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Posteriorly augmented glenoid components in anatomic total shoulder arthroplasty (TSA) address posterior glenoid bone loss with inconsistent results. The purpose of this study is to identify pre- and postoperative factors that impact range of motion and function after augmented TSA in patients with B2 or B3 glenoid morphology.A retrospective review was performed of all patients who underwent TSA with a step type augment by a single surgeon between 2009 and 2018. Patients with a Walch type B2 or B3 glenoid were included. Outcomes included forward elevation (FE), external rotation (ER), internal rotation (IR), Single Assessment Numeric Evaluation (SANE), and Visual Analog Scale for pain (VAS). Preoperative imaging was reviewed to assess glenoid retroversion and posterior humeral head subluxation relative to the scapular body and mid-glenoid face. Postoperative measurements included glenoid retroversion, subluxation relative to the scapular body, subluxation relative to the central glenoid peg, and center-peg osteolysis. Measurements were performed by investigators blinded to range of motion and functional outcome scores.Fifty patients (mean age, 68.1 + 8.0) with a mean follow-up of 42.0 months (Range, 24-106 months) were included. Glenoid morphology included 41 B2 and 9 B3 glenoids. One patient had center-peg osteolysis and one patient had glenoid component loosening. The average preoperative FE, ER, and IR was 110°, 21°, and S1, respectively. The average postoperative FE, ER, and IR was 155°, 42°, and L1, respectively. The mean postoperative VAS score was 0.5 + 0.8 and mean SANE score was 94.5 + 5.6. Patients with B3 glenoids were associated with better postoperative internal rotation compared to B2 glenoids (T10 vs L1, p=0.024), with no other differences in range of motion between the glenoid types. Preoperative glenoid retroversion did not significantly impact postoperative range of motion. Postoperative glenoid component retroversion and residual posterior subluxation relative to the scapular body or glenoid face did not correlate with range of motion in any plane. However, posterior subluxation relative to the glenoid face was moderately associated with lower SANE scores (r= -0.448, p=0.006).Patients achieved excellent functional outcomes and pain improvement after TSA with an augmented glenoid component. Postoperative range of motion and function had no clinically important associations with pre- or postoperative glenoid retroversion or humeral head subluxation in our cohort of posteriorly augmented total shoulder arthroplasties except for worse functional scores with increased humeral head subluxation in relation to the glenoid surface.

Background:The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. Methods:In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. Findings:156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30–44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3(IQR 349–828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2–9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. Interpretation:Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital.

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1–4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin–IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.

Lumateperone is indicated for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate (Calabrese et al., 2021). It is currently under evaluation for the treatment of major depressive disorder (www.ClinicalTrials.gov). Lumateperone acts by selectively modulating serotonin, dopamine, and glutamate neurotransmission in the brain. However, other mechanisms could be involved in the actions of lumateperone, and because of the connection between the immune system and psychiatric health, we hypothesized that lumateperone might improve symptoms of depression, at least in part, by normalizing pathologic inflammation. Here, we show that in male and female C57BL/6 mice subjected to an acute immune challenge, lumateperone reduced aberrantly elevated levels of key proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) in both brain and serum; lumateperone also reduced proinflammatory cytokines in male mice under acute behavioral stress. Further, we demonstrate that lumateperone altered key genes/pathways involved in maintaining tissue integrity and supporting blood–brain barrier function, such as claudin-5 and intercellular adhesion molecule 1. In addition, in acutely stressed male Sprague Dawley rats, lumateperone conferred anxiolytic- and antianhedonic-like properties while enhancing activity in the mammalian target of rapamycin complex 1 pathway in the PFC. Together, our preclinical findings indicate that lumateperone, in addition to its ability to modulate multiple neurotransmitter systems, could also act by reducing the impact of acute inflammatory challenges.SIGNIFICANCE STATEMENTLumateperone is indicated in adults to treat schizophrenia and depressive episodes associated with bipolar I or II disorder, as monotherapy and adjunctive therapy with lithium or valproate. Because aberrant immune system activity is associated with increased depressive symptoms, the relationship between lumateperone and immune function was studied. Here, lumateperone reduced the levels of proinflammatory cytokines that were increased following an immune challenge or stress in mice. Additionally, lumateperone altered genes and pathways that maintain blood–brain barrier integrity, restored an index of blood–brain barrier function, reduced anxiety-like behavior in rodents, and enhanced mammalian target of rapamycin complex 1 pathway signaling in the PFC. These results highlight the anti-inflammatory actions of lumateperone and describe how lumateperone may reduce immune pathophysiology, which is associated with depressive symptoms.

