Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Spontaneously Sliding Multipole Spin Density Waves in Cold Atoms.

We report on the observation of spontaneously drifting coupled spin and quadrupolar density waves in the ground state of laser driven Rubidium atoms. These laser-cooled atomic ensembles exhibit spontaneous magnetism via light mediated interactions when submitted to optical feedback by a retroreflecting mirror. Drift direction and chirality of the waves arise from spontaneous symmetry breaking. The observations demonstrate a novel transport process in out-of-equilibrium magnetic systems.

Asynchronous lecture participation negatively predicts exam scores for females and students of color in an introductory physiology course during COVID-19.

In response to COVID-19, educators rapidly pivoted to new and innovative ways of delivering lecture material. The ability to host synchronous lectures on platforms like Zoom gave students continued access to classroom material in the face of an ongoing pandemic. The purpose of this study was to investigate the differences in exam scores between students attending a physiology class (PHSL3051) synchronously via Zoom or asynchronously by viewing recorded lectures posted after class. Students in PHSL3051 were evaluated with four unit exams and one cumulative final exam. Although pooled analysis of all students showed that synchronous lecture viewing positively predicted exam scores, this positive association was even larger when the data were analyzed by gender and ethnicity. For female-identified students and students of color (SOC), attending lectures synchronously was associated with average scores on every unit exam that were higher by 2.7-7.4 percentage points. Moreover, the greater a student's synchronous participation in the course throughout the semester, the better that student's performance on the cumulative final exam was likely to be. These data highlight the need to better understand how different groups of undergraduate students select and respond to different assessment methods used in the same course, which may have long-term effects on their overall performance at 4-year institutions.NEW & NOTEWORTHY This study examined the relationship between lecture attendance (synchronous or asynchronous) and exam scores throughout the semester. Although everyone in the course benefited from synchronous lecture attendance, our data indicated that students of color (SOC) and female-identified students benefited most. SOC and female-identified students who participated synchronously had even higher mean scores on all exams within the course compared with SOC and female-identified students who participated asynchronously by watching recordings of the same lectures.

ICD-10 diagnosis codes in electronic health records do not adequately capture fracture complexity for proximal humerus fractures.

BACKGROUND: The ability to do comparative effectiveness research (CER) for proximal humerus fractures (PHF) using data in electronic health record (EHR) systems and administrative claims databases was enhanced by the 10th revision of the International Classification of Diseases (ICD-10), which expanded the diagnosis codes for PHF to describe fracture complexity including displacement and the number of fracture parts. However, these expanded codes only enhance secondary use of data for research if the codes selected and recorded correctly reflect the fracture complexity. The objective of this project was to assess the accuracy of ICD-10 diagnosis codes documented during routine clinical practice for secondary use of EHR data. METHODS: A sample of patients with PHFs treated by orthopedic providers across a large, regional health care system between January 1, 2016, and December 31, 2018, were retrospectively identified from the EHR. Four fellowship-trained orthopedic surgeons reviewed patient radiographs and recorded the Neer Classification characteristics of displacement, number of parts, and fracture location(s). The fracture characteristics were then reviewed by a trained coder, and the most clinically appropriate ICD-10 diagnosis code based on the number of fracture parts was assigned. We assessed congruence between ICD-10 codes documented in the EHR and radiograph-validated codes, and assessed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for EHR-documented ICD-10 codes. RESULTS: There were 761 patients with unilateral, closed PHF who met study inclusion criteria. On average, patients were 67 years of age and 77% were female. Based on radiograph review, 37% were 1-part fractures, 42% were 2-part, 11% were 3-part, and 10% were 4-part fractures. Of the EHR diagnosis codes recorded during clinical practice, 59% were "unspecified" fracture diagnosis codes that did not identify the number of fracture parts. Examination of fracture codes revealed PPV was highest for 1-part (PPV = 0.66, 95% confidence interval [CI] 0.60-0.72) and 4-part fractures (PPV = 0.67, 95% CI 0.13-1.00). CONCLUSIONS: Current diagnosis coding practices do not adequately capture the fracture complexity needed to conduct subgroup analysis for PHF. Conclusions drawn from population studies or large databases using ICD-10 codes for PHF classification should be interpreted within this limitation. Future studies are warranted to improve diagnostic coding to support large observational studies using EHR and administrative claims data.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194.

