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We analyze the progression of COVID-19 in the United States over a nearly one-year period beginning March 1, 2020 with a novel metric motivated by queueing models, tracking partial-average day-of-event and cumulative probability distributions for events, where events are points in time when new cases and new deaths are reported. The partial average represents the average day of all events preceding a point of time, and is an indicator as to whether the pandemic is accelerating or decelerating in the context of the entire history of the pandemic. The measure supplements traditional metrics, and also enables direct comparisons of case and death histories on a common scale. We also compare methods for estimating actual infections and deaths to assess the timing and dynamics of the pandemic by location. Three example states are graphically compared as functions of date, as well as Hong Kong as an example that experienced a pronounced recent wave of the pandemic. In addition, statistics are compared for all 50 states. Over the period studied, average case day and average death day varied by two to five months among the 50 states, depending on data source, with the earliest averages in New York and surrounding states, as well as Louisiana.

ELT-2 is the major transcription factor required for Caenorhabditis elegans intestinal development. ELT-2 expression initiates in embryos to promote development and then persists after hatching through the larval and adult stages. Though the sites of ELT-2 binding are characterized and the transcriptional changes that result from ELT-2 depletion are known, an intestine-specific transcriptome profile spanning developmental time has been missing. We generated this dataset by performing Fluorescence Activated Cell Sorting (FACS) on intestine cells at distinct developmental stages. We analyzed this dataset in conjunction with previously conducted ELT-2 studies to evaluate the role of ELT-2 in directing the intestinal gene regulatory network through development. We found that only 33% of intestine-enriched genes in the embryo were direct targets of ELT-2 but that number increased to 75% by the L3 stage. This suggests additional transcription factors promote intestinal transcription especially in the embryo. Furthermore, only half of ELT-2’s direct target genes were dependent on ELT-2 for their proper expression levels, and an equal proportion of those responded to elt-2 depletion with over-expression as with under-expression. That is, ELT-2 can either activate or repress direct target genes. Additionally, we observed that ELT-2 repressed its own promoter, implicating new models for its autoregulation. Together, our results illustrate that ELT-2 impacts roughly 20–50% of intestine-specific genes, that ELT-2 both positively and negatively controls its direct targets, and that the current model of the intestinal regulatory network is incomplete as the factors responsible for directing the expression of many intestinal genes remain unknown.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

Subjective perception of time is altered during vigorous exercise. This could be due in part to the fatigue associated with physical activity at high intensities. The aim of this study was to determine the effect of fatigue, specifically, on subjective time perception. Twenty-six healthy, untrained subjects (17 men/9 women; age = 26.0 ± 4.3 years; V̇O2peak = 38.13 ± 5.62 mL/kg/min) completed a maximal aerobic exercise test on a cycle ergometer. Time perception was assessed before (PRE) and after (POST) the exercise test using a time production task. Relative error of the timing task was significantly higher for POST (0.112 ± 0.260) than for PRE (0.028 ± 0.173), p = .032, η2 = .178. Subjects produced ~ 8.4% more time than the target intervals when fatigued, which is indicative of a slower sense of time perception. A shift in attentional focus from timing to the sensations associated with fatigue is a possible factor to explain this result. Future studies which investigate the effects of exercise on time perception should consider the impact of fatigue experienced during exercise.

We analyze the effect of the assimilation of surface velocities from two HF-Radars (HFR) and satellite SST in an ocean circulation model covering the northwestern Mediterranean Sea.One HFR observes the area in front of Toulon (France), the other covers the area adjacent to the coast near La Spezia (Italy).The ROMS 4D-Var DA package is used to analyze a three-month period, from September to November 2020.The DA is implemented to have a sequence of 3-day assimilation windows, each followed by a 3-day forecast cycle in which the model evolves without adjustments.Boundary conditions are from the CMEMS Analysis-Forecast product and atmospheric forcing from ECMWF high resolution model (1/10 degree).The impact of the DA is quantified by comparing the analysis and forecast runs with a freerun that is unaffected by any assimilation procedure.The results show that both the analysis and the forecast perform better than the freerun considering the HFR and SST observations used in the assimilation procedure.Moreover, eulerian velocities derived from surface drifters are used as an independent dataset to further validate the quality of the DA output.Within the area covered by the HFRs, both the analysis and forecast surface velocities show greater agreement with the drifter data than the surface velocities from the freerun.However, in the rest of the domain, surface circulation improvements and deteriorations tend to balance out, and mean squared error and correlation values are comparable for analysis, forecast, and freerun.We also analyzed the impact of the observation typology and of the control vector on coastal transport for the upper 50 m at three transects.Two of them are located at the HFR areas and the other in between.Both HFR and SST data have a significant effect on surface transport increment.The HFR observations contribute to the change in the transport magnitude while the SST tends to change the velocity distribution along the transect, leaving the transport magnitude unchanged.Coastal transport is, in general, mostly affected by corrections to initial conditions in all three transects. The changes to the boundary conditions and atmospheric forcings have different importance depending on the transects analysed.

