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Accurate staging of non-small cell lung cancer (NSCLC) is crucial for allocation to surgical, medical or multimodal treatment. EUS and endobronchial ultrasound (EBUS) have gained ground in the diagnosis and staging of lung cancer in addition to radiological imaging (e.g., computed tomography, fluoroscopy, and magnetic resonance imaging), nuclear medicine techniques (e.g. positron emission tomography, PET), combined techniques (e.g., fluorodesoxyglucosepositron emission tomography scanning), and sonographic imaging including conventional transcutaneous mediastinal and lung ultrasound. By using one single echoendoscope in both the trachea and the esophagus, surgical staging procedures (e.g. mediastinoscopy and video assisted thoracoscopy) can be avoided in a considerable proportion of patients with NSCLC.

Given the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g. nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution’s research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors’ experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.

Background Disease of the pilonidal sinus is a common condition that affects mainly young adults. Options for management include excision of the sinus tracts, leaving the wound open to heal by secondary intention. The aim of this study was to compare wound healing with dialkylcarbamoyl chloride (DACC)‐coated dressings versus alginate dressings. Methods This multicentre trial randomized consecutive patients undergoing surgery for pilonidal disease to postoperative wound care with either DACC‐coated or alginate dressings. The primary outcome was the proportion of wounds healed after 75 days. Secondary outcomes were the local status of wounds during the healing process, the quality assessment of the dressings by the patient, and the time needed to return to usual activities. Results A total of 246 patients were included: 120 in the DACC‐coated group and 126 in the alginate group. In per‐protocol analysis, there were significantly more patients with completely healed wounds after 75 days in the DACC group than in the alginate group: 78 of 103 (75·7 per cent) versus 58 of 97 (60 per cent) respectively (odds ratio 2·55, 95 per cent c.i. 1·12 to 5·92; P = 0·023). During follow‐up, wounds with alginate dressings had more fibrin than those with DACC‐coated dressings, but the difference was not significant (P = 0·079). There was no difference between the two arms in patients' assessment of the dressings. Conclusion The number of wounds completely healed at 75 days was significantly higher for DACC‐coated compared with alginate dressings. However, the preplanned, clinically significant improvement in healing of 20 per cent was not reached. Registration number: NCT02011802 ( https://clinicaltrials.gov/)., This multicentre RCT compared the efficacy of dialkylcarbamoyl chloride (DACC)‐coated dressings with alginate dressings for wound healing after pilonidal sinus excision. In per‐protocol analysis, significantly more patients had completely healed wounds at 75 days in the DACC group than in the alginate group: 78 of 103 (75·7 per cent) versus 58 of 97 (60 per cent) respectively (odds ratio 2·55, 95 per cent c.i. 1·12 to 5·92; P = 0·023). No clinically important difference

Software developers are generally interested in developing better habits to increase their workplace productivity and well-being, but have difficulties identifying concrete goals and actionable strategies to do so. In several areas of life, such as the physical activity and health domain, self-reflection has been shown to be successful at increasing people's awareness about a problematic behavior, motivating them to define a self-improvement goal, and fostering goal-achievement. We therefore designed a reflective goal-setting study to learn more about developers’ goals and strategies to improve or maintain good habits at work. In our study, 52 professional software developers self-reflected about their work on a daily basis during two to three weeks, which resulted in a rich set of work habit goals and actionable strategies that developers pursue at work. We also found that purposeful, continuous self-reflection not only increases developers’ awareness about productive and unproductive work habits (84.5 percent), but also leads to positive self-improvements that increase developer productivity and well-being (79.6 percent). We discuss how tools could support developers with a better trade-off between the cost and value of workplace self-reflection and increase long-term engagement.

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).

Significance Exercise is a powerful antiaging intervention that protects against cardiovascular disease, dementia, diabetes, sarcopenia, and cancer. How exercise promotes health benefits to multiple tissues in the body, however, remains poorly understood. We establish a young adult swim exercise regimen for the short-lived nematode Caenorhabditis elegans that induces health benefits at the neuromuscular, intestinal, and cognitive levels and protects against neurodegeneration in models of tauopathy, Alzheimer’s disease, and Huntington’s disease. Importantly, we found that swim exercise performed exclusively in early adulthood promotes long-lasting systemic benefits that are still detectable in midlife. The advantages of C. elegans as a short-lived genetic model will allow for dissection of the molecular circuitry involved in system-wide exercise benefits., Regular physical exercise is the most efficient and accessible intervention known to promote healthy aging in humans. The molecular and cellular mechanisms that mediate system-wide exercise benefits, however, remain poorly understood, especially as applies to tissues that do not participate directly in training activity. The establishment of exercise protocols for short-lived genetic models will be critical for deciphering fundamental mechanisms of transtissue exercise benefits to healthy aging. Here we document optimization of a long-term swim exercise protocol for Caenorhabditis elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase of adulthood. We found that multiple daily swim sessions are essential for exercise adaptation, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters, such as mitochondrial respiration and midlife survival, increases functional healthspan of the pharynx and intestine, and enhances nervous system health by increasing learning ability and protecting against neurodegeneration in models of tauopathy, Alzheimer’s disease, and Huntington’s disease. Remarkably, swim training only during early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into midlife. Our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health, and establish the foundation for exploiting the powerful advantages of this genetic model for the dissection of the exercise-dependent molecular circuitry that confers system-wide health benefits to aging adults.