The current assessment estimated exposure to four low- and no-calorie sweeteners (LNCS) (aspartame, acesulfame potassium (AceK), steviol glycosides and sucralose) from beverages in Brazil, Canada, Mexico and the United States, using up-to-date nationally representative consumption data and industry reported-use level information. Two modelling scenarios were applied - the probabilistic model was guided by reported use level data, with estimated intake for an individual leveraging market-weighted average use level of a particular LNCS in any given LNCS-sweetened beverage type, while the distributional (brand-loyal) model assumed consumer behaviour-led patterns, namely that an individual will be brand loyal to a pre-determined beverage type. Consumer-only and general population intake estimates were derived for the overall population and individual age categories, and compared to the respective acceptable daily intake (ADI) as established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) for each LNCS. The mean, 90th percentile and 95th percentile intake estimates were substantially lower than the ADI in both modelling scenarios, regardless of the population group or market. In the probabilistic model, the highest consumer-only intake was observed for AceK in Brazilian adolescents (95th percentile, 12.4% of the ADI), while the highest 95th percentile intakes in the distributional model were observed for sucralose in Canadian adults at 20.9% of the ADI. This study provides the latest insights into current intakes of LNCS from water-based non-alcoholic LNCS-sweetened beverages in these regions, aligning well with those published elsewhere.

Septic arthritis is a serious condition with significant morbidity and mortality, routinely diagnosed using culture. The FDA has recently approved the rapid molecular BioFire® Joint Infection Panel (BJIP) for synovial fluid. We aimed to evaluate the BJIP compared to culture and its potential use in patient management. A multicentre retrospective evaluation of BJIP was conducted in the UK and Ireland. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated between the BJIP and routine culture. A multidisciplinary team (MDT) discussion addressing the optimal or potential case use of the assay practice was facilitated. Three hundred ninety-nine surplus synovial fluid samples (~ 70% from native joints) from eight centres were processed using BJIP in addition to routine culture. An increased yield of positive results was detected using BJIP compared to routine culture (98 vs 83), giving an overall PPA of 91.6% and overall NPA of 93% for the BJIP compared to culture results. The BJIP detected resistant markers and additional organisms that could influence antibiotic choices including Neisseria gonorrhoeae and Kingella kingae. The MDT agreed that the assay could be used, in addition to standard methods, in adult and children patients with specialist advice use based on local needs. Rapid results from BJIP were assessed as having potential clinical impact on patient management. Organisms not included in the panel may be clinically significant and may limit the value of this test for PJI.

