Nodavirus RNA replication crown architecture reveals proto-crown precursor and viral protein A conformational switching.

Positive-strand RNA viruses replicate their genomes in virus-induced membrane vesicles, and the resulting RNA replication complexes are a major target for virus control. Nodavirus studies first revealed viral RNA replication proteins forming a 12-fold symmetric "crown" at the vesicle opening to the cytosol, an arrangement recently confirmed to extend to distantly related alphaviruses. Using cryoelectron microscopy (cryo-EM), we show that mature nodavirus crowns comprise two stacked 12-mer rings of multidomain viral RNA replication protein A. Each ring contains an ~19 nm circle of C-proximal polymerase domains, differentiated by strikingly diverged positions of N-proximal RNA capping/membrane binding domains. The lower ring is a "proto-crown" precursor that assembles prior to RNA template recruitment, RNA synthesis, and replication vesicle formation. In this proto-crown, the N-proximal segments interact to form a toroidal central floor, whose 3.1 Å resolution structure reveals many mechanistic details of the RNA capping/membrane binding domains. In the upper ring, cryo-EM fitting indicates that the N-proximal domains extend radially outside the polymerases, forming separated, membrane-binding "legs." The polymerase and N-proximal domains are connected by a long linker accommodating the conformational switch between the two rings and possibly also polymerase movements associated with RNA synthesis and nonsymmetric electron density in the lower center of mature crowns. The results reveal remarkable viral protein multifunctionality, conformational flexibility, and evolutionary plasticity and insights into (+)RNA virus replication and control.

Population Immunity and Covid-19 Severity with Omicron Variant in South Africa.

BACKGROUND: The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified on November 25, 2021, in Gauteng province, South Africa. Data regarding the seroprevalence of SARS-CoV-2 IgG in Gauteng before the fourth wave of coronavirus disease 2019 (Covid-19), in which the omicron variant was dominant, are needed. METHODS: We conducted a seroepidemiologic survey from October 22 to December 9, 2021, in Gauteng to determine the seroprevalence of SARS-CoV-2 IgG. Households included in a previous seroepidemiologic survey (conducted from November 2020 to January 2021) were contacted; to account for changes in the survey population, there was a 10% increase in the households contacted, with the use of the same sampling framework. Dried-blood-spot samples were tested for IgG against SARS-CoV-2 spike protein and nucleocapsid protein with the use of quantitative assays. We also evaluated Covid-19 epidemiologic trends in Gauteng, including cases, hospitalizations, recorded deaths, and excess deaths from the start of the pandemic through January 12, 2022. RESULTS: Samples were obtained from 7010 participants, of whom 1319 (18.8%) had received a Covid-19 vaccine. The seroprevalence of SARS-CoV-2 IgG ranged from 56.2% (95% confidence interval [CI], 52.6 to 59.7) among children younger than 12 years of age to 79.7% (95% CI, 77.6 to 81.5) among adults older than 50 years of age. Vaccinated participants were more likely to be seropositive for SARS-CoV-2 than unvaccinated participants (93.1% vs. 68.4%). Epidemiologic data showed that the incidence of SARS-CoV-2 infection increased and subsequently declined more rapidly during the fourth wave than it had during the three previous waves. The incidence of infection was decoupled from the incidences of hospitalization, recorded death, and excess death during the fourth wave, as compared with the proportions seen during previous waves. CONCLUSIONS: Widespread underlying SARS-CoV-2 seropositivity was observed in Gauteng before the omicron-dominant wave of Covid-19. Epidemiologic data showed a decoupling of hospitalizations and deaths from infections while omicron was circulating. (Funded by the Bill and Melinda Gates Foundation.).

North American tree migration paced by climate in the West, lagging in the East.

Tree fecundity and recruitment have not yet been quantified at scales needed to anticipate biogeographic shifts in response to climate change. By separating their responses, this study shows coherence across species and communities, offering the strongest support to date that migration is in progress with regional limitations on rates. The southeastern continent emerges as a fecundity hotspot, but it is situated south of population centers where high seed production could contribute to poleward population spread. By contrast, seedling success is highest in the West and North, serving to partially offset limited seed production near poleward frontiers. The evidence of fecundity and recruitment control on tree migration can inform conservation planning for the expected long-term disequilibrium between climate and forest distribution.