Evidence-based medicine is replete with studies assessing quality and bias, but few evaluating research integrity or trustworthiness. A recent Cochrane review of psychological interventions for chronic pain identified trials with a shared lead author with highly divergent results. We sought to systematically identify all similar trials from this author to explore their risk of bias, governance procedures, and trustworthiness. We searched OVID MEDLINE, EMBASE, CENTRAL, and PEDro from 2010 to December 22, 2021 for trials. We contacted the authors requesting details of trial registration, ethical approval, protocol, and access to the trial data for verification. We used the Cochrane risk-of-bias tool and the Cochrane Pregnancy and Childbirth group's Trustworthiness Screening Tool to guide systematic exploration of trustworthiness. Ten trials were included: 9 compared cognitive behavioural therapy and physical exercise to usual care, exercise alone, or physiotherapy and 1 compared 2 brief cognitive behavioural therapy programmes. Eight trials reported results divergent from the evidence base. Assessment of risk of bias and participant characteristics identified no substantial concerns. Responses from the lead author did not satisfactorily explain this divergence. Trustworthiness screening identified concerns about research governance, data plausibility at baseline, the results, and apparent data duplication. We discuss the findings within the context of methods for establishing the trustworthiness of research findings generally. Important concerns regarding the trustworthiness of these trials reduce our confidence in them. They should probably not be used to inform the results and conclusions of systematic reviews, in clinical training, policy documents, or any relevant instruction regarding adult chronic pain management.

The low quality of included trials, insufficient rigour in review methodology, ignorance of key pain issues, small size, and over-optimistic judgements about the direction and magnitude of treatment effects all devalue systematic reviews, supposedly the 'gold standard' of evidence. Available evidence indicates that almost all systematic reviews in the published literature contain fatal flaws likely to make their conclusions incorrect and misleading. Only 3 in every 100 systematic reviews are deemed to have adequate methods and be clinically useful. Examples of research waste and questionable ethical standards abound: most trials have little hope of providing useful results, and systematic review of hopeless trials inspires no confidence. We argue that results of most systematic reviews should be dismissed. Forensically critical systematic reviews are essential tools to improve the quality of trials and should be encouraged and protected.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

An activity-guided fractionation approach applied to thermally treated, enzymatically hydrolyzed mushroom, Agaricus bisporus L., protein led to the identification of several saltiness- and kokumi-enhancing peptides. The identification was accomplished by employing a combination of solid-phase extraction (SPE), gel-permeation chromatography (GPC), and semipreparative reverse-phase high-performance liquid chromatography (RP-HPLC), coupled with sensory analysis. As a result, this study led to the identification of a collection of common mushroom derived tastants, including 5'-mononucleotides and free amino acids, along with several taste-modulating pyroglutamyl dipeptides, including pyroglutamylcysteine (pGlu-Cys), pyroglutamylvaline (pGlu-Val), pyroglutamylaspartic acid (pGlu-Asp), pyroglutamylglutamic acid (pGlu-Glu), and pyroglutamylproline (pGlu-Pro). The taste-modulating thresholds for the pyroglutamyl dipeptides were calculated in a model mushroom broth containing natural concentrations of guanosine 5'-monophosphate and 14 amino acids, all with dose-over-threshold (DoT) factors ≥1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to quantitate the pyroglutamyl dipeptides, and their concentrations ranged from 2 to 58 μmol/L; however, they were determined to be present in the hydrolysate below their individual taste-modulating thresholds. Despite being present below their individual thresholds, when the dipeptides were collectively added to a model mushroom broth at their natural concentrations (143 μmol/L combined), both salty (p = 0.0061) and kokumi (p = 0.0025) taste attributes were significantly enhanced, demonstrating a synergistic subthreshold taste-modulating effect. This study lays the groundwork for future investigations on the saltiness-enhancing potential of mixtures of subthreshold levels of pyroglutamyl dipeptides found in mushrooms and other sources.