Thousands of orthopedic surgeons in the United State face medical malpractice claims annually; however, little is known regarding the common causes for litigation against shoulder surgeons. In addition, the current analysis does not take into consideration how surgical frequency affects the litigation likelihood. The purpose of our investigation was to identify the most common causes of litigation against shoulder surgeons in the United States adjusting for surgical frequency.The VerdictSearch database was used using the search terms "medical malpractice," "shoulder," and "NOT cancer." Results were queried, and all studies pertaining to orthopedic shoulder surgery included. Data gathered included cause of lawsuit, indemnity paid, type of surgery performed, results of the cases, verdict or settlement, and, if applicable, technical error. A query of a multisurgeon institutional database was conducted to determine how frequently surgeries were performed. Then the frequency of litigation was adjusted by the procedure frequency to determine which surgery has the greatest likelihood to be litigated relative to rotator cuff surgery.Forty-five cases were included in our study. After adjusting for the procedure frequency, the most likely procedure to be litigated, relative to rotator cuff repair, was manipulation under anesthesia (MUA), 251 times more likely to be litigated, and washout/lavage procedures, 17 times more likely to be litigated. Injection and total shoulder arthroplasty were 23 and 14 times less likely to be litigated relative to rotator cuff repair, respectively. In addition, the average age of the patients was 47 years, and 53% of the cases involved a male plaintiff. The most commonly litigated procedures were rotator cuff repair (42%), MUA (13%), and humeral open reduction and internal fixation (9%). The most commonly cited symptoms for litigation against shoulder surgeons were pain (60%) and loss of range of motion (40%). Of the 45 cases, 44% ended in physician loss, with the average indemnity paid via verdict being $1,118,714 vs. $416,875 for settlement.This study identifies that MUA and lavage/washout procedures are much more likely to be litigated relative to rotator cuff repair. Rotator cuff repair is actually one of the least likely procedures to be litigated. Furthermore, settlement may represent a method of decreasing the indemnity paid for malpractice cases for which surgeons are implicated.

The arterial vasculature can be divided into large conduit arteries, intermediate contractile arteries, resistance arteries, arterioles, and capillaries. Resistance arteries and arterioles primarily function to control systemic blood pressure. The resistance arteries are composed of a layer of endothelial cells oriented parallel to the direction of blood flow, which are separated by a matrix layer termed the internal elastic lamina from several layers of smooth muscle cells oriented perpendicular to the direction of blood flow. Cells within the vessel walls communicate in a homocellular and heterocellular fashion to govern luminal diameter, arterial resistance, and blood pressure. At rest, potassium currents govern the basal state of endothelial and smooth muscle cells. Multiple stimuli can elicit rises in intracellular calcium levels in either endothelial cells or smooth muscle cells, sourced from intracellular stores such as the endoplasmic reticulum or the extracellular space. In general, activation of endothelial cells results in the production of a vasodilatory signal, usually in the form of nitric oxide or endothelial-derived hyperpolarization. Conversely, activation of smooth muscle cells results in a vasoconstriction response through smooth muscle cell contraction. © 2022 American Physiological Society. Compr Physiol 12: 1-35, 2022.

PHOSP-COVID is a national UK multi-centre cohort study of patients who were hospitalised for COVID-19 and subsequently discharged.PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalisation, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments, and to serve as a platform to enable future studies, including clinical trials.Data collected covered a wide range of physical measures, biological samples, and Patient Reported Outcome Measures (PROMs).Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA, or in Tier 2 where they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at five (range 2-7) months and 12 (range 10-14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites.All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research.In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022.Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals.

Microresonator based dual frequency combs offer an integrated photonic solution to a wide range of technological challenges, including spectroscopy, range finding, material characterization and hyperspectral imaging. These applications require a high level of mutual coherence between combs, but achieving such stability can be demanding. Here we experimentally demonstrate that comb generation exploiting the rich structure of the nonlinear electro-optic tensor in lithium niobate can generate ultra-stable dual combs, with the two combs naturally having orthogonal polarizations. We theoretically explore the application of our technique to dual frequency comb generation from the far infrared (IR) to the ultraviolet (UV). Our combs have relative linewidths as low as ~400 μHz, and require no stabilization or post-processing methods.

