studies recognized X-ray as standard imaging option for knee OA diagnosis, the imaging features are limited to bony changes and less sensitive to short-term OA changes. Researchers have recommended the usage of MRI to study the hidden OA-related radiomic features in soft tissues and bony structures. Furthermore, ultrasound imaging features should be explored to make it more feasible for point-of-care diagnosis. Traditional knee OA diagnosis mainly relies on manual interpretation of medical images based on the Kellgren-Lawrence (KL) grading scheme, but this approach is consistently prone to human resource and time constraints and less effective for OA prevention. Recent studies revealed the capability of machine learning approaches in automating knee OA diagnosis and prognosis, through three major tasks: knee joint localization (detection and segmentation), classification of OA severity, and prediction of disease progression. AI-aided diagnostic models improved the quality of knee OA diagnosis significantly in terms of time taken, reproducibility, and accuracy. Prognostic ability was demonstrated by several prediction models in terms of estimating possible OA onset, OA deterioration, progressive pain, progressive structural change, progressive structural change with pain, and time to total knee replacement (TKR) incidence. Despite research gaps, machine learning techniques still manifest huge potential to work on demanding tasks such as early knee OA detection and estimation of future disease events, as well as fundamental tasks such as discovering the new imaging features and establishment of novel OA status measure. Continuous machine learning model enhancement may favour the discovery of new OA treatment in future., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this study., (Copyright © 2022 Yun Xin Teoh et al.)

We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Osteoarthritis (OA), especially knee OA, is the most common form of arthritis, causing significant disability in patients worldwide. Manual diagnosis, segmentation, and annotations of knee joints remain as the popular method to diagnose OA in clinical practices, although they are tedious and greatly subject to user variation. Therefore, to overcome the limitations of the commonly used method as above, numerous deep learning approaches, especially the convolutional neural network (CNN), have been developed to improve the clinical workflow efficiency. Medical imaging processes, especially those that produce 3-dimensional (3D) images such as MRI, possess ability to reveal hidden structures in a volumetric view. Acknowledging that changes in a knee joint is a 3D complexity, 3D CNN has been employed to analyse the joint problem for a more accurate diagnosis in the recent years. In this review, we provide a broad overview on the current 2D and 3D CNN approaches in the OA research field. We reviewed 74 studies related to classification and segmentation of knee osteoarthritis from the Web of Science database and discussed the various state-of-the-art deep learning approaches proposed. We highlighted the potential and possibility of 3D CNN in the knee osteoarthritis field. We concluded by discussing the possible challenges faced as well as the potential advancements in adopting 3D CNNs in this field., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Pauline Shan Qing Yeoh et al.)

Background: Transversus abdominis plane (TAP) block and intraperitoneal local anesthetics (IPLA) are widely investigated techniques that potentially improve analgesia after bariatric surgery. The analgesic efficacy of TAP block has been shown in previous studies, but the performance of TAP block can be difficult in patients with obesity. We performed a systematic review and meta-analysis to compare the analgesic efficacy of TAP block and IPLA. An alternative technique is useful in clinical setting when TAP block is not feasible., Methods: We searched PubMed, Embase, and CENTRAL from inception until August 2020 for randomized controlled trials comparing both techniques. The primary outcome was cumulative morphine consumption at 24 h. Secondary pain-related outcomes included pain score at rest and on movement at 2, 6, 12, and 24 h; postoperative nausea and vomiting; and length of hospital stay., Results: We included 23 studies with a total of 2,178 patients. TAP block is superior to control in reducing opioid consumption at 24 h, improving pain scores at all the time points and postoperative nausea and vomiting. The cumulative opioid consumption at 24 h for IPLA is less than control, while the indirect comparison between IPLA with PSI and control showed a significant reduction in pain scores at rest, at 2 h, and on movement at 12 h, and 24 h postoperatively., Conclusions: Transversus abdominis plane block is effective for reducing pain intensity and has superior opioid-sparing effect compared to control. Current evidence is insufficient to show an equivalent analgesic benefit of IPLA to TAP block., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Prolotherapy and other injections, primarily acting on pathways associated with maladaptive tissue repair, are recommended for recalcitrant chronic soft tissue injuries (CSTI). However, selection of injection is challenging due to mixed results. This network meta-analysis (NMA) aimed to compare prolotherapy with other therapies, particularly injections, for CSTI and establish robustness of the results., Methodology: Pubmed, Medline, SPORTDiscus and Google scholar were searched from inception to 4th January 2021 for randomised controlled trials (RCTs) involving injection therapies (e.g. blood derivatives, corticosteroid, hyaluronic acid, botulinum toxin) for CSTI. The primary and secondary outcomes were pain and function, respectively, at (or nearest to) 6 months. Effect size (ES) was presented as standardised mean difference with 95% confidence interval (CI). Frequentist random effect NMA was used to generate the overall estimates, subgroup estimates (by region and measurement time point) and sensitivity analyses., Results: A total of 91 articles (87 RCTs; 5859 participants) involving upper limb (74%), lower limb (23%) and truncal/hip (3%) injuries were included. At all time points, prolotherapy had no statistically significant pain benefits over other therapies. This observation remained unchanged when tested under various assumptions and with exclusion of studies with high risk of bias. Although prolotherapy did not offer statistically significant functional improvement compared to most therapies, its ES was consistently better than non-injections and corticosteroid injection for both outcomes. At selected time points and for selected injuries, prolotherapy demonstrated potentially better pain improvement over placebo (<4 months: shoulder [ES 0.65; 95% CI 0.00 to 1.30]; 4-8 months: elbow [ES 0.91; 95% CI 0.12 to 1.70]; >8 months: shoulder [ES 2.08; 95% CI 1.49, to 2.68]). Injections generally produced greater ES when combined with non-injection therapy., Conclusion: While clinical outcomes were generally comparable across types of injection therapy, prolotherapy may be used preferentially for selected conditions at selected times., Competing Interests: The authors have declared that no competing interests exist.

