The frequency of genes encoding three putative group B streptococcal virulence factors among invasive and colonizing isolates

BACKGROUND: Group B Streptococcus (GBS) causes severe infections in very young infants and invasive disease in pregnant women and adults with underlying medical conditions. GBS pathogenicity varies between and within serotypes, with considerable variation in genetic content between strains. Three proteins, Rib encoded by rib, and alpha and beta C proteins encoded by bca and bac, respectively, have been suggested as potential vaccine candidates for GBS. It is not known, however, whether these genes occur more frequently in invasive versus colonizing GBS strains. METHODS: We screened 162 invasive and 338 colonizing GBS strains from different collections using dot blot hybridization to assess the frequency of bca, bac and rib. All strains were defined by serotyping for capsular type, and frequency differences were tested using the Chi square test. RESULTS: Genes encoding the beta C protein (bac) and Rib (rib) occurred at similar frequencies among invasive and colonizing isolates, bac (20% vs. 23%), and rib (28% vs. 20%), while the alpha (bca) C protein was more frequently found in colonizing strains (46%) vs, invasive (29%). Invasive strains were associated with specific serotype/gene combinations. CONCLUSION: Novel virulence factors must be identified to better understand GBS disease

Weight-loss and exercise for communities with arthritis in North Carolina (we-can): design and rationale of a pragmatic, assessor-blinded, randomized controlled trial

Background: Recently, we determined that in a rigorously monitored environment an intensive diet-induced weight loss of 10% combined with exercise was significantly more effective at reducing pain in men and women with symptomatic knee osteoarthritis (OA) than either intervention alone. Compared to previous long-term weight loss and exercise trials of knee OA, our intensive diet-induced weight loss and exercise intervention was twice as effective at reducing pain intensity. Whether these results can be generalized to less intensively monitored cohorts is unknown. Thus, the policy relevant and clinically important question is: Can we adapt this successful solution to a pervasive public health problem in real-world clinical and community settings? This study aims to develop a systematic, practical, cost-effective diet-induced weight loss and exercise intervention implemented in community settings and to determine its effectiveness in reducing pain and improving other clinical outcomes in persons with knee OA. Methods/Design: This is a Phase III, pragmatic, assessor-blinded, randomized controlled trial. Participants will include 820 ambulatory, community-dwelling, overweight and obese (BMI ≥ 27 kg/m2) men and women aged ≥ 50 years who meet the American College of Rheumatology clinical criteria for knee OA. The primary aim is to determine whether a community-based 18-month diet-induced weight loss and exercise intervention based on social cognitive theory and implemented in three North Carolina counties with diverse residential (from urban to rural) and socioeconomic composition significantly decreases knee pain in overweight and obese adults with knee OA relative to a nutrition and health attention control group. Secondary aims will determine whether this intervention improves self-reported function, health-related quality of life, mobility, and is cost-effective. Discussion: Many physicians who treat people with knee OA have no practical means to implement weight loss and exercise treatments as recommended by numerous OA treatment guidelines. This study will establish the effectiveness of a community program that will serve as a blueprint and exemplar for clinicians and public health officials in urban and rural communities to implement a diet-induced weight loss and exercise program designed to reduce knee pain and improve other clinical outcomes in overweight and obese adults with knee OA

The first 20 months of the COVID-19 pandemic: Mortality, intubation and ICU rates among 104,590 patients hospitalized at 21 United States health systems

Main objective There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. Study design and methods University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. Results and significance The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. Conclusions Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. Trial registration ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528)

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

Investigation of Circuit-Level Oxide Degradation and Its Effect on CMOS Inverter Operation and MOSFET Characteristics

Circuit-level oxide degradation effects on CMOS inverter circuit operation and individual MOSFET behavior is investigated. Individual PMOSFET and NMOSFET devices are assembled off-wafer in the inverter configuration through a switch matrix. A range of gate oxide degradation mechanisms are induced by applying a ramped voltage stress (RVS) of various magnitudes to the input of the inverter. A novel circuit model is used to simulate the voltage transfer curves (VTCs) of degraded inverters. At the transistor level, increased gate leakage currents of nearly eight orders of magnitude are observed, in addition to severely reduced on-currents (\u3e 50 percent reduction), and large threshold voltage (Vth) shifts (\u3e 100 mV). At the circuit-level, stress of either polarity results in inverter performance degradation. For the DC characteristics, oxide degradation attributed to limited hard breakdown (LHBD) in the NMOSFET and hard breakdown (HBD) in the PMOSFET, results in decreased output voltage swing (\u3e 260 mV). Under the same conditions, inverter degradation in the voltage-time (V-t) domain exposes much larger changes in performance. For instance, significant increase in the rise time results in the output voltage being pulled up to only 660 mV (VDD = 1.8 V) before switching low. From a circuit reliability viewpoint, it may be possible for subsequent circuit stages to compensate for a few degraded devices, but in highspeed circuits, increased rise/fall and delay times may cause timing issues. Furthermore, increased gate or off-state leakage currents can potentially load previous circuit stages or result in increased power consumption

Effects of Circuit-Level Stress on Inverter Performance and MOSFET Characteristics

The effects of circuit-level stress on both inverter operation and MOSFET characteristics have been investigated. Individual MOSFETs, with gate oxide thickness of 3.2 nm and active dimensions of 25 µm × 25 µm, are connected in an inverter configuration off-wafer via a low-leakage switch matrix. Inverters are stressed with a ramped voltage stress (RVS) of various magnitudes to induce different degrees of gate oxide degradation. In addition, voltage transfer curves (VTCs) of degraded inverters are simulated using a new circuit model. At the transistor level, both the PMOSFET and the NMOSFET show increased gate leakage current up to eight orders of magnitude, severely reduced on-currents and transconductances (gm), and large threshold voltage (Vt) shifts of 100 mV or more. Different trends in inverter performance are observed following positive and negative stress. However, regardless of the stress polarity, circuit-level stress results in inverter performance degradation, such as reduced output swing, switching point shifts, and increased rise/fall times. After the largest positive RVS, the output voltage swing has decreased from 1.8 V fresh, to 1.54 V post-stress. Much larger changes in the inverter voltage (V-t) time domain performance are observed. The minimum output low voltage is similar to that of the VTC, but the rise time increased significantly enough that the output voltage is only pulled up to 660 mV (VDD = 1.8 V) before it switches low. In terms of circuit reliability, it may be possible for subsequent circuit stages to compensate for a few degraded devices, but increased rise/fall and delay times may cause timing issues in high-speed circuits. Furthermore, increased gate or off-stage leakage currents can potentially load previous circuit stages or result in increased power consumption