Medial clavicle fractures pose a concern for mediastinal compromise because of their proximity to the sternoclavicular joint. However, the true incidence of this complication is unknown. The purpose of this study was to evaluate fracture configuration and determine the incidence of mediastinal compromise following medial clavicle fractures. A retrospective analysis of all patients treated for isolated medial one-third clavicle fractures at a single institution was performed. Patient demographics, the mechanism of injury, complications, and treatment were recorded. The fracture pattern and orientation were determined from a review of injury radiographs and computed tomography scans. The incidence of subsequent mediastinal compromise was then identified via a chart review. One hundred five patients were included for analysis. Twenty-two patients (20.8%) had computed tomography scans for review. The average age was 56 years, with 53% of patients being male. Sixty-eight percent of patients reported a high-energy mechanism of injury. No patients demonstrated evidence of mediastinal compression on physical examination. No patients required hospitalization for complications secondary to mediastinal compromise. Ninety percent (n=94) of patients were treated nonoperatively. Forty-three percent of fractures were nondisplaced. The remaining fractures demonstrated anterior or superior displacement of the lateral fragment, with a 0% incidence of posterior displacement. The most common indication for surgery was fracture displacement (n=10). A classification of medial clavicle fractures was developed using data from our cohort and a literature review. Medial clavicle fractures rarely demonstrate posterior displacement. Despite fracture proximity, mediastinal injury is exceedingly uncommon. [ Orthopedics . 2023;46(3):e161–e166.]

BACKGROUND: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. METHODS: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. RESULTS: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50–81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000–1.001]; P =0.037 and 1.263 [95% CI, 1.049–1.520]; P =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001–1.005]; P =0.001 and 1.365 [95% CI, 1.185–1.573]; P P =0.009) and 0.17 (95% CI, 0.06–0.45; P P =0.019) and 0.27 (95% CI, 0.09–0.78, P =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. CONCLUSIONS: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.

Protein translation, one of the most energy-consumptive processes in a eukaryotic cell, requires robust regulation, especially under energy-deprived conditions. A critical component of this regulation is the suppression of translational elongation through reduced ribosome association of the GTPase eukaryotic elongation factor 2 (eEF-2) resulting from its specific phosphorylation by the calmodulin (CaM)-activated α–kinase eEF-2 kinase (eEF-2K). It has been suggested that the eEF-2K response to reduced cellular energy levels is indirect and mediated by the universal energy sensor AMP-activated protein kinase (AMPK) through direct stimulatory phosphorylation and/or downregulation of the eEF-2K-inhibitory nutrient-sensing mTOR pathway. Here, we provide structural, biochemical, and cell-biological evidence of a direct energy-sensing role of eEF-2K through its stimulation by ADP. A crystal structure of the nucleotide-bound complex between CaM and the functional core of eEF-2K phosphorylated at its primary stimulatory site (T348) reveals ADP bound at a unique pocket located on the face opposite that housing the kinase active site. Within this basic pocket (BP), created at the CaM/eEF-2K interface upon complex formation, ADP is stabilized through numerous interactions with both interacting partners. Biochemical analyses using wild-type eEF-2K and specific BP mutants indicate that ADP stabilizes CaM within the active complex, increasing the sensitivity of the kinase to CaM. Induction of energy stress through glycolysis inhibition results in significantly reduced enhancement of phosphorylated eEF-2 levels in cells expressing ADP-binding compromised BP mutants compared to cells expressing wild-type eEF-2K. These results suggest a direct energy-sensing role for eEF-2K through its cooperative interaction with CaM and ADP.