BACKGROUND Osteoarthritis (OA) is a leading cause of pain and disability worldwide. Knee OA accounts for nearly four fifths of the burden of OA internationally, and 10% of United Kingdom adults have the condition. Recommended treatments for osteoarthritis include information, education, exercise, physiotherapy, weight-loss, medication, and surgery. There are concerns that knee replacement surgery is overused, while non-surgical treatments are underutilized. Shared Decision-Making (SDM) has been proposed to support patients to make more informed choices about their care, whilst reducing inequities in access to treatment. We evaluated the experience of a team adapting a SDM tool for knee OA from one health service to another, and the implementation potential of the tool in the Bristol North Somerset and South Gloucestershire (BNSSG) area. The tool aims to prepare patients’ and clinicians for SDM, by providing evidence-based information about treatment options. OBJECTIVE To explore the experiences of a team adapting a SDM tool from one health context to another, and the implementation potential of the tool in the BNSSG area. METHODS An agile methodology was used to respond to recruitment challenges and to ensure study aims could be addressed within time restrictions. An online survey was disseminated to clinicians to gain feedback on experiences of using the SDM tool. Qualitative interviews were conducted by phone or videocall with a purposive sample of stakeholders involved in adapting and implementing the tool in the BNSSG area. Survey findings were summarised as frequencies and percentages. Content analysis was conducted on qualitative data using framework analysis, and data mapped directly to the 14 domains of the Theoretical Domains Framework. RESULTS This study highlights barriers and facilitators to adapting tools from one health context to another and implementing them in the new health context. We recommend tools selected for adaptation should have a has a strong evidence base, and evidence of effectiveness and acceptability to the target users in the original context. Legal advice should be sought and agreements draw up among collaborators at the beginning of the project. Existing guidance for the development and adaptation of interventions should be utilised. Co-design methods should be applied to improve the accessibility and acceptability of the adapted tool. CONCLUSIONS This study highlights barriers and facilitators to adapting a tools from one health context to another, and implementing them in the new health context. Consequently, we have several recommendations for teams undertaking similar work. Candidate tools selected for adaptation should have a has a strong evidence base, and evidence of effectiveness and acceptability to the target users in the original context. Legal advice should be sought at the beginning of the project, and agreements draw up among collaborators, to ensure all parties are clear on expectations. Existing guidance for the development and adaptation of interventions should be utilised. Co-design methods can be used to improve the accessibility and acceptability of the adapted tool. CLINICALTRIAL Not applicable

Mechanical ventilation (MV) is a life-saving treatment for individuals suffering from respiratory insufficiency. Nonetheless, MV is linked to a slew of problems and an increased risk of death. The goal of this research is to determine how MV affects gene expression in direct and periphery human tissues. For performance evaluation and feature analysis, classification algorithms were used to Genotype-Tissue Expression Project gene expression datasets from six representative tissues: liver, adipose, skin, nerve-tibial, muscle, and lung. To identify ventilation and non-ventilation data and evaluate prediction performance for the six tissues, we used 18 prediction models based on the Random Forest (RF), decision tree, and ANN (Artificial Neural Network) approaches. The AUC, accuracy, precision, recall, and F1-measure have been utilized in the model comparison to assess each model's prediction ability. Then, for each tissue, we performed feature analysis to identify MV marker genes, proceeded by pathway enrichment assessment for these genes. XGBoost outperformed the other approaches and predicted samples that had experienced MV with an average accuracy of 0.951 and an average AUC of 0.945 for the six tissues. The feature analysis identified a number of MV marker genes, some of which were shared by many tissues. The majority of MV marker genes were associated with inflammation and fibrosis, as well as cell growth and movement control. Inflammatory as well as viral pathways were considerably enriched in MV marker genes. When compared to the other models, the XGBoost technique displayed significantly improved performance and feature analysis. XGBoost was useful in discovering tissue-specific marker genes for detecting MV-related transcriptome alterations. Our findings indicate that MV is related with decreased tissue growth and motility, as well as increased inflammation and damage, not just in direct tissues like the lungs, but also in peripheral tissues, and that it should be carefully evaluated before being applied.