Multimodal Exercise and Cognitive Training Program Improves Cognitive Function in Amnestic Mild Cognitive Impairment.

OBJECTIVE: To investigate the preliminary efficacy of a combined physical exercise + cognitive training intervention for older adults with amnestic mild cognitive impairment (aMCI). DESIGN: Randomized clinical trial. SETTING: Veteran Affairs Hospital, Palo Alto, CA. PARTICIPANTS: Sample included 72 community-dwelling volunteers (mean age 72.4 ± 9.5) diagnosed with aMCI. INTERVENTION: Participants were randomized to either a combined aerobic and resistance exercise + cognitive training (CARE+CT) or stretching exercise + CT (SE+CT). MEASUREMENTS: Primary outcomes included intervention specific assessments of word list and name-face recall. Secondary cognitive outcomes included standardized composite scores that reflect cognitive domains (e.g., learning and memory, executive function, processing speed, visuospatial ability, language). Secondary physiological outcomes included VO2 max and functional capacity (e.g., distance walked 6-minute walk test). APOE and BDNF were determined from whole blood samples. RESULTS: Controlling for age and employment status, linear mixed effects models revealed that all participants experienced significant improvement in the delayed recall of word list, learning and memory and executive function. Only the CARE+CT condition had significant improvement in processing speed and functional capacity. APOE4 status impacted cognitive benefits of those in the SE+CT condition. CONCLUSIONS: Results provide preliminary support for combined exercise and cognitive training interventions for older adults with aMCI. Further research is needed to understand the mechanisms involved as well as the impact of these interventions in diverse samples. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01962038.

New forays into measurement of ocular biomechanics.

PURPOSE OF REVIEW: The field of corneal biomechanics has rapidly progressed in recent years, reflecting technological advances and an increased understanding of the clinical significance of measuring these properties. This review will evaluate in-vivo biomechanical properties obtained by current technologies and compare them regarding their relevance to established biomechanical properties obtained by gold-standard ex-vivo techniques normally conducted on elastic materials. RECENT FINDINGS: Several new technologies have appeared in recent years, including vibrational optical coherence tomography (VOCT) and the corneal indentation device (CID). These techniques provide promising new opportunities for minimally invasive and accurate measurements of corneal viscoelastic properties. SUMMARY: Alterations in corneal biomechanics are known to occur in several corneal degenerative diseases and after refractive surgical procedures. The measurement of corneal biomechanical properties has the capability to diagnose early disease and monitor corneal disease progression. Several new technologies have emerged in recent years, allowing for more accurate and less invasive measurements of corneal biomechanical properties, most notably the elastic modulus.

Is there tree senescence? The fecundity evidence.

Despite its importance for forest regeneration, food webs, and human economies, changes in tree fecundity with tree size and age remain largely unknown. The allometric increase with tree diameter assumed in ecological models would substantially overestimate seed contributions from large trees if fecundity eventually declines with size. Current estimates are dominated by overrepresentation of small trees in regression models. We combined global fecundity data, including a substantial representation of large trees. We compared size-fecundity relationships against traditional allometric scaling with diameter and two models based on crown architecture. All allometric models fail to describe the declining rate of increase in fecundity with diameter found for 80% of 597 species in our analysis. The strong evidence of declining fecundity, beyond what can be explained by crown architectural change, is consistent with physiological decline. A downward revision of projected fecundity of large trees can improve the next generation of forest dynamic models.

A comparison of iCare and Goldmann applanation tonometry measurements during the COVID-19 pandemic: a retrospective study.