Funding: This study was supported by urgency funding from the U.K.’s Science and Technology Facilities Council (STFC) as part of the project “Curation and Preliminary Examination of the Winchcombe Carbonaceous Chondrite Fall.” Additional work was funded by STFC through grants ST/N000846/1, ST/T002328/1, ST/T506096/1, and ST/W001128/1 (to L.D., M.R.L., and L.J.Ha.); ST/V000675/1 (to K.H.J. and R.H.J.); ST/P005225/1 (to R.T.); ST/S000348/1 (to M.V.G., P.J.W., and M.J.B.); ST/R00143X/1 (to J.B. and L.J.Hi.); ST/S000615/1 (to G.S.C.); ST/V000799/1 (to P.G.); and ST/V000888/1 (to T.E.). A.J.K. and H.C.B. acknowledge funding support from UK Research and Innovation (UKRI) grant MR/T020261/1. P.L.C. acknowledges funding support from UKRI grant MR/S03465X/1. K.H.J. acknowledges funding support from the Royal Society, grant URF\R\201009. L.J.Ha. and M.R.L. acknowledge funding from Natural Environment Research Council (NERC) National Environmental Isotope Facility (NEIF) grant no. 2406.0321. L.D., M.R.L., and L.J.Ha. acknowledge COVID-19 funding support from the University of Glasgow, UK. D.V. was supported in part by NASA cooperative agreement 80NSSC21M0073. P.P. and I.Sy. acknowledge funding from the VEGA agency, project no.1/0421/20. A.J.T.J. acknowledges support from the European Union and the State of Hungary, cofinanced by the European Regional Development Fund in the project of GINOP-2.3.2-15-2016-00009 “ICER.” P.M.S. acknowledges support from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 945298. FRIPON was initiated by funding from ANR (grant N.13-BS05-0009-03), carried out by the Paris Observatory, Muséum National d’Histoire Naturelle, Paris-Saclay University, and Institut Pythéas (LAM-CEREGE). FRIPON data are hosted and processed at Institut Pythéas SIP (Service Informatique Pythéas). The Desert Fireball Network team and Global Fireball Observatory are funded by the Australian Research Council (DP200102073). Direct links between carbonaceous chondrites and their parent bodies in the solar system are rare. The Winchcombe meteorite is the most accurately recorded carbonaceous chondrite fall. Its pre-atmospheric orbit and cosmic-ray exposure age confirm that it arrived on Earth shortly after ejection from a primitive asteroid. Recovered only hours after falling, the composition of the Winchcombe meteorite is largely unmodified by the terrestrial environment. It contains abundant hydrated silicates formed during fluid-rock reactions, and carbon- and nitrogen-bearing organic matter including soluble protein amino acids. The near-pristine hydrogen isotopic composition of the Winchcombe meteorite is comparable to the terrestrial hydrosphere, providing further evidence that volatile-rich carbonaceous asteroids played an important role in the origin of Earth's water. Publisher PDF

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.

Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 × 10-6). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response.

More than 130 million individuals in the United States have now received at least one dose of a COVID-19 vaccine. Currently, all adults in the Unites States now have access to one of three COVID-19 vaccines. As part of the vaccination procedure, Emergency Use Authorization (EUA) fact sheets, which contain information regarding the vaccine, are provided. The purpose of this study was to analyze the ease of reading (i.e., readability) of the EUA-approved fact sheets for the vaccines currently available in the United States, the V-Safe adverse event survey script, and the Centers for Disease Control and Prevention (CDC) website information on COVID-19 vaccines designed for the general public in the United States.We acquired the Pfizer, Moderna, and Janssen EUA fact sheets, as well as the V-Safe survey script and the CDC website information regarding COVID-19 vaccines. These documents were analyzed for their complexity regarding the following readability factors: average length of paragraphs, sentences, and words; font size and style; use of passive voice; the Gunning-Fog index; the Flesch Reading Ease index; and the Flesch-Kincaid Grade Level index.Only the V-Safe adverse-event survey script met readability standards for adequate comprehension. The mean readability scores of the EUA fact sheets and the CDC website were as follows: Flesch Reading Ease score (44.35 avg); Flesch-Kincaid Grade Level (10.48 avg); and Gunning-Fog index (11.8 avg).These scores indicate that at least a 10th-grade level education would be required to understand these reading materials.The average person in the United States would have difficulty understanding the information provided in the EUA fact sheets and CDC COVID-19 vaccine website documents; however, the V-Safe survey was written at an adequate reading level. To ensure that the general public fully understands information regarding COVID-19 vaccines, greater care and effort should be given to the development of simplified information material.

