Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions. DESIGN: Systematic review and network meta-analysis. METHODS: Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool. DATA SOURCES: Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression. RESULTS: 218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges' g -0.62, 95% credible interval -0.80 to -0.45), yoga (n=1047, κ=33, g -0.55, -0.73 to -0.36), strength training (n=643, κ=22, g -0.49, -0.69 to -0.29), mixed aerobic exercises (n=1286, κ=51, g -0.43, -0.61 to -0.24), and tai chi or qigong (n=343, κ=12, g -0.42, -0.65 to -0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments. CONCLUSIONS: Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018118040.

Expanding mental health services in low- and middle-income countries: A task-shifting framework for delivery of comprehensive, collaborative, and community-based care.

This paper proposes a framework for comprehensive, collaborative, and community-based care (C4) for accessible mental health services in low-resource settings. Because mental health conditions have many causes, this framework includes social, public health, wellness and clinical services. It accommodates integration of stand-alone mental health programs with health and non-health community-based services. It addresses gaps in previous models including lack of community-based psychotherapeutic and social services, difficulty in addressing comorbidity of mental and physical conditions, and how workers interact with respect to referral and coordination of care. The framework is based on task-shifting of services to non-specialized workers. While the framework draws on the World Health Organization's Mental Health Gap Action Program and other global mental health models, there are important differences. The C4 Framework delineates types of workers based on their skills. Separate workers focus on: basic psychoeducation and information sharing; community-level, evidence-based psychotherapeutic counseling; and primary medical care and more advanced, specialized mental health services for more severe or complex cases. This paper is intended for individuals, organizations and governments interested in implementing mental health services. The primary aim is to provide a framework for the provision of widely accessible mental health care and services.

Temperature-Dependent Carrier Extraction and the Effects of Excitons on Emission and Photovoltaic Performance in Cs0.05FA0.79MA0.16Pb(I0.83Br0.17)3 Solar Cells.

The photovoltaic parameters of triple cation perovskite [Cs0.05FA0.79MA0.16Pb(I0.83Br0.17)3] solar cells are investigated focusing on the electro-optical properties and differences in performance at low and high temperatures. The signature of a parasitic barrier to carrier extraction is observed at low temperatures, which results in a loss of performance at T < 200 K. Intensity-dependent measurements indicate extraction across this parasitic interface is limited by a combination of the exciton binding energy and thermionic emission. However, the photovoltaic performance of the device is recovered at low intensity─where the photocarrier generation rate threshold is lower than the thermionic extraction rate. Loss of solar cell performance is also observed to be strongly correlated to an increase in photoluminescence intensity, indicating inhibited carrier extraction results in strong radiative recombination and that these systems do not appear to be limited by significant thermally activated non-radiative processes. Evidence of limited carrier extraction due to excitonic effects is also observed with a strong anti-correlation in photoluminescence and carrier extraction observed at lower temperatures.

Stable iPSC-derived NKX2-1+ lung bud tip progenitor organoids give rise to airway and alveolar cell types.

Bud tip progenitors (BTPs) in the developing lung give rise to all epithelial cell types found in the airways and alveoli. This work aimed to develop an iPSC organoid model enriched with NKX2-1+ BTP-like cells. Building on previous studies, we optimized a directed differentiation paradigm to generate spheroids with more robust NKX2-1 expression. Spheroids were expanded into organoids that possessed NKX2-1+/CPM+ BTP-like cells, which increased in number over time. Single cell RNA-sequencing analysis revealed a high degree of transcriptional similarity between induced BTPs (iBTPs) and in vivo BTPs. Using FACS, iBTPs were purified and expanded as induced bud tip progenitor organoids (iBTOs), which maintained an enriched population of bud tip progenitors. When iBTOs were directed to differentiate into airway or alveolar cell types using well-established methods, they gave rise to organoids composed of organized airway or alveolar epithelium, respectively. Collectively, iBTOs are transcriptionally and functionally similar to in vivo BTPs, providing an important model for studying human lung development and differentiation.

A multimodal iPSC platform for cystic fibrosis drug testing.

Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.

Stem cells, cell therapies, and bioengineering in lung biology and disease 2021.

The 9th biennial conference titled "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases" was hosted virtually, due to the ongoing COVID-19 pandemic, in collaboration with the University of Vermont Larner College of Medicine, the National Heart, Lung, and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, and the International Society for Cell & Gene Therapy. The event was held from July 12th through 15th, 2021 with a pre-conference workshop held on July 9th. As in previous years, the objectives remained to review and discuss the status of active research areas involving stem cells (SCs), cellular therapeutics, and bioengineering as they relate to the human lung. Topics included 1) technological advancements in the in situ analysis of lung tissues, 2) new insights into stem cell signaling and plasticity in lung remodeling and regeneration, 3) the impact of extracellular matrix in stem cell regulation and airway engineering in lung regeneration, 4) differentiating and delivering stem cell therapeutics to the lung, 5) regeneration in response to viral infection, and 6) ethical development of cell-based treatments for lung diseases. This selection of topics represents some of the most dynamic and current research areas in lung biology. The virtual workshop included active discussion on state-of-the-art methods relating to the core features of the 2021 conference, including in situ proteomics, lung-on-chip, induced pluripotent stem cell (iPSC)-airway differentiation, and light sheet microscopy. The conference concluded with an open discussion to suggest funding priorities and recommendations for future research directions in basic and translational lung biology.