Comprised of only 20 cells, the Caenorhabditis elegans intestine is the nexus of many life-supporting functions, including digestion, metabolism, aging, immunity, and environmental response. Critical interactions between the C. elegans host and its environment converge within the intestine, where gut microbiota concentrate. Therefore, the ability to isolate intestine tissue away from the rest of the worm is necessary to assess intestine-specific processes. This protocol describes a method for hand dissecting adult C. elegans intestines. The procedure can be performed in fluorescently labeled strains for ease or training purposes. Once the technique is perfected, intestines can be collected from unlabeled worms of any genotype. This microdissection approach allows for the simultaneous capture of host intestinal tissue and gut microbiota, a benefit to many microbiome studies. As such, downstream applications for the intestinal preparations generated by this protocol can include but are not limited to RNA isolation from intestinal cells and DNA isolation from captured microbiota. Overall, hand dissection of C. elegans intestines affords a simple and robust method to investigate critical aspects of intestine biology.

Introduction Fellowship directors (FD) in sports medicine are distinguished leaders and mentors of trainees. There is little literature available regarding their demographics and unique factors and training that have allowed them to rise to their prominent positions. The goal of this study was to identify FDs' demographics, research output, and education with an emphasis on surveying the diversity in these leadership positions. Methods The Accreditation Council for Graduate Medical Education Public Accreditation Data System was used to identify all accredited and active orthopaedic sports medicine fellowship positions for 2019 to 2020. Primary data points for the FDs included race/ethnicity, age, sex, residency and fellowship training institutions, year of fellowship completion, year of hire at the current institution, year of FD appointment, and H-index. Student t-tests were used to compare FDs who trained at their current institution versus those who did not. Significance was set at P Results The 87 active sports medicine fellowship programs surveyed were led by 86 FDs and 2 co-FDs. One (1.1%) FD was female, whereas 87 (98.9%) were male. The mean age of the 88 total FDs was 54.5 years (n = 81). FDs were predominantly White (n = 75, 85.2%), followed by Asian American (n = 6, 6.8%), African American (n = 3, 3.4%), Middle Eastern (n = 3, 3.4%), and then Hispanic/Latino (n = 1, 1.1%). Certain associations were observed between FDs' residency and fellowship and future leadership positions. The most frequently reported training locations were Hospital for Special Surgery (residency, N = 10) and the Steadman Clinic (Vail) (fellowship, N = 10). The mean H-index was 22.33 ± 16.88, and FDs leading the fellowship where they trained had significantly lower mean H-indices than FDs who were not (12.57 ± 12.57 versus 24.85 ± 17.56, respectively) (P = 0.02). Conclusion More diversity is possible among sports medicine FDs, who are prominent leaders. Moreover, certain programs are associated with producing a greater number of FDs.

The randomised controlled trial is the foundation of clinical research; yet there is concern that many trials have flaws in design, conduct, and reporting that undermine trustworthiness. Common flaws in trials include high risk of bias, small size, outcomes irrelevant to clinical care and patient's experience, and inability to detect efficacy even if present. These flaws carry forward into systematic reviews, which can confer the label of 'high-quality evidence' on inadequate data. Trials can be futile because their flaws mean that they cannot deliver any meaningful result in that different results in a small number of patients would be sufficient to change conclusions. Some trials have been discovered to be fabricated, the number of which is growing. The fields of anaesthesia and pain have more fabricated trials than other clinical fields, possibly because of increased vigilance. This narrative review examines these themes in depth whilst acknowledging an inescapable conclusion: that much of our clinical evidence is in trouble, and special measures are needed to bolster quality and confidence.

Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to target previously undruggable targets. However, it has been more challenging to identify orally bioavailable TPD molecules due to the physicochemical properties of the large molecules and narrow structure-activity relationship (SAR) compared to conventional small molecule inhibitors. In the present study, we identified orally active TPD molecules that selectively and potently degrade SMARCA2 protein and induce synthetic lethality in SMARCA4-deficient cancer cells. SMARCA2 (BRM) and SMARCA4 (BRG1) are the two mutually exclusive catalytic core subunits of SWI/SNF complexes that play an important role in controlling gene expression by remodeling chromatin. The complexes are mutated in more than 20% of human cancers and subsets of solid tumors lose expression of SMARCA4 protein due to damaging mutations or gene deletion. The SMARCA4-deficient cancer cells are highly dependent on the paralog gene SMARCA2 for their survival and thus SMARCA2 has been suggested as an attractive therapeutic target for patients with SMARCA4-deficient cancers. We have recently identified SMARCA2 selective degraders that demonstrate oral bioavailability in mice with favorable pharmacokinetic properties, and acceptable DMPK and safety profiles in rodent studies. These SMARCA2 degraders show 50 to 300-fold DC50 selectivity for SMARCA2 over SMARCA4 in our cellular assays. When pre-treated with a proteasome inhibitor or neddylation inhibitor, the degradation of SMARCA2 was rescued, confirming that the degradation is mediated by the ubiquitin-proteasome-dependent pathway. These TPD molecules inhibit only SMARCA4-deficient cancer cell proliferation (NCI-H838, NCI-H1693, HT1080 SMARCA4 KO) with IC50 values ranging from 3-10 nM, but not SMARCA4 WT cells (Calu-6, NCI-H520, HT1080 WT). Oral administration of our SMARCA2 degraders resulted in significant tumor growth inhibition of SMARCA4-deficient lung cancer xenografts at well tolerated doses. The treated tumor tissues show robust SMARCA2 protein reduction for more than 72h post dosing, consistent with the SMARCA2 degradation kinetics-based pharmacodynamic prediction model. In summary, our orally bioavailable SMARCA2 degraders induce synthetic lethality in SMARCA4-deficient cancers in vitro and in vivo. Efforts to further evaluate these compounds in additional models and in combination with other agents are ongoing. Citation Format: Koichi Ito, Artem Shvartsbart, Joseph Rager, Anjana Agarwal, Michael Hulse, Komali Vykuntam, Min Wang, Justin Kurian, Miles Cowart, Joy Cote, Monisha Sivakumar, Jack Carter, Jessica Burtell, Alex Grego, Andrew Moore, Neha Bhagwat, Stefan Ruepp, Tom Emme, Liang Lu, Philip Pitis, Corey Basch, Klare Bersch, Song Mei, Raul Leal, John Rose, Danielle Roth, Ganfeng Cao, Kris Vaddi, Sandy Geeganage, Bruce Ruggeri, Andrew Combs, Peggy Scherle. Selective and orally bioavailable SMARCA2 targeted degraders induce synthetic lethality in SMARCA4- deficient solid tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6277.

The SWI/SNF complex plays an important role in controlling gene expression via chromatin remodeling. One of its catalytic subunits, SMARCA4, is frequently mutated in multiple tumor types, and SMARCA4-deficient cells are highly dependent on the other catalytic subunit, SMARCA2, for survival. Therefore, targeting SMARCA2 with selective protein degraders has therapeutic potential in SMARCA4 deficient human cancers. We have previously described the development of a potent and selective SMARCA2 targeted degrader, PRT3789, that demonstrates robust degradation of SMARCA2 protein and excellent preclinical efficacy in SMARCA4-del models (Hulse, et al. 2022). PRT3789 will be evaluated in a Phase 1 clinical trial in patients with SMARCA4-mutant cancer. In order to assess target engagement following clinical administration of PRT3789, we developed two pharmacodynamic (PD) assays to measure SMARCA2 protein degradation and changes in SMARCA2 target gene expression in human peripheral mononuclear cells (PBMCs). We used the MSD® S-PLEX platform for the development of a sensitive and quantitative, plate-based immunoassay for determining the protein concentration of SMARCA2 in human PBMC lysates. This assay exhibits a wide dynamic range of detection for SMARCA2 with an LLOD at 1.5 pg/mL, as well as exhibiting acceptable spike recovery and minimal cross-reactivity to SMARCA4. In addition, we optimized the PBMC isolation protocol and lysis conditions to enable sensitive detection of SMARCA2 protein. In order to demonstrate downstream gene expression changes as a consequence of SMARCA2 protein degradation, we developed a secondary qPCR assay. PBMCs from healthy human donors were treated ex vivo with PRT3789 for 24 - 48 hours, followed by RNA-sequencing to identify differentially expressed genes. We refined an 8-gene panel that showed robust expression in PBMCs, as well as consistent and dose-dependent changes in response to PRT3789 treatment. We further calculated a differential gene expression (DGE) score based on expression of this gene panel that correlates with SMARCA2 protein degradation. In summary, we describe the development and characterization of two independent clinically relevant PD assays that can be used to evaluate target engagement in blood samples following PRT3789 administration. Citation Format: Andrew Moore, Carly Bachner, Lalitha Srinivasan, Pradeep Kurup, Alex Grego, Caroline Vitkovitsky, Koichi Ito, Neha Bhagwat, Peggy Scherle. Development of pharmacodynamic assays for quantifying SMARCA2 protein degradation and target gene expression in response to a SMARCA2 degrader (PRT3789) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2792.