BACKGROUND Parenteral nutrition (PN) is a complicated therapy in which having specially trained clinicians can provide benefit, but it can be difficult to provide this level of expertise to all patients requiring PN. Creation of a virtual nutrition support team (NST) model allows patients across multiple hospitals to receive care from NST clinicians using remote conferencing technology on a daily basis. This study reviewed retrospective data from before and after implementation of the virtual model to assess quality indicators. METHODS The NST was developed including a team of dietitians and pharmacists with a physician medical director. Practice guidelines were developed to provide consistent methods for ordering and monitoring patients receiving PN. Patient charts in both the preintervention and postintervention groups were reviewed for indication for PN, duration of therapy, blood glucose levels, and demographic data. RESULTS A greater proportion of patients in the postintervention period had appropriate orders (97.2%) compared with patients in the preintervention period (58.9%) (P

Rural Eastern Cape, South Africa.To identify steps in the TB preventive care cascade from routinely collected data among TB patients at a district hospital prior to the implementation of a novel TB program.This was a retrospective study. We adapted the TB prevention cascade to measure indicators routinely collected at district hospitals for TB using a cascade framework to evaluate outcomes in the cohort of close contacts.A total of 1,722 charts of TB patients were reviewed. The majority of patients (87%) were newly diagnosed with no previous episodes of TB. A total of 1,548 (90%) patients identified at least one close contact. A total of 7,548 contacts were identified with a median of 4.9 (range 1-16) contacts per patient. Among all contacts identified, 2,913 (39%) were screened for TB. Only 15 (0.5%) started TB preventive therapy and 122 (4.4%) started TB treatment. Nearly 25% of all medical history and clinical information was left unanswered among the 1,722 TB charts reviewed.Few close contacts were screened or started on TB preventive therapy in this cohort. Primary care providers for TB care in district health facilities should be informed of best practices for screening and treating TB infection and disease.Le Cap Est rural, le Cap, Afrique du Sud.Identifier les étapes de la cascade de soins préventifs de la TB à partir des données de routine recueillies parmi des patients dans un hôpital de district avant la mise en œuvre d’un nouveau programme TB.Ceci était une étude rétrospective. Nous avons adapté la cascade de prévention de la TB pour mesurer les indicateurs recueillis en routine dans les hôpitaux de district pour la TB en utilisant un cadre en cascade afin d’évaluer les résultats dans la cohorte des contacts étroits.Un total de 1 722 dossiers de patients TB a été revu. La majorité des patients (87%) avait un diagnostic nouveau sans épisode de TB préalable. Un total de 1 548 (90%) patients ont identifié au moins un contact étroit ; 7 548 contacts ont été identifiés avec une médiane de 4,9 (fourchette 1–16) contacts par patient. Parmi tous les contacts identifiés, 2 913 (39%) ont eu une recherche de TB. Seulement 15 (0,5%) ont initié le traitement préventif et 122 (4,4%) ont mis en route le traitement de TB. Près de 25% de tous les antécédents et autres informations cliniques n’était pas remplis dans les 1 722 dossiers TB revus.Peu de contacts étroits ont été dépistés ou mis sous traitement préventif de TB dans cette cohorte. Les prestataires de soins de santé primaires pour la TB dans les structures de santé des districts doivent être informés des meilleures pratiques pour le dépistage et le traitement de la TB infection et maladie.

Background There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. Methods Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). Results The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38–.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29–.46). Conclusions Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May., Treatment of moderate to severe coronavirus disease 2019 (COVID-19) with remdesivir and dexamethasone was associated with a lower risk of mechanical ventilation and a significant better overall 30-day survival as compared to standard care alone.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. “Traceback” cascade testing —outreach to potential probands and relatives—is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program’s feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program’s feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.