PURPOSE: To evaluate factors associated with differences in intraocular pressure (IOP) readings between iCare and Goldmann applanation tonometry (GAT) in established glaucoma patients. METHODS: This retrospective comparative study included clinical data of 350 eyes from 350 established glaucoma patients who had iCare and GAT IOP measured by an ophthalmic technician and a glaucoma specialist, respectively. The main outcome measure was the difference in IOP measurements of the right eyes with iCare and GAT. RESULTS: The intraclass correlation coefficient (ICC) between GAT and iCare was 0.90. The mean IOP difference between tonometers was - 0.18 ± 2.89 mmHg. Bland-Altman plots indicated a 95% limit of agreement of - 5.8 to 5.5 mmHg. Central corneal thickness (CCT) and age were significantly correlated with the difference in IOPs of the iCare and GAT. GAT-IOP and age were significantly associated with the absolute difference in measured IOP of the two tonometers. The difference in measurements was not significantly associated with prior glaucoma surgery, average global index of optical coherence tomography, axial length, technician years of experience and certification, and IOP range. CONCLUSION: Although there is good agreement between the iCare and GAT mean values, these devices are not interchangeable in glaucoma patients due to the wide range of the limit of agreement.

Design and rationale of re-energize fontan: Randomized exercise intervention designed to maximize fitness in fontan patients.

In this manuscript, we describe the design and rationale of a randomized controlled trial in pediatric Fontan patients to test the hypothesis that a live-video-supervised exercise (aerobic+resistance) intervention will improve cardiac and physical capacity; muscle mass, strength, and function; and endothelial function. Survival of children with single ventricles beyond the neonatal period has increased dramatically with the staged Fontan palliation. Yet, long-term morbidity remains high. By age 40, 50% of Fontan patients will have died or undergone heart transplantation. Factors that contribute to onset and progression of heart failure in Fontan patients remain incompletely understood. However, it is established that Fontan patients have poor exercise capacity which is associated with a greater risk of morbidity and mortality. Furthermore, decreased muscle mass, abnormal muscle function, and endothelial dysfunction in this patient population is known to contribute to disease progression. In adult patients with 2 ventricles and heart failure, reduced exercise capacity, muscle mass, and muscle strength are powerful predictors of poor outcomes, and exercise interventions can not only improve exercise capacity and muscle mass, but also reverse endothelial dysfunction. Despite these known benefits of exercise, pediatric Fontan patients do not exercise routinely due to their chronic condition, perceived restrictions to exercise, and parental overprotection. Limited exercise interventions in children with congenital heart disease have demonstrated that exercise is safe and effective; however, these studies have been conducted in small, heterogeneous groups, and most had few Fontan patients. Critically, adherence is a major limitation in pediatric exercise interventions delivered on-site, with adherence rates as low as 10%, due to distance from site, transportation difficulties, and missed school or workdays. To overcome these challenges, we utilize live-video conferencing to deliver the supervised exercise sessions. Our multidisciplinary team of experts will assess the effectiveness of a live-video-supervised exercise intervention, rigorously designed to maximize adherence, and improve key and novel measures of health in pediatric Fontan patients associated with poor long-term outcomes. Our ultimate goal is the translation of this model to clinical application as an "exercise prescription" to intervene early in pediatric Fontan patients and decrease long-term morbidity and mortality.

Practical guidelines for exercise prescription in patients with chronic heart failure.

Chronic heart failure (HF) is a major cause of morbidity, mortality, disability, and health care costs. A hallmark feature of HF is severe exercise intolerance, which is multifactorial and stems from central and peripheral pathophysiological mechanisms. Exercise training is internationally recognized as a Class 1 recommendation for patients with HF, regardless of whether ejection fraction is reduced or preserved. Optimal exercise prescription has been shown to enhance exercise capacity, improve quality of life, and reduce hospitalizations and mortality in patients with HF. This article will review the rationale and current recommendations for aerobic training, resistance training, and inspiratory muscle training in patients with HF. Furthermore, the review provides practical guidelines for optimizing exercise prescription according to the principles of frequency, intensity, time (duration), type, volume, and progression. Finally, the review addresses common clinical considerations and strategies when prescribing exercise in patients with HF, including considerations for medications, implantable devices, exercise-induced ischemia, and/or frailty.