BackgroundChronic postsurgical pain can severely impair patient health and quality of life. This systematic review update evaluated the effectiveness of systemic drugs to prevent chronic postsurgical pain.MethodsThe authors included double-blind, placebo-controlled, randomized controlled trials including adults that evaluated perioperative systemic drugs. Studies that evaluated same drug(s) administered similarly were pooled. The primary outcome was the proportion reporting any pain at 3 or more months postsurgery.ResultsThe authors identified 70 new studies and 40 from 2013. Most evaluated ketamine, pregabalin, gabapentin, IV lidocaine, nonsteroidal anti-inflammatory drugs, and corticosteroids. Some meta-analyses showed statistically significant—but of unclear clinical relevance—reductions in chronic postsurgical pain prevalence after treatment with pregabalin, IV lidocaine, and nonsteroidal anti-inflammatory drugs. Meta-analyses with more than three studies and more than 500 participants showed no effect of ketamine on prevalence of any pain at 6 months when administered for 24 h or less (risk ratio, 0.62 [95% CI, 0.36 to 1.07]; prevalence, 0 to 88% ketamine; 0 to 94% placebo) or more than 24 h (risk ratio, 0.91 [95% CI, 0.74 to 1.12]; 6 to 71% ketamine; 5 to 78% placebo), no effect of pregabalin on prevalence of any pain at 3 months (risk ratio, 0.88 [95% CI, 0.70 to 1.10]; 4 to 88% pregabalin; 3 to 80% placebo) or 6 months (risk ratio, 0.78 [95% CI, 0.47 to 1.28]; 6 to 68% pregabalin; 4 to 69% placebo) when administered more than 24 h, and an effect of pregabalin on prevalence of moderate/severe pain at 3 months when administered more than 24 h (risk ratio, 0.47 [95% CI, 0.33 to 0.68]; 0 to 20% pregabalin; 4 to 34% placebo). However, the results should be interpreted with caution given small study sizes, variable surgical types, dosages, timing and method of outcome measurements in relation to the acute pain trajectory in question, and preoperative pain status.ConclusionsDespite agreement that chronic postsurgical pain is an important topic, extremely little progress has been made since 2013, likely due to study designs being insufficient to address the complexities of this multifactorial problem.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects (benefits and harms) of different interventions aimed at controlling pain associated with panretinal photocoagulation, in people with severe non‐proliferative diabetic retinopathy and proliferative diabetic retinopathy, according to the classification of ETDRS 1991.

Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy - as second- or third-line treatment - in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.

Background Approximately 20% of people experience chronic postsurgical pain after total knee replacement. The STAR randomised controlled trial (ISCRTN92545361) evaluated the clinical- and cost-effectiveness of a new multifaceted and personalised care pathway, compared with usual care, for people with pain at three months after total knee replacement. We report trial participants’ experiences of postoperative pain and the acceptability of the STAR care pathway, which consisted of an assessment clinic at three months, and up to six follow-up telephone calls over 12 months. Methods Semi-structured interviews were conducted with 27 people (10 men, 17 women) between February 2018 and January 2020. Participants were sampled purposively from the care pathway intervention group and interviewed after completion of the final postoperative trial questionnaire at approximately 15 months after knee replacement. Interviews were audio-recorded, transcribed, anonymised and analysed using inductive thematic analysis. Findings Many participants were unprepared for the severity and impact of postoperative pain, which they described as extreme and constant and that tested their physical and mental endurance. Participants identified ‘low points’ during their recovery, triggered by stiffening, pain or swelling that caused feelings of anxiety, depression, and pain catastrophising. Participants described the STAR assessment clinic as something that seemed “perfectly normal” suggesting it was seamlessly integrated into NHS care. Even in the context of some ongoing pain, the STAR care pathway had provided a source of support and an opportunity to discuss concerns about their ongoing recovery. Conclusions People who have knee replacement may be unprepared for the severity and impact of postoperative pain, and the hard work of recovery afterwards. This highlights the challenges of preparing patients for total knee replacement and suggests that clinical attention is needed if exercise and mobilising is painful beyond the three month postoperative period. The STAR care pathway is acceptable to people with pain after total knee replacement.