Emergency Medical Services Responder Manual Ventilation Performance.

OBJECTIVE: Manual ventilation is a basic skill that every emergency medical services (EMS) responder is expected to perform proficiently. Improper manual ventilation may result in significant morbidity; however, there is no feedback mechanism or method of control for the volume, pressure, or frequency during manual ventilation. In this study, we aimed to quantify the volume and peak pressures of manually delivered breaths using a simulated lung. METHODS: One hundred ninety-nine volunteer EMS responders from the EMS World Expo 2019 and EMS Today 2020 participated in this study. Each volunteer manually ventilated a simulated lung using a bag-valve-mask (BVM) for 18 breaths. Descriptive statistics were computed for peak pressures (Ppeak) and tidal volumes (VT)), and a multivariable linear regression was conducted to determine whether there was an independent correlation between Ppeak or VT and seven different variables. RESULTS: Both Ppeak and VT delivered by EMS responders had a high level of variability; 82.9% of clinicians delivered at least one breath exceeding the recommended safety thresholds; and 98.0% delivered at least one breath that was inadequate or excessive. Our results showed no likely clinical significant role of sex, hand size, frequency of use, or years of experience in determining Ppeak and VT. Tidal volumes were significantly higher in males (p < 0.001), those using two-hand manual ventilation (p < 0.001), shorter hand length (p = 0.013), higher confidence (p < 0.001), and more years of experience (p < 0.001). Peak pressures were significantly higher in those using two-hand manual ventilation (p < 0.001), wider hand width (p = 0.004), higher confidence (p < 0.001), less frequent use of the BVM per month (p < 0.001), more experience (p < 0.001). CONCLUSIONS: Our study demonstrated large variability of VT and Ppeak within and, to a lesser degree, between clinicians. Of the seven variables that might have affected tidal volume or peak pressures, only the use of two hands versus one hand had a potentially clinically significant effect. Our study identifies a clear need for BVM improvement to ensure every practitioner can deliver breaths at appropriate volumes and safe pressures.

The Fall of the Nation's First Gender-Affirming Surgery Clinic.

Johns Hopkins Hospital established the first gender-affirming surgery (GAS) clinic in the United States in 1966. Operating for more than 13 years, the clinic was abruptly closed in 1979. According to the hospital, the decision was made in response to objective evidence claiming that GAS was ineffective. However, this evidence directly contradicted many contemporaneous studies and faced immediate criticism from the scientific community. Despite this resistance, it took the hospital nearly 40 years to resume performing GAS. Scientific evidence-imbued in scandal, bias, and moralism-was instrumentalized to serve broader institutional interests. The burgeoning field of plastic surgery tethered and then untethered GAS from its auspices in response to poor technical outcomes and transphobia. No longer serving surgeons' interests, the clinic was marginalized to "barely minimal facilities" in 1974, five years before GAS was formally banned. Over the next 5 years, the clinic co-inhabited space with the Department of Obstetrics and Gynecology. Simultaneously, the Department of Obstetrics and Gynecology navigated scandals related to reproductive technology (namely, the Dalkon Shield [A.H. Robins] controversy) until the clinic space was demolished in 1979. The study that informed the GAS ban was preferentially funded in keeping with the political economy of biomedical research. This article presents a spatial argument for how the closure of the nation's first GAS clinic was not based in empirical data alone but was manipulated to fuel political and institutional agendas.

Large-Area Periodic Arrays of Atomically Flat Single-Crystal Gold Nanotriangles Formed Directly on Substrate Surfaces.