Exploring Barriers and Facilitators to Reducing the Environmental Impact of the Operating Room.

INTRODUCTION: The operating room (OR) is a major contributor to greenhouse gas emissions both nationally and globally. Successful implementation of quality improvement initiatives requires understanding of key stakeholders' perspectives of the issues at hand. Our aim was to explore surgical, anesthesia, and OR staff member perspectives on barriers and facilitators to reducing OR waste. MATERIALS AND METHODS: Identified stakeholders from a single academic medical center were interviewed to identify important barriers and facilitators to reducing surgical waste. Two team members with qualitative research experience used deductive logic guided by the Theoretical Domains Framework of behavior change to identify themes within transcripts. RESULTS: Nineteen participants including surgeons (n = 3, 15.8%), surgical residents (n = 5, 26.3%), an anesthesiologist (n = 1, 5.3%), anesthesia residents (n = 2, 10.5%), nurse anesthetists (n = 2, 10.5%), nurses (n = 5, 26.3%), and a surgical technologist (n = 1, 5.3%) were interviewed. Twelve of the 14 themes within the Theoretical Domains Framework were discovered in transcripts. Barriers within these themes included lack of resources to pursue environmental sustainability in the OR and the necessity of maintaining sterility for patient safety. Facilitators included emphasizing surgeon leadership within the OR to reduce unused supplies and spreading awareness of the environmental and economic impact of surgical waste. CONCLUSIONS: Interviewed stakeholders were able to identify areas where improvements around surgical waste reduction and management could be made at the institution by describing barriers and facilitators to sustainability-driven interventions. Future surgical waste reduction initiatives at this institution will be guided by these important perspectives.

The effectiveness and tolerability of fixed-dose combination netarsudil 0.02%/latanoprost 0.005% at a tertiary glaucoma center.

PURPOSE: To assess real-world effectiveness and tolerability of fixed-dose combination netarsudil 0.02%/latanoprost 0.005% (FCNL) in management of glaucoma patients in a tertiary eye care center. METHODS: This retrospective cohort study included glaucoma patients initiated on FCNL from January 2018 to July 2021 with at least 1-month follow-up. Demographic and clinical data were collected at baseline and at follow-up visits through 12 months. Patient-solicited side effects were recorded at each visit. Maximum glaucoma pharmacotherapy was defined as surgery/laser being the next treatment option following an intensive pharmacotherapy regimen, or when pharmacotherapy could not be increased due to allergy/intolerance or all pharmacologic mechanisms already being in use. RESULTS: Seventy-nine eyes of 47 patients were included. Mean age was 67.7 ± 14.7 years. Baseline IOP was 18.7 ± 4.9 mmHg; mean change in IOP (∆IOP) each study visit compared to baseline ranged from - 1.6 ± 3.5 to - 4.4 ± 4.1 mmHg (all p < 0.05). The eyes on maximum glaucoma pharmacotherapy (73.4%) had similar ∆IOP compared to those on non-maximal therapy at each visit (p > 0.2 for all). Forty-three (54.4%) eyes were switched from a prostaglandin analog alone, producing a 1-month IOP reduction of - 4.7 ± 3.9 mmHg at 1 month which remained significant at each visit for the 12-month study period (all p < 0.05). Across all study visits, conjunctival hyperemia was documented in 26 (32.9%) eyes. Subjective blurry vision was reported in 22 (27.8%) eyes without significant worsening of visual acuity at any visit (all p > 0.05). Six (7.6%) and 7 (8.9%) eyes required further medical or surgical/laser intervention, respectively. Kaplan-Meier analysis revealed no significant difference in the need for subsequent medical or surgical intervention between those on maximum and non-maximal pharmacotherapy (p > 0.4). CONCLUSION: FCNL was well-tolerated and demonstrated a significant and sustained reduction in IOP, even as last-line therapy before incisional or laser surgery in those on maximum glaucoma pharmacotherapy. FCNL is a viable treatment option for glaucomatous eyes before consideration of surgical intervention.