Microblogging platform Twitter allows researchers to showcase their work, receive constructive feedback, find jobs, and build scientific collaborations. While existing literature has analyzed the benefits of Twitter in the development and distribution of scientific knowledge, most of the studies only took into account a limited number of researchers, which affected the generalizability of derived results. Our study analyzed the activity of 6,000 biomedical scientists on Twitter using data-driven approaches, a third of whom were female. Furthermore, we estimated that up to a quarter of the members of the scientific community are engaged on Twitter. While the number of male scientists joining the microblogging platform every year has decreased, the number of female scientists has remained roughly the same. Scientists are very selective in who they are following as compared to the general public. We also found that the type of tweets and retweets one posts may affect the number of followers, specifically, that a moderate to high level of professionalism and a high level of positivity is correlated with followers count. Moreover, female scientists send fewer negative tweets as compared to male scientists (31.1% for females and 34.7% for males). Our analysis could provide insights and launch a conversation on the advantages and limitations of using Twitter for disseminating scientific information and engaging in constructive discussion and collaborations within the scientific community.

Truncal acne is common, and the psychosocial burden may be underestimated as patients most often complain of facial acne. The Acne Symptom and Impact Scale (ASIS) is a 17-item patient-reported outcome (PRO) measure designed to assess the signs and impacts of acne vulgaris. ASIS has previously been validated in a prospective, non-interventional study as a reliable PRO instrument for facial acne. In a pilot study, ASIS, and an additional 10 new questions that focused on the concerns of patients (ASIS-C), were given to 10 patients with moderate-to-severe truncal acne vulgaris who received 3 months of monotherapy with oral sarecycline, a narrow-spectrum tetracycline-class antibiotic. ASIS-C questionnaires were also given to 10 acne-free control subjects. Average ASIS-C answers decreased by 4% for Signs, 15% for Impact, and 16% for Concerns in the 10 patients, with greater decreases of 5% for Signs, 20% for Impact, and 19% for Concerns in the 60% of patients whose truncal acne was clear or almost clear after 12 weeks of sarecycline treatment. In this study, sarecycline was effective in reducing the psychosocial burden associated with truncal acne based on the ASIS-C PRO measures.

Sarecycline is a novel, narrow-spectrum, third generation tetracycline class antibiotic approved by the Food and Drug Administration (FDA) for the treatment of moderate-to-severe acne in patients ages nine and older. Recently, focus has increased on whether treatment responses differ in acne in skin of color. Here, we aimed to analyze the efficacy of using sarecycline in Hispanics. We report pooled post hoc analysis of efficacy data on sarecycline in Hispanics with acne from two phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trials, SC1401 and SC1402. Of 2002 patients in the pooled trials with moderate-to-severe acne, 26.9% were Hispanic. Facial inflammatory lesion counts decreased as early as week 3 by 26% (p = 0.0279), with continued reduction by 41% by week 6 (p = 0.0003), by 51% by week 9 (p < 0.0001), and by 55% by week 12 (p < 0.0001). Acne is the most common skin condition diagnosed in Hispanics, and this study illustrates a statistically significant reduction in acne in Hispanic patients with moderate-to-severe acne treated with oral sarecycline. Therefore, oral sarecycline shows promising results as a safe and effective treatment for acne in Hispanics.