BackgroundThe current standard of care for tetanus prophylaxis management in patients with open wounds likely results in overtreatment and unnecessary costs. Point-of-care immunochromatographic tests, known as Tetanus Quick Sticks (TQS), have been developed to qualitatively measure tetanus immunoglobulin levels. Multiple studies advocate their use in EDs. We aim to evaluate the diagnostic accuracy and cost-effectiveness of TQS to assess their relevance in frontline emergency care.MethodsA systematic review was undertaken following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was conducted in MEDLINE, Embase, Global Health, The Health Management Information Consortium and The Cochrane Library. Studies were eligible if sensitivity, specificity or cost-efficacy of TQS was reported. At least two authors independently assessed and extracted data from each study. A meta-analysis was conducted to evaluate summary sensitivity and specificity estimates for TQS.Results12 studies were suitable for inclusion (n=1 662 865 participants): 1 modelling and 11 prospective observational cohort studies. Eight studies assessed diagnostic accuracy; the summary estimate for sensitivity was 90% (95% CI, 89% to 90%) with specificity 97% (95% CI, 95% to 100%). Six studies investigated cost-efficacy, reporting lower healthcare costs when using TQS instead of the current method of vaccination history, due to a decrease in unnecessary tetanus vaccine and immunoglobulin administration. Based on the current NHS supply chain data, TQS use could save £173.05 per tetanus-prone patient.ConclusionTQS could confer the greatest cost savings if used in combination with vaccination history in patients with tetanus-prone wounds. A quality assurance process is recommended prior to implementation of TQS in EDs.

Scar massage is a widely used treatment modality in hand therapy. This intervention is thoroughly discussed in the literature relating to burns rehabilitation, however, the evidence for its use in treating linear scars following surgery is limited.To collate the empirical literature on scar massage for the treatment of postsurgical cutaneous scars.Scoping review.Medline, EMBASE, CINAHL, AMED, Scopus, ProQuest DissertationsTheses Global, and the Joanna Briggs Institute were searched from inception to December 2020. Two researchers used a data extraction tool to record key demographic, intervention and outcome data, and to apply the Oxford Levels of Evidence for each study.Twenty-five studies met the inclusion criteria, reporting on a combined sample of 1515 participants. Only two papers addressed hand or wrist scars (92 participants). While all studies reported favorable outcomes for scar massage, there were 45 different outcome measures used and a propensity towards non-standardized assessment. Intervention protocols varied from a single session to three treatments daily for 6 months. The results from 13 studies were confounded by the implementation of additional rehabilitation interventions.The overall findings suggest that while there may be benefits to scar massage in reducing pain, increasing movement and improving scar characteristics; there is a lack of consistent research methods, intervention protocols and outcome measures. This scoping review highlights the heterogenous nature of research into scar massage following surgery and supports the need for further research to substantiate its use in the clinical setting.

This study aimed to evaluate distal triceps tendon tear patterns using a systematic classification based on the tendon's layered structure.We retrospectively identified Magnetic resonance imaging (MRI) examinations with triceps tendon tears that underwent reconstructive surgery. Magnetic resonance images were reviewed independently by 2 musculoskeletal radiologists to determine tendon layer involvement and ancillary findings, including tear size, involvement of triceps lateral expansion, and presence of olecranon bursal fluid. Surgical reports were scrutinized for level of anatomic detail and correlation with imaging findings.We identified 69 triceps tendon tears in 68 subjects (61 men, 7 women; mean age, 45 ± 12 years) who underwent surgical reconstruction. On MRI, the superficial layer was always involved with either a partial or full-thickness tear. The most common tear pattern was a combination of superficial layer full-thickness tear with deep layer partial tear (25 of 69 [36%]). Mean tear length was 24 ± 12 mm. We found no cases of isolated deep layer tears. Involvement of triceps lateral expansion and presence of bursal fluid correlated positively with tear severity of superficial and deep layers (P0.001). Detailed surgical correlation was limited, with only 9 of 69 (13%) of surgical reports containing information specifically addressing individual tendon layers.Triceps tendon tears show tear patterns following its layered structure and can be assessed by MRI. Radiologists and surgeons are encouraged to describe tear patterns considering both superficial and deep tendon layers.