RISK FACTORS FOR SURGERY OR BLINDNESS IN NEOVASCULAR GLAUCOMA EYES TREATED WITH ANTI-VEGF INJECTIONS BY A RETINA SPECIALIST.

PURPOSE: To determine baseline patient characteristics that predict the need for glaucoma surgery or blindness in eyes with neovascular glaucoma (NVG) despite intravitreal antivascular endothelial growth factor therapy. METHODS: This is a retrospective cohort study of patients with NVG who had not previously received glaucoma surgery and were treated with intravitreal antivascular endothelial growth factor injections at the time of diagnosis, from September 8, 2011, to May 8, 2020, at a large, retina subspecialty practice. RESULTS: Of 301 newly presenting NVG eyes, 31% required glaucoma surgery and 20% progressed to no light perception vision despite treatment. Patients with intraocular pressure >35 mmHg ( P < 0.001), two or more topical glaucoma medications ( P = 0.003), worse than 20/100 vision ( P = 0.024), proliferative diabetic retinopathy ( P = 0.001), eye pain or discomfort ( P = 0.010), and new patient status ( P = 0.015) at the time of NVG diagnosis were at a higher risk of glaucoma surgery or blindness regardless of antivascular endothelial growth factor therapy. The effect of panretinal photocoagulation was not statistically significant in a subgroup analysis of patients without media opacity ( P = 0.199). CONCLUSION: Several baseline characteristics at the time of presentation to a retina specialist with NVG seem to portend a higher risk of uncontrolled glaucoma despite the use of antivascular endothelial growth factor therapy. Prompt referral of these patients to a glaucoma specialist should be strongly considered.

The effectiveness and safety profile of netarsudil 0.02% in glaucoma treatment: real-world 6-month outcomes.

PURPOSE: To evaluate the efficacy and safety profile of netarsudil 0.02% ophthalmic solution in a tertiary glaucoma referral center. METHODS: This retrospective cohort study included patients with glaucoma initiated on netarsudil 0.02% at a single institution from November 2017 to September 2018. Demographic and clinical data were collected, including intraocular pressure (IOP) and drug side effects at baseline and 1-, 3-, and 6-month follow-up visits. RESULTS: A total of 340 eyes of 233 patients were included; mean ± SD patient age was 69.1 ± 12.5 years. One hundred twenty (48%) eyes experienced ≥ 20% decreases in IOP at the 1-month study visit; this effect was maintained through the 6-month visit. IOP-lowering effects in patients using ≥ 3 topical glaucoma medications were similar (all p > 0.1). Eighteen (7.4%) and 7 (2.9%) patients experienced increases in IOP of ≥ 3 and ≥ 5 mmHg, respectively. Across all study visits, conjunctival hyperemia was noted at a rate of 27.6%, and though frequently reported, complaints of blurred vision (31.1%) did not manifest in significant worsening of visual acuity. The rate of drug discontinuation due to insufficient IOP-lowering and side effects was 15.6% and 24.8%, respectively. Twenty-nine (11.4%) and 82 (32.3%) eyes required additional medical and surgical/laser intervention, respectively. CONCLUSION: Commonly used as the last-line medical therapy in this case series, netarsudil safely and significantly reduced IOP in patients with glaucoma, even in those using ≥ 3 glaucoma medications. Increases in IOP of ≥ 3 mmHg occurred in a small number of patients. Subjective vision changes and conjunctival hyperemia were the most frequently reported side effects.

Promotion and maintenance of physically active lifestyle in older outpatients 2 years after acute coronary syndrome.