Repeated injury promotes tracheobronchial tissue stem cell attrition.

Chronic lung disease has been attributed to stem cell aging and/or exhaustion. We investigated these mechanisms using mouse and human tracheobronchial tissue-specific stem cells (TSC). In mouse, chromatin labeling and flow cytometry demonstrated that naphthalene (NA) injury activated a subset of TSC. These activated TSC continued to proliferate after the epithelium was repaired and a clone study demonstrated that ~96% of activated TSC underwent terminal differentiation. Despite TSC attrition, epithelial repair after a second NA injury was normal. The second injury accelerated proliferation of previously activated TSC and a nucleotide-label retention study indicated that the second injury recruited TSC that were quiescent during the first injury. These mouse studies indicate that (a) injury causes selective activation of the TSC pool; (b) activated TSC are predisposed to further proliferation; and (c) the activated state leads to terminal differentiation. In human TSC, repeated proliferation also led to terminal differentiation and depleted the TSC pool. A clone study identified long- and short-lived TSC and showed that short-lived TSC clones had significantly shorter telomeres than their long-lived counterparts. The TSC pool was significantly depleted in dyskeratosis congenita donors, who harbor mutations in telomere biology genes. The remaining TSC had short telomeres and short lifespans. Collectively, the mouse and human studies support a model in which epithelial injury increases the biological age of the responding TSC. When applied to chronic lung disease, this model suggests that repeated injury accelerates the biological aging process resulting in abnormal repair and disease initiation.

Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition.

Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors (n = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors (n = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

"Between a Rock and a Hard Place": A Case Report of Stone Fragment Impaction Causing a Retained Ureteroscope Requiring Open Surgical Intervention.

Background: Ureteroscopy is frequently used for small renal and ureteral calculi. Rarely cases have been reported of retained ureteroscopes as a complication. With the limited number of cases, it is important to add these to the literature to mitigate the future risk from this complication that can lead to significant morbidity. We present our unique experience with a retained ureteroscope requiring open surgical intervention. Case Presentation: Our case is a 65-year-old female undergoing ureteroscopy for a 2 cm right ureteropelvic junction obstructing stone. After laser lithotripsy, there was significant buildup of stone debris distally along the ureteroscope. Conservative measures failed to remove the ureteroscope, so an open surgical approach was taken. The ureteroscope was removed, and a ureteral reimplant was performed. Postoperative CT shows residual hydronephrosis, but there is no obstruction seen on renal Lasix scan. Conclusions: This is a rare, but real, complication that urologists must be aware of. Preventive measures with pre-stenting early intraoperative stenting, using a ureteral access sheath, or using a single-use flexible ureteroscope could be considered especially when treating larger stones endoscopically.

Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells.

Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, we follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. We employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modeling and therapeutic screening applications.

Assessing cell-specific effects of genetic variations using tRNA microarrays.

BACKGROUND: By definition, effect of synonymous single-nucleotide variants (SNVs) on protein folding and function are neutral, as they alter the codon and not the encoded amino acid. Recent examples indicate tissue-specific and transfer RNA (tRNA)-dependent effects of some genetic variations arguing against neutrality of synonymous SNVs for protein biogenesis. RESULTS: We performed systematic analysis of tRNA abunandance across in various models used in cystic fibrosis (CF) research and drug development, including Fischer rat thyroid (FRT) cells, patient-derived primary human bronchial epithelia (HBE) from lung biopsies, primary human nasal epithelia (HNE) from nasal curettage, intestinal organoids, and airway progenitor-directed differentiation of human induced pluripotent stem cells (iPSCs). These were compared to an immortalized CF bronchial cell model (CFBE41o-) and two widely used laboratory cell lines, HeLa and HEK293. We discovered that specific synonymous SNVs exhibited differential effects which correlated with variable concentrations of cognate tRNAs. CONCLUSIONS: Our results highlight ways in which the presence of synonymous SNVs may alter local kinetics of mRNA translation; and thus, impact protein biogenesis and function. This effect is likely to influence results from mechansistic analysis and/or drug screeining efforts, and establishes importance of cereful model system selection based on genetic variation profile.

2017 WONOEP appraisal: Studying epilepsy as a network disease using systems biology approaches.

The revolution in high-throughput omics technologies has dramatically expanded our understanding of the epilepsies as complex diseases. It is now clear that further progress in treating the full spectrum of seizure disorders requires a systems-level framework for analyzing and integrating data from multiple omics technologies that moves beyond the search for single molecular alterations to an understanding of dysregulated pathways in epilepsy. Taking such a pathway-centered view requires further integrating the tools of systems biology into epilepsy research. In this appraisal, we highlight and summarize systems biology approaches in basic epilepsy studies as they were discussed during the 2017 Workshop on the Neurobiology of Epilepsy (WONOEP). During the 3-day event, participants exchanged emerging results and thoughts on developing the systems biology of epilepsy, and the promise and limitations of these approaches for the near term.