The advancement of nanoenabled wafer-based devices requires the establishment of core competencies related to the deterministic positioning of nanometric building blocks over large areas. Within this realm, plasmonic single-crystal gold nanotriangles represent one of the most attractive nanoscale components but where the formation of addressable arrays at scale has heretofore proven impracticable. Herein, a benchtop process is presented for the formation of large-area periodic arrays of gold nanotriangles. The devised growth pathway sees the formation of an array of defect-laden seeds using lithographic and vapor-phase assembly processes followed by their placement in a growth solution promoting planar growth and threefold symmetric side-faceting. The nanotriangles formed in this high-yield synthesis distinguish themselves in that they are epitaxially aligned with the underlying substrate, grown to thicknesses that are not readily obtainable in colloidal syntheses, and present atomically flat pristine surfaces exhibiting gold atoms with a close-packed structure. As such, they express crisp and unambiguous plasmonic modes and form photoactive surfaces with highly tunable and readily modeled plasmon resonances. The devised methods, hence, advance the integration of single-crystal gold nanotriangles into device platforms and provide an overall fabrication strategy that is adaptable to other nanomaterials.

Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Laparoscopic and robotic pyeloplasty as minimally invasive alternatives to the open approach for the treatment of uretero-pelvic junction obstruction in infants: a multi-institutional comparison of outcomes and learning curves.

BACKGROUND: Since the development of minimally invasive surgery (MIS), laparoscopic and robotic approaches have been widely adopted. However, little has been published detailing the learning curve of MIS, especially in infants. OBJECTIVE: To quantify the learning curve of laparoscopic (LP) and robot-assisted laparoscopic pyeloplasty (RAL-P) for treatment of uretero-pelvic junction obstruction (UPJO) in infants evidenced by number of cases, operative time, success and complications. PATIENTS AND METHODS: Between 2009 and 2017, we retrospectively reviewed pyeloplasty cases for treatment of UPJO in infants at three academic institutions. The primary outcome was success. Secondary outcomes were UPJO recurrence, complications, and operative time as a surrogate of skill acquisition. Continuous variables were analyzed by t test, Welch-test, and one-way ANOVA. Non-continuous variables were analyzed by Chi-squared test or Fisher's exact test. Learning curves (LC) were studied by r-to-z transformation and CUSUM. RESULTS: Thirty-nine OP, 26 LP, and 39 RAL-P had mean operative times (OT) of 106, 121, and 151 min, respectively. LCs showed plateau in OT after 18 and 13 cases for LP and RAL-P, respectively. RAL-P showed a second phase of further improvements after 37 cases. At 16 months follow-up, there were similar rates of success and complications between the three groups. CONCLUSIONS: Despite different duration of learning phases, proficiency was achieved in both LP and RAL-P as evidenced by stabilization of operative time and similar success rates and complications to OP. Before and after achievement of proficiency, LP and RAL-P can be safely learned and implemented for treatment of UPJO in infants.

Resolvin D2 promotes host defense in a 2 - hit model of sepsis with secondary lung infection.

In the development of sepsis, there is early, massive inflammation which can lead to multiple organ failure. Later there is an immunosuppressed phase where the host is susceptible to secondary infections or is unable to clear existing infection. Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipids which resolve infection by decreasing bacteria load and reducing systemic inflammatory response. There has been little work studying if SPMs given late, can promote host defense. We examined if an SPM, Resolvin D2 (RvD2) could promote host defense in a 2-hit mouse model of cecal ligation and puncture (CLP) sepsis and secondary Pseudomonas aeruginosa lung infection. RvD2 given 48 h after mild CLP (1st hit), increased gene expression of Toll-like receptor-2 (TLR-2) and alveolar macrophage/monocyte phagocytic ability compared to CLP mice given saline vehicle. In this model, RvD2 did not affect plasma IL-6 or IL-10. These effects induced by RvD2, lowered lung bacterial load and decreased mortality after the secondary infection of Pseudomonas aeruginosa (2nd hit). Splenic T-cell numbers were also increased in RvD2 treated mice compared to saline vehicle treated animals. The results suggest that RvD2 promoted mechanisms of host defense in a 2-hit model sepsis and secondary lung infection.

Bayesian emulation and history matching of JUNE.