AIMS: To examine long-term changes in lifestyle and exercise capacity of older patients hospitalized for acute coronary syndrome (ACS) involved in an innovative centre- and home-based exercise-based secondary prevention program. METHODS: A sample of 118 patients with ACS (age 76 [72-80] years) was analysed. Long-term changes in self-reported weekly leisure-time physical activity (wLTPA), walking speed (WS), and estimated cardiorespiratory fitness (eCRF, VO2peak, mL/kg/min) were the outcome variables. The program consisted of seven individual on-site sessions including motivational interviewing to reach exercise goals. Exercise prescription was based on the results of a standardized moderate and perceptually regulated treadmill walk to estimate VO2peak. wLTPA, WS, and eCRF were assessed at 1 (baseline), 2, 3, 4, 6, 12, and 24 months after discharge. RESULTS: 87, 76, and 70 patients completed follow-up at 6, 12, and 24 months, respectively. wLTPA significantly increased during the follow-up period (median METs/H/week 2.5, 11.2, 12.0, and 13.4 at baseline, 6, 12, and 24 months, respectively; P < 0.0001). At baseline, 18% of the sample met the current international guidelines for physical activity, while 75%, 70%, and 76% of them met the recommended values at 6-, 12-, and 24-month follow-up sessions, respectively. These results were associated with increasing median WS (2.9 ± 1.0, 4.3 ± 1.2, 4.5 ± 1.1, 4.5 ± 1.2 km/h, respectively, P < 0.0001), and VO2peak (16.5, 21.4, 21.1, 21.3 mL/kg/min, respectively, P < 0.0001). CONCLUSIONS: This early, individualized exercise intervention improved long-term adherence to a physically active lifestyle, walking capacity, and eCRF in older patients after ACS. Larger studies are needed to confirm short- and long-term clinical benefits of this intervention.

Successful 10-second one-legged stance performance predicts survival in middle-aged and older individuals.

OBJECTIVES: Balance quickly diminishes after the mid-50s increasing the risk for falls and other adverse health outcomes. Our aim was to assess whether the ability to complete a 10- s one-legged stance (10-second OLS) is associated with all-cause mortality and whether it adds relevant prognostic information beyond ordinary demographic, anthropometric and clinical data. METHODS: Anthropometric, clinical and vital status and 10-s OLS data were assessed in 1702 individuals (68% men) aged 51-75 years between 2008 and 2020. Log-rank and Cox modelling were used to compare survival curves and risk of death according to ability (YES) or inability (NO) to complete the 10-s OLS test. RESULTS: Overall, 20.4% of the individuals were classified as NO. During a median follow-up of 7 years, 7.2% died, with 4.6% (YES) and 17.5% (NO) on the 10-s OLS. Survival curves were worse for NO 10-s OLS (log-rank test=85.6; p<0.001). In an adjusted model incorporating age, sex, body mass index and comorbidities, the HR of all-cause mortality was higher (1.84 (95% CI: 1.23 to 2.78) (p<0.001)) for NO individuals. Adding 10-s OLS to a model containing established risk factors was associated with significantly improved mortality risk prediction as measured by differences in -2 log likelihood and integrated discrimination improvement. CONCLUSIONS: Within the limitations of uncontrolled variables such as recent history of falls and physical activity, the ability to successfully complete the 10-s OLS is independently associated with all-cause mortality and adds relevant prognostic information beyond age, sex and several other anthropometric and clinical variables. There is potential benefit to including the 10-s OLS as part of routine physical examination in middle-aged and older adults.

Management of lymphocele following anterior lumbar interbody fusion, case report and review of literature.

While anterior lumbar interbody fusion (ALIF) is known as an established and safe procedure for treatment of degenerative disc disease, albeit rare, the development of postoperative intra-abdominal or retroperitoneal collection of lymph warrants timely diagnosis and management. This study presents the case of a 62-year-old male who underwent L4-L5 and L5-S1 ALIF and developed a persistent left-sided fluid collection, resulting in a symptomatic retroperitoneal lymphocele confirmed by computed tomography (CT). After percutaneous drainage by interventional radiology (IR), output remained high at 1 liter (L) per day, necessitating sclerotherapy with doxycycline and ethanol. In the absence of improvement, a lymphangiogram demonstrating a persistent lymph leak and glue embolization was performed. Due to refractory symptoms, retroperitoneal exploration with methylene blue dye was utilized for lymphatic mapping, and a lymphatic capillary leak in proximity to the left iliac artery was identified and successfully ligated with resolution of symptoms. With suspected fluid collections following ALIF, confirmation with CT or ultrasound (US) imaging followed by percutaneous drainage and testing of fluid is necessary. In mild cases, drainage alone or nonsurgical chemical sclerotherapy may suffice. In symptomatic refractory cases, localization of the site with lymphangiogram or US-guided injection of methylene blue dye allows for easier identification and definitive management with either transabdominal laparoscopic fenestration or retroperitoneal surgical exploration and ligation.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

The evolutionary assembly of forest communities along environmental gradients: recent diversification or sorting of pre-adapted clades?