Background: Deaf and hard-of-hearing (DHH) patients have trouble communicating with community pharmacists and accessing the healthcare system. This study explored the views on a proposed mobile health (mHealth) app in terms of design and features, that will be able to bridge the communication gap between community pharmacists and DHH patients., Methods: A community-based participatory research method was utilized. Two focus group discussions (FGDs) were conducted in Malaysian sign language (BIM) with a total of 10 DHH individuals. Respondents were recruited using purposive sampling. Video-recordings were transcribed and analyzed using a thematic approach., Results: Two themes emerged: (I) challenges and scepticism of the healthcare system; and (II) features of the mHealth app. Respondents expressed fears and concerns about accessing healthcare services, and stressed on the need for sign language interpreters. There were also concerns about data privacy and security. With regard to app features, the majority preferred videos instead of text to convey information about their disease and medication, due to their lower literacy levels., Conclusions: For an mHealth app to be effective, app designers must ensure the app is individualised according to the cultural and linguistic diversity of the target audience. Pharmacists should also educate patients on the potential benefits of the app in terms of assisting patients with their medicine-taking., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/mhealth.2020.01.04). Dr. SAJ has a patent DITE (TM2018019083) issued. Dr. UDP has a patent DITE (TM2018019083) issued. The other authors have no conflicts of interest to declare., (2021 mHealth. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research and antiviral discovery are hampered by the lack of a cell-based virus replication system that can be readily adopted without biosafety level 3 (BSL-3) restrictions. Here, the construction of a noninfectious SARS-CoV-2 reporter replicon and its application in deciphering viral replication mechanisms and evaluating SARS-CoV-2 inhibitors are presented. The replicon genome is replication competent but does not produce progeny virions. Its replication can be inhibited by RdRp mutations or by known SARS-CoV-2 antiviral compounds. Using this system, a high-throughput antiviral assay has also been developed. Significant differences in potencies of several SARS-CoV-2 inhibitors in different cell lines were observed, which highlight the challenges of discovering antivirals capable of inhibiting viral replication in vivo and the importance of testing compounds in multiple cell culture models. The generation of a SARS-CoV-2 replicon provides a powerful platform to expand the global research effort to combat COVID-19., Competing Interests: Competing interest statement: All authors are employees of Merck and Company, Inc. A provisional patent application on the discoveries of this work has been filed., (Copyright © 2021 the Author(s). Published by PNAS.)

Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Nasopharyngeal carcinoma (NPC) is originated from the epithelial cells of nasopharynx, Epstein-Barr virus (EBV)-associated and has the highest incidence and mortality rates in Southeast Asia. Late presentation is a common issue and early detection could be the key to reduce the disease burden. Sensitivity of plasma EBV DNA, an established NPC biomarker, for Stage I NPC is controversial. Most newly reported NPC biomarkers have neither been externally validated nor compared to the established ones. This causes difficulty in planning for cost-effective early detection strategies. Our study systematically evaluated six established and four new biomarkers in NPC cases, population controls and hospital controls. We showed that BamHI-W 76 bp remains the most sensitive plasma biomarker, with 96.7% (29/30), 96.7% (58/60) and 97.4% (226/232) sensitivity to detect Stage I, early stage and all NPC, respectively. Its specificity was 94.2% (113/120) against population controls and 90.4% (113/125) against hospital controls. Diagnostic accuracy of BamHI-W 121 bp and ebv-miR-BART7-3p were validated. Hsa-miR-29a-3p and hsa-miR-103a-3p were not, possibly due to lower number of advanced stage NPC cases included in this subset. Decision tree modeling suggested that combination of BamHI-W 76 bp and VCA IgA or EA IgG may increase the specificity or sensitivity to detect NPC. EBNA1 99 bp could identify NPC patients with poor prognosis in early and advanced stage NPC. Our findings provided evidence for improvement in NPC screening strategies, covering considerations of opportunistic screening, combining biomarkers to increase sensitivity or specificity and testing biomarkers from single sampled specimen to avoid logistic problems of resampling., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Streptococcus pneumoniae ( S. pneumoniae ) is one of the main causative agents of pneumococcal diseases. To date, more than 90 distinct serotypes have been identified. Implementation of vaccines has caused a drastic reduction in vaccine-serotype pneumococcal diseases but increase in cases due to non-vaccine serotype has been observed in Malaysia. However, further investigation on different serotype incidence in Malaysia is needed and the rate of pneumococcal vaccination for new-born babies in Malaysia remains low. The recent emergence of drug-resistant S. pneumoniae (DRSP) has also been a global concern, especially penicillin resistance. This study determined the serotypes of S. pneumoniae strains ( n = 95) isolated from nasopharyngeal specimens from children admitted to UMMC from 2013 to 2015. In accordance with previous studies, PCR result showed 40% of NT isolates were successfully typed as 3 less common serotypes, namely 9N/L, 17A, and 23B. The repetitive-element PCR (REP-PCR) result revealed genetic variations among the strains whereby five major clusters were observed at the similarity of 80% by clustering analysis based on fingerprint data. Penicillin-binding proteins ( pbp s) of selected isolates were studied by PCR and sequencing. Three strains with ≤19-mm diameter zone for Oxacillin Disc Diffusion (ODD) test previously were recorded to have mutation on all pbp1a, pbp2b, and pbp2x with MIC of 4 µg/ml, which were penicillin-intermediate resistance according to the CLSI breakpoints.

Background: Exercise is an effective treatment for osteoarthritis. However, the effect may vary from one patient (or study) to another., Objective: To evaluate the efficacy of exercise and its potential determinants for pain, function, performance, and quality of life (QoL) in knee and hip osteoarthritis (OA)., Methods: We searched 9 electronic databases (AMED, CENTRAL, CINAHL, EMBASE, MEDLINE Ovid, PEDro, PubMed, SPORTDiscus and Google Scholar) for reports of randomised controlled trials (RCTs) comparing exercise-only interventions with usual care. The search was performed from inception up to December 2017 with no language restriction. The effect size (ES), with its 95% confidence interval (CI), was calculated on the basis of between-group standardised mean differences. The primary endpoint was at or nearest to 8 weeks. Other outcome time points were grouped into intervals, from<1 month to≥18 months, for time-dependent effects analysis. Potential determinants were explored by subgroup analyses. Level of significance was set at P≤0.10., Results: Data from 77 RCTs (6472 participants) confirmed statistically significant exercise benefits for pain (ES 0.56, 95% CI 0.44-0.68), function (0.50, 0.38-0.63), performance (0.46, 0.35-0.57), and QoL (0.21, 0.11-0.31) at or nearest to 8 weeks. Across all outcomes, the effects appeared to peak around 2 months and then gradually decreased and became no better than usual care after 9 months. Better pain relief was reported by trials investigating participants who were younger (mean age<60 years), had knee OA, and were not awaiting joint replacement surgery., Conclusions: Exercise significantly reduces pain and improves function, performance and QoL in people with knee and hip OA as compared with usual care at 8 weeks. The effects are maximal around 2 months and thereafter slowly diminish, being no better than usual care at 9 to 18 months. Participants with younger age, knee OA and not awaiting joint replacement may benefit more from exercise therapy. These potential determinants, identified by study-level analyses, may have implied ecological bias and need to be confirmed with individual patient data., (Crown Copyright © 2019. Published by Elsevier Masson SAS. All rights reserved.)