We analyze JUNE: a detailed model of COVID-19 transmission with high spatial and demographic resolution, developed as part of the RAMP initiative. JUNE requires substantial computational resources to evaluate, making model calibration and general uncertainty analysis extremely challenging. We describe and employ the uncertainty quantification approaches of Bayes linear emulation and history matching to mimic JUNE and to perform a global parameter search, hence identifying regions of parameter space that produce acceptable matches to observed data, and demonstrating the capability of such methods. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Community trial evaluating the integration of Indigenous healing practices and a harm reduction approach with principles of seeking safety in an Indigenous residential treatment program in northern Ontario.

OBJECTIVE: Our primary objective was to evaluate how the Indigenous Healing and Seeking Safety (IHSS) model impacted residential addiction treatment program completion rates. Our secondary objective was to evaluate health service use 6 months before and 6 months after residential treatment for clients who attended the program before and after implementing IHSS. METHODS: We observed clients of the Benbowopka Residential Treatment before IHSS implementation (from April 2013 to March 31, 2016) and after IHSS implementation (from January 1, 2018 - March 31, 2020). The program data were linked to health administration data, including the Ontario Health Insurance Plan (OHIP) physician billing, the Registered Persons Database (RPDB), the National Ambulatory Care Reporting System (NACRS), and the Discharge Abstract Database (DAD). Chi-square tests were used to compare patient characteristics in the no-IHSS and IHSS groups. We used logistic regression to estimate the association between IHSS and treatment completion. We used generalized estimating equation (GEE) regression model to evaluate health service use (including primary care visits, ED visits overall and for substance use, hospitalizations and mental health visits), Results: There were 266 patients in the no-IHSS group and 136 in the IHSS group. After adjusting for individual characteristics, we observed that IHSS was associated with increased program completion rates (odds ratio = 1.95, 95% CI 1.02-3.70). There was no significant association between IHSS patients' health service use at time one or time two. Primary care visits time 1: aOR 0.55, 95%CI 0.72-1.13, time 2: aOR 1.13, 95%CI 0.79-1.23; ED visits overall time 1: aOR 0.91, 95%CI 0.67-1.23, time 2: aOR 1.06, 95%CI 0.75-1.50; ED visits for substance use time 1: aOR 0.81, 95%CI 0.47-1.39, time 2: aOR 0.79, 95%CI 0.37-1.54; Hospitalizations time 1: aOR 0.78, 95%CI 0.41-1.47, time 2: aOR 0.76, 95%CI 0.32-1.80; Mental health visits time 1: aOR 0.66, 95%CI 0.46-0.96, time 2: aOR 0.92 95%CI 0.7-1.40. CONCLUSIONS: Our results indicate that IHSS positively influenced program completion but had no significant effect on health service use. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (identifier number NCT04604574). First registration 10/27/2020.

Sampling strategy, characteristics and representativeness of the InGef research database.

OBJECTIVES: The aim of this study was to describe the sampling strategy as well as characteristics and the external validity of a representative sample database drawn from the German InGef research database. STUDY DESIGN: This is a retrospective cohort study using anonymized claims data for the year 2019. METHODS: The InGef research database is an anonymized healthcare database with longitudinal claims data from approximately 8.8 Mio insurees. A sample of four million insurees was drawn intended to be representative for the German population with respect to age, sex and region. In addition to demographic information, data on hospitalization rates, mortality rates and drug prescription rates were analysed from the InGef sample database for the year 2019 to demonstrate validity and representativeness. Corresponding national reference data were obtained from official sources. RESULTS: The distributions of sex and age were similar in the InGef sample database and Germany (proportion of women: 50.8% vs 50.7%; mean age: 44.1 vs 43.9 years). The proportion of insurees living in the eastern part of Germany was lower in the InGef sample database (16.5% vs 19.5%). There was good accordance with German reference data with respect to hospitalization rates and overall mortality rates. Prescription rates for the 20 most often reimbursed drug classes were slightly higher in the InGef sample database. CONCLUSIONS: The InGef sample database shows good overall agreement with the German population on measures of morbidity, mortality and drug usage.