Recent studies have demonstrated that ecological processes that shape community structure and dynamics change along environmental gradients. However, much less is known about how the emergence of the gradients themselves shape the evolution of species that underlie community assembly. In this study, we address how the creation of novel environments leads to community assembly via two nonmutually exclusive processes: immigration and ecological sorting of pre-adapted clades (ISPC), and recent adaptive diversification (RAD). We study these processes in the context of the elevational gradient created by the uplift of the Central Andes. We develop a novel approach and method based on the decomposition of species turnover into within- and among-clade components, where clades correspond to lineages that originated before mountain uplift. Effects of ISPC and RAD can be inferred from how components of turnover change with elevation. We test our approach using data from over 500 Andean forest plots. We found that species turnover between communities at different elevations is dominated by the replacement of clades that originated before the uplift of the Central Andes. Our results suggest that immigration and sorting of clades pre-adapted to montane habitats is the primary mechanism shaping tree communities across elevations.

In-vivo imaging of the conventional aqueous outflow system.

PURPOSE OF REVIEW: The aim of this study was to provide a comprehensive summary of in-vivo imaging techniques of the aqueous outflow system and discuss its role in improving our understanding of glaucoma pathogenesis and management. RECENT FINDINGS: Our understanding of the aqueous outflow system is largely derived from ex-vivo studies. Recent innovations in imaging technology and techniques enable in-vivo evaluation of the conventional outflow system in real-time. Optical coherence tomography allows for noninvasive, high-resolution, volumetric imaging of ocular tissues. Dynamic structural changes have been observed at the trabecular meshwork and Schlemm's canal. In parallel, aqueous angiography using injected tracers show a similar dynamism with variable and pulsatile flow signals. SUMMARY: In-vivo imaging enable real-time evaluation of the conventional aqueous outflow pathway. This emerging field shows great promise to expand our understanding of the pathogenesis and treatment of glaucoma.

Impact of the COVID-19 lockdown on the arrhythmic burden of patients with implantable cardioverter-defibrillators.

BACKGROUND: In Italy, a nationwide full lockdown was declared between March and May 2020 to hinder the novel coronavirus disease 2019 (COVID-19) pandemic. The potential individual health effects of long-term isolation are largely unknown. The current study investigated the arrhythmic consequences of the COVID-19 lockdown in patients with defibrillators (ICDs) living in the province of Ferrara, Italy. METHODS: Both the arrhythmias and the delivered ICD therapies as notified by the devices were prospectively collected during the lockdown period (P1) and compared to those occurred during the 10 weeks before the lockdown began (P2) and during the same period in 2019 (P3). Changes in outcome over the three study periods were evaluated for significance using McNemar's test. RESULTS: A total of 413 patients were included in the analysis. No differences were found concerning either arrhythmias or shocks or anti-tachycardia pacing. Only the number of patients experiencing non-sustained ventricular tachycardias (NSVTs) during P1 significantly decreased as compared to P2 (p = 0.026) and P3 (p = 0.009). The subgroup analysis showed a significant decrease in NSVTs during P1 for men (vs. P2, p = 0.014; vs. P3, p = 0.040) and younger patients (vs. P2, p = 0.002; vs. P3, p = 0.040) and for ischemic etiology (vs. P2, p = 0.003). No arrhythmic deaths occurred during P1. CONCLUSIONS: The complete nationwide lockdown, as declared by the Italian government during the first COVID-19 pandemic peak, did not impact on the incidence of arrhythmias in an urban cohort of patients with ICDs.