A smart curtailment approach for reducing bat fatalities and curtailment time at wind energy facilities.

The development and expansion of wind energy is considered a key global threat to bat populations. Bat carcasses are being found underneath wind turbines across North and South America, Eurasia, Africa, and the Austro-Pacific. However, relatively little is known about the comparative impacts of techniques designed to modify turbine operations in ways that reduce bat fatalities associated with wind energy facilities. This study tests a novel approach for reducing bat fatalities and curtailment time at a wind energy facility in the United States, then compares these results to operational mitigation techniques used at other study sites in North America and Europe. The study was conducted in Wisconsin during 2015 using a new system of tools for analyzing bat activity and wind speed data to make near real-time curtailment decisions when bats are detected in the area at control turbines (N = 10) vs. treatment turbines (N = 10). The results show that this smart curtailment approach (referred to as Turbine Integrated Mortality Reduction, TIMR) significantly reduced fatality estimates for treatment turbines relative to control turbines for pooled species data, and for each of five species observed at the study site: pooled data (-84.5%); eastern red bat (Lasiurus borealis, -82.5%); hoary bat (Lasiurus cinereus, -81.4%); silver-haired bat (Lasionycteris noctivagans, -90.9%); big brown bat (Eptesicus fuscus, -74.2%); and little brown bat (Myotis lucifugus, -91.4%). The approach reduced power generation and estimated annual revenue at the wind energy facility by ≤ 3.2% for treatment turbines relative to control turbines, and we estimate that the approach would have reduced curtailment time by 48% relative to turbines operated under a standard curtailment rule used in North America. This approach significantly reduced fatalities associated with all species evaluated, each of which has broad distributions in North America and different ecological affinities, several of which represent species most affected by wind development in North America. While we recognize that this approach needs to be validated in other areas experiencing rapid wind energy development, we anticipate that this approach has the potential to significantly reduce bat fatalities in other ecoregions and with other bat species assemblages in North America and beyond.

CFTR modulator theratyping: Current status, gaps and future directions.

BACKGROUND: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations. METHODS: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants. RESULTS: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients. CONCLUSIONS: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.

Author Correction: Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis.

This corrects the article DOI: 10.1038/ncomms15857.

Mode-locking in advection-reaction-diffusion systems: An invariant manifold perspective.

Fronts propagating in two-dimensional advection-reaction-diffusion systems exhibit a rich topological structure. When the underlying fluid flow is periodic in space and time, the reaction front can lock to the driving frequency. We explain this mode-locking phenomenon using the so-called burning invariant manifolds (BIMs). In fact, the mode-locked profile is delineated by a BIM attached to a relative periodic orbit (RPO) of the front element dynamics. Changes in the type (and loss) of mode-locking can be understood in terms of local and global bifurcations of the RPOs and their BIMs. We illustrate these concepts numerically using a chain of alternating vortices in a channel geometry.

Prediction and generation of binary Markov processes: Can a finite-state fox catch a Markov mouse?

Understanding the generative mechanism of a natural system is a vital component of the scientific method. Here, we investigate one of the fundamental steps toward this goal by presenting the minimal generator of an arbitrary binary Markov process. This is a class of processes whose predictive model is well known. Surprisingly, the generative model requires three distinct topologies for different regions of parameter space. We show that a previously proposed generator for a particular set of binary Markov processes is, in fact, not minimal. Our results shed the first quantitative light on the relative (minimal) costs of prediction and generation. We find, for instance, that the difference between prediction and generation is maximized when the process is approximately independently, identically distributed.

Improving access to urologists through an electronic consultation service.

INTRODUCTION: Access to specialist services is limited by wait times and geographic availability. Champlain Building Access to Specialist Advice (BASE) has been implemented in our service region to facilitate access to specialists by primary care providers (PCPs). Through a secure web-based system, PCPs are able to send eConsults instead of requesting a formal in-office consultation. METHODS: Urology eConsults completed through the Champlain BASE service from March 2013 to January 2015 were analyzed. Each consult was characterized in regard to the type of question asked by the referring physician and the clinical content of the referral. Using the mandatory close-out surveys, we analyzed rates of referral avoidance, physician satisfaction, and overall impact on patient care. RESULTS: Of 190 eConsultations, 70% were completed in less than 10 minutes. The most common clinical questions related to the interpretation of imaging reports (16%) and tests to choose for investigating a condition (15%). The most common diagnoses were hematuria (13%) and renal mass (8%). In 35% of cases, referral to a urologist had originally been contemplated and was avoided. In 8% of cases, a PCP did not believe a consultation was initially needed, but a referral was ultimately initiated after the eConsultation. CONCLUSIONS: Our study shows that although certain clinical presentations still require a formal in-person urological consultation, eConsultations can potentially reduce unnecessary clinic visits while identifying patients who may benefit from early urological consultation. Through both these mechanisms, we may improve timely access to urologists.