Is contact between men who have sex with men and non-governmental organizations providing harm reduction associated with improved HIV outcomes?

OBJECTIVES: There is a high prevalence of HIV (5.2% in 2018) among men who have sex with men (MSM) in Ukraine. HIV testing, condom provision and facilitated linkage to HIV treatment have been funded by various bodies through non-governmental organizations (NGOs). We investigated whether contact with these NGOs was associated with improved prevention and treatment outcomes among MSM in Ukraine. METHODS: Data were taken from four rounds of integrated bio-behavioural surveys among MSM in Ukraine (2011, N = 5950; 2013, N = 8101; 2015, N = 4550; 2018, N = 5971) including HIV testing combined with questionnaire responses. Data were analysed using mixed-effect regression models, which estimated associations between being an NGO client and behavioural, HIV testing and HIV treatment outcomes, adjusted for demographic factors. RESULTS: Those MSM who were NGO clients were more likely than non-clients to have been HIV tested in the last year [adjusted odds ratio (aOR) = 7.01, 95% confidence interval (CI): 6.45-7.62] or ever (aOR = 11.00, 95% CI: 9.77-12.38), to have used a condom for the last anal sex act (aOR = 1.32, 95% CI: 1.21-1.43), and to have recently either bought or received condoms (aOR = 21.27, 95% CI: 18.01-25.12). HIV-positive MSM were more likely to have contact with NGOs (aOR = 1.61, 95% CI: 1.39-1.86). Among the HIV-positive MSM, those who were NGO clients were more likely to be registered at an AIDS centre (aOR = 2.24, 95% CI: 1.61-3.11) and to be on antiretroviral treatment (aOR = 2.20, 95% CI: 1.51-3.20). CONCLUSIONS: In Ukraine, being in contact with MSM-targeted NGOs is associated with better outcomes for HIV prevention, testing and treatment, suggesting that NGO harm reduction projects for MSM have had a beneficial impact on reducing HIV transmission and morbidity.

Bone turnover markers as determinants of bone density and fracture in men with distal forearm fractures: the pathogenesis examined in the Mr F study.

The pathogenesis for low-trauma wrist fractures in men is not fully understood. This study found that these men had evidence of significantly higher bone turnover compared with control subjects. Bone turnover markers were negative predictors of bone mineral density and were a predictor of fracture. INTRODUCTION: Men with distal forearm fractures have reduced bone density, an increased risk of osteoporosis and of further fractures. The aim of this study was to investigate whether or not men with distal forearm fractures had evidence of altered bone turnover activity. METHODS: Fifty eight men with low-trauma distal forearm fracture and 58 age-matched healthy control subjects were recruited. All subjects underwent a DXA scan of the forearm, both hips, and lumbar spine, biochemical investigations, and health questionnaires. Measurements of beta crosslaps (ßCTX), procollagen type I N-terminal propeptide (PINP), sclerostin, Dickkopf-1 (Dkk1), and fibroblast growth factor 23 (FGF 23) were made. RESULTS: Men with fracture had significantly higher PINP than controls at 39.2 ng/ml (SD 19.5) versus 33.4 ng/ml (SD13.1) (p<0.001). They also had significantly higher ßCTX at 0.45 ng/ml (SD 0.21) versus 0.37 ng/ml (SD 0.17) (p= 0.037). Fracture subjects had significantly lower aBMD and PINP was a negative predictor of aBMD at the total hip and ßCTX a negative predictor of forearm aBMD. Sclerostin was a positive predictor of aBMD at the lumbar spine and hip sites. Sex hormone binding globulin (SHBG) at 37nmol/L (SD 15.0) was lower in fracture cohort compared to 47.9 nmol/L (SD 19.2) (p=0.001) in control. Multiple regression revealed that the best model for prediction of fracture included SHBG, P1NP, and ultra-distal forearm aBMD. The likelihood of distal forearm fracture was decreased by 5.1% for each nmol/L increase in SHBH and by 1.4% for every mg/cm2 increase in ultra-distal forearm aBMD, but increased by 6.1 % for every ng/ml increase in P1NP. Men in the highest quartile of PINP had a significantly greater likelihood of distal forearm fracture than those in the lowest quartile. CONCLUSION: The fracture group had significantly higher PINP and ßCTX compared with the control group, and these markers were negative predictors of aBMD at the total hip and forearm sites, respectively. Sclerostin was a positive predictor of the variance of spinal and hip aBMD. Likelihood of forearm fracture was best predicted by a combination of SHBG, PINP, and ultra-distal forearm aBMD. Findings of such cross-sectional data should be treated with caution, as longitudinal studies would be required to confirm or refute them.