Microtubule (MT)–associated protein 7 (MAP7) is a required cofactor for kinesin-1–driven transport of intracellular cargoes. Using cryo–electron microscopy and single–molecule imaging, we investigated how MAP7 binds MTs and facilitates kinesin-1 motility. The MT-binding domain (MTBD) of MAP7 bound MTs as an extended α helix between the protofilament ridge and the site of lateral contact. Unexpectedly, the MTBD partially overlapped with the binding site of kinesin-1 and inhibited its motility. However, by tethering kinesin-1 to the MT, the projection domain of MAP7 prevented dissociation of the motor and facilitated its binding to available neighboring sites. The inhibitory effect of the MTBD dominated as MTs became saturated with MAP7. Our results reveal biphasic regulation of kinesin-1 by MAP7 in the context of their competitive binding to MTs.

We previously showed that treating NOD mice with an agonistic monoclonal anti-TLR4/MD2 antibody (TLR4-Ab) reversed acute type 1 diabetes (T1D). Here, we show that TLR4-Ab reverses T1D by induction of myeloid-derived suppressor cells (MDSCs). Unbiased gene expression analysis after TLR4-Ab treatment demonstrated upregulation of genes associated with CD11b+Ly6G+ myeloid cells and downregulation of T-cell genes. Further RNA sequencing of purified, TLR4-Ab–treated CD11b+ cells showed significant upregulation of genes associated with bone marrow–derived CD11b+ cells and innate immune system genes. TLR4-Ab significantly increased percentages and numbers of CD11b+ cells. TLR4-Ab–induced CD11b+ cells, derived ex vivo from TLR4-Ab–treated mice, suppress T cells, and TLR4-Ab–conditioned bone marrow cells suppress acute T1D when transferred into acutely diabetic mice. Thus, the TLR4-Ab–induced CD11b+ cells, by the currently accepted definition, are MDSCs able to reverse T1D. To understand the TLR4-Ab mechanism, we compared TLR4-Ab with TLR4 agonist lipopolysaccharide (LPS), which cannot reverse T1D. TLR4-Ab remains sequestered at least 48 times longer than LPS within early endosomes, alters TLR4 signaling, and downregulates inflammatory genes and proteins, including nuclear factor-κB. TLR4-Ab in the endosome, therefore, induces a sustained, attenuated inflammatory response, providing an ideal “second signal” for the activation/maturation of MDSCs that can reverse acute T1D.

Supplementary Methods, Figure Legend from PrLZ Protects Prostate Cancer Cells from Apoptosis Induced by Androgen Deprivation via the Activation of Stat3/Bcl-2 Pathway

Supplementary Figure 1 from PrLZ Protects Prostate Cancer Cells from Apoptosis Induced by Androgen Deprivation via the Activation of Stat3/Bcl-2 Pathway

BackgroundManagement of adults with atrial fibrillation (AF) or atrial flutter in the emergency department (ED) includes rate reduction, cardioversion, and stroke prevention. Different approaches to these components of care may lead to variation in frequency of hospitalization and stroke prevention actions, with significant implications for patient experience, cost of care, and risk of complications. Standardization using evidence-based recommendations could reduce variation in management, preventable hospitalizations, and stroke risk.MethodsWe describe the rationale for our ED-based AF treatment recommendations. We also describe the development of an electronic clinical decision support system (CDSS) to deliver these recommendations to emergency physicians at the point of care. We implemented the CDSS at three pilot sites to assess feasibility and solicit user feedback. We will evaluate the impact of the CDSS on hospitalization and stroke prevention actions using a stepped-wedge cluster randomized pragmatic clinical trial across 13 community EDs in Northern California.DiscussionWe hypothesize that the CDSS intervention will reduce hospitalization of adults with isolated AF or atrial flutter presenting to the ED and increase anticoagulation prescription in eligible patients at the time of ED discharge and within 30days. If our hypotheses are confirmed, the treatment protocol and CDSS could be recommended to other EDs to improve management of adults with AF or atrial flutter.Trial registrationClinicalTrials.gov NCT05009225 .Registered on17 August 2021.