Rationale: We aim to describe the clinical characteristics and outcomes of patients who received Tocilizumab for COVID-19 pneumonia at our institution between March 20 and October 26, 2020. Methods: In this single center, retrospective, observational study, we identified 55 adults admitted with COVID-19 pneumonia who received Tocilizumab. Demographic data, symptoms, laboratory values, treatments, and clinical outcomes were collected. Data was compared between those who received Tocilizumab and all patients admitted with COVID-19. Primary outcome was 28-day mortality. Secondary outcomes included role of concomitant steroid use and change in eosinophil counts, ferritin, AST, CRP and D-Dimer values. Results: Of the 589 patients admitted with COVID-19 pneumonia, 55 received Tocilizumab as part of their treatment course. Patient demographics of those who received Tocilizumab include a mean age of 58 years with 73% male, 51% with diabetes, and 58% with hypertension. 4/55 (7.3%) were immunocompromised. Common presenting symptoms on admission were fever (62%), cough (78%) and dyspnea (89%). 35/55 (64%) were admitted to the ICU during their hospitalization;their mean P/F ratio was 127. Tocilizumab was administered on average admission day 4 (1-19). A second dose was given to 17 (31%) of patients, with 11 given the following day. Average hospital length of stay (LOS) postadministration was 17 days. Average white blood cell (WBC) count on day of Tocilizumab administration was 11, with an absolute lymphocyte count of 0.96. Mean IL-6 on hospital admission was 48.3. Two days post Tocilizumab administration there was a peak in ferritin, percent eosinophils, and AST. Both two-and five-day post-Tocilizumab CRP levels decreased while D-Dimer increased (Table 1). All Tocilizumab patients received antibiotics. In addition, three received hydroxychloroquine, 16 Remdesivir, and 51 convalescent plasma. 31 (56%) received steroids. On Day 2, those who did not receive steroids had, on average, more than double the percent of eosinophils in their blood (3.21% vs 1.53%). This difference decreased by Day 5. In time period of interest, COVID-19 admission mortality was 63/589 (10.6%) and 40/77 (52%) for mechanically ventilated patients. For Tocilizumab recipients, 25/55 patients were mechanically ventilated and 12/25 (48%) died. Overall, 28-day mortality was 11/55 (20%), with hospital mortality up to 16/55 (29%). This was similar to our larger cohort ICU mortality of 29.3%. Conclusion: Tocilizumab recipients in our cohort had a mortality similar to overall COVID ICU mortality. It appeared to be well tolerated except for an increase in eosinophilia if with no concomitant steroid use.

What is a good workday for a software developer? What is a typical workday? We seek to answer these two questions to learn how to make good days typical. Concretely, answering these questions will help to optimize development processes and select tools that increase job satisfaction and productivity. Our work adds to a large body of research on how software developers spend their time. We report the results from 5,971 responses of professional developers at Microsoft, who reflected about what made their workdays good and typical, and self-reported about how they spent their time on various activities at work. We developed conceptual frameworks to help define and characterize developer workdays from two new perspectives: good and typical. Our analysis confirms some findings in previous work, including the fact that developers actually spend little time on development and developers’ aversion for meetings and interruptions. It also discovered new findings, such as that only 1.7 percent of survey responses mentioned emails as a reason for a bad workday, and that meetings and interruptions are only unproductive during development phases; during phases of planning, specification and release, they are common and constructive. One key finding is the importance of agency, developers’ control over their workday and whether it goes as planned or is disrupted by external factors. We present actionable recommendations for researchers and managers to prioritize process and tool improvements that make good workdays typical. For instance, in light of our finding on the importance of agency, we recommend that, where possible, managers empower developers to choose their tools and tasks.

Metformin is found in the majority of lakes and streams in the United States, leading to widespread environmental exposure. Results of the present study indicate that extended duration metformin exposure at critical developmental periods leads to decreased survival rates in zebrafish (danio rerio), an NIH approved human model. Significant abnormalities are seen with extended duration metformin exposure from 4 h post fertilization up to 5 days post fertilization, although short term metformin exposure for 24 h at 4–5 days post fertilization did not lead to any significant abnormalities. Both extended and short term duration did however have an impact on locomotor activity of zebrafish, and several genes involved in neurological and cardiovascular development were differentially expressed after exposure to metformin. The changes seen in behavior, gene expression and morphological abnormalities caused by metformin exposure should be examined further in future studies in order to assess their potential human health implications as metformin prescriptions continue to increase worldwide.

Objective Hydroxychloroquine has been proposed as a primary prophylactic agent against coronavirus disease 2019 (COVID-19). This study aimed to investigate if patients treated with hydroxychloroquine for a non-COVID-19 indication had a lower risk of verified infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared with matched controls. Methods A cohort comprising all persons in Denmark collecting hydroxychloroquine prescriptions in 2020 and 2019 (i.e., both during and before SARS-CoV-2 was confirmed in Denmark), matched by age and sex with controls, was studied. Data were collected using the Danish national registries, which contain complete information on patient health data, prescriptions and microbiological test results. The main outcome was microbiologically verified SARS-CoV-2 infection. Results In total, 5488 hydroxychloroquine users were matched with 54,486 non-users. At baseline, the groups differed in terms of diagnoses of pulmonary disease, cardiovascular disease, renal disease, gastrointestinal/metabolic disease and dementia, as well as treatment with antirheumatic drugs. The final model was adjusted for these potential confounders. Use of hydroxychloroquine for non-COVID-19 indications was not associated with any change in confirmed SARS-CoV-2 (hazard ratio 0.90, 95% confidence interval 0.76–1.07). This result was robust in the propensity-score-matched sensitivity analysis. Conclusion This study, which is the largest to date to investigate