Incidence of acute complications of herpes zoster among immunocompetent adults in England: a matched cohort study using routine health data.

BACKGROUND: Herpes zoster can cause rare but serious complications; the frequency of these complications has not been well described. OBJECTIVES: To quantify the risks of acute non-postherpetic neuralgia (PHN) zoster complications, to inform vaccination policy. METHODS: We conducted a cohort study among unvaccinated immunocompetent adults with incident zoster, and age-, sex- and practice-matched control adults without zoster, using routinely collected health data from the UK Clinical Practice Research Datalink (years 2001 to 2018). Crude attributable risks of complications were estimated as the difference between Kaplan-Meier-estimated 3-month cumulative incidences in patients with zoster vs. controls. We used Cox models to obtain hazard ratios for our primary outcomes in patients with and without zoster. Primary outcomes were ocular, neurological, cutaneous, visceral and zoster-specific complications. We also assessed whether antivirals during acute zoster protected against the complications. RESULTS: In total 178 964 incident cases of zoster and 1 799 380 controls were included. The absolute risks of zoster-specific complications within 3 months of zoster diagnosis were 0·37% [95% confidence interval (CI) 0·34-0·39] for Ramsay Hunt syndrome, 0·01% (95% CI 0·0-0·01) for disseminated zoster, 0·04% (95% CI 0·03-0·05) for zoster death and 0·97% (95% CI 0·92-1·00) for zoster hospitalization. For other complications, attributable risks were 0·48% (95% CI 0·44-0·51) for neurological complications, 1·33% (95% CI 1·28-1·39) for ocular complications, 0·29% (95% CI 0·26-0·32) for cutaneous complications and 0·78% (95% CI 0·73-0·84) for visceral complications. Attributable risks were higher among patients > 50 years old. Patients with zoster had raised risks of all primary outcomes relative to controls. Antiviral prescription was associated with reduced risk of neurological complications (hazard ratio 0·61, 95% CI 0·53-0·70). CONCLUSIONS: Non-PHN complications of zoster were relatively common, which may affect cost-effectiveness calculations for zoster vaccination. Clinicians should be aware that zoster can lead to various complications, besides PHN.

Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Lipoxin A4 promotes reduction and antibiotic efficacy against Pseudomonas aeruginosa biofilm.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients. P. aeruginosa readily forms biofilms which can reduce the efficacy of antibiotics used to eradicate the pathogen. We have previously shown that a Specialized Pro-resolving Mediator (SPM), Lipoxin A4 (LxA4) is a quorum sensing inhibitor which can reduce P. aeruginosa virulence. In this study, we examined the direct actions of LxA4 and RvD2 on P. aeruginosa biofilm formation and virulence gene expression. The influence of LxA4 on antibiotic efficacy and the combined effects on biofilm formation were also investigated. LxA4 and RvD2 reduced P. aeruginosa biofilm formation and virulence gene expression. LxA4 increased ciprofloxacin inhibition on biofilm formation but did not affect ciprofloxacin's action on non-adherent bacteria. On the other hand, LxA4 increased bacterial killing action of imipenem but did not affect imipenem's action on biofilm. We also found that LxA4 can increase ciprofloxacin's bacterial killing ability in established biofilm. Together these results suggest that LxA4 has direct effects on P. aeruginosa biofilm formation and can increase antibiotic efficacy directly.