Assess international interventional radiology (IR) training standards and trainee satisfaction to identify challenges and drive positive change. An anonymous survey was created using Survey Monkey and distributed as a single-use web link via eight IR national and international societies around the world. It consisted of two parts: the first assessed the general exposure of radiology trainees to IR and whether this influenced their decision to pursue a career in IR; the second focussed on satisfaction and quality of training by those who are in training or have recently completed an IR training program. There were 496 participants of which 274 were eligible to complete part one of the survey and 222 were eligible to complete the whole survey. UK and Europe contributed 52% of the responses. The USA and Middle East contributed 23%, and the rest of the world 9%. Over half of responders expressed that exposure early in their career was the main inspiration to pursue a career in IR. Overall satisfaction with training was high across all regions; however, satisfaction regarding vascular training varied. The negative impact of competition from other specialities ranged from 9% (USA) to 61% (UK). Great variability was reported regarding the amount of time spent dedicated to IR and IR on call. Despite significant progress in creating structured and comprehensive IR training, there is still room for improvement. Early promotion of IR is essential for on-going high-quality recruitment. Monitoring and standardization of the training environment at a national and international level are necessary to equip IR trainees and to consolidate IR’s speciality status in the medical field.

To evaluate risk factors (treatment-related, comorbidities, and lifestyle) for breast cancer-related lymphedema (BCRL) within the context of a Prospective Surveillance and Early Intervention (PSEI) model of care for subclinical BCRL.The parent randomized clinical trial assigned patients newly diagnosed with breast cancer to PSEI with either bioimpedance spectroscopy (BIS) or tape measurement (TM). Surgical, systemic and radiation treatments, comorbidities, and lifestyle factors were recorded. Detection of subclinical BCRL (change from baseline of either BIS L-Dex ≥6.5 or tape volume ≥ 5% and 10%) triggered an intervention with compression therapy. Volume change from baseline ≥10% indicated progression to chronic lymphedema and need for complex decongestive physiotherapy. In this secondary analysis, multinomial logistic regressions including main and interaction effects of the study group and risk factors were used to test for factor associations with outcomes (no lymphedema, subclinical lymphedema, progression to chronic lymphedema after intervention, progression to chronic lymphedema without intervention). Post hoc tests of significant interaction effects were conducted using Bonferroni-corrected alphas of .008; otherwise, an alpha of .05 was used for statistical significance.The sample (n = 918; TM = 457; BIS = 461) was female with a median age of 58.4 years. Factors associated with BCRL risk included axillary lymph node dissection (ALND) (p .001), taxane-based chemotherapy (p .001), regional nodal irradiation (RNI) (p ≤ .001), body mass index30 (p = .002), and rurality (p = .037). Mastectomy, age, hypertension, diabetes, seroma, smoking, and air travel were not associated with BCRL risk.Within the context of 3 years of PSEI for subclinical lymphedema, variables of ALND, taxane-based chemotherapy, RNI, body mass index30, and rurality increased risk.

Individuals diagnosed with post-traumatic stress disorder (PTSD) are often in a state of hyperarousal due to overactive sympathetic nervous system activity. This in turn causes resting blood pressure to increase which leads to chronic hypertension. Those diagnosed with PTSD are at an increased risk for developing hypertension and cardiovascular disease. Beta-hydroxybutyrate, a ketone body, has been shown to directly inhibit sympathetic drive at the receptor site. Beta-hydroxybutyrate is both a fuel source and signaling molecule that is produced by the liver from partially broken-down fat. In addition to endogenous sources, beta-hydroxybutyrate can be paired with salt and consumed exogenously. Exogenous ketone salt supplementation has been shown to decrease systolic blood pressure (SBP) in healthy populations. Therefore, the primary purpose of this study was to determine if supplementing with ketone salts for 6-weeks altered SBP or diastolic blood pressure (DBP) in adults diagnosed with PTSD compared to a placebo supplement. This clinical trial included a randomized, double-blinded, parallel-arm and placebo-controlled design. Participants included males and females previously diagnosed with PTSD that were between the ages of 21-65 years. Sixteen participants completed the study; nine consumed ketone salts for six-weeks and seven consumed the placebo supplement. Thirteen subjects were included in the analyses due to incomplete data. Blood pressure was measured in a fasted and rested state immediately before and after the six-week supplementation period. Two 2X2 mixed ANOVAs were used to analyze the SBP and DBP between group and time points. Although the ketone supplementation group experienced an average lowering of SBP (6.14 mmHg) and DBP (4 mmHg) following the supplementation period, no significant interaction was found for SBP, F (1, 11) = 1.18, p = .30, η 2 = .10, or DBP, F (1, 11) = 1.24, p = .29, η 2 = .10. The results demonstrated that 6-weeks of ketone salt supplementation did not significantly alter SBP or DBP in this population. However, the sample size for this study was small and thus, this study should be repeated in a larger sample for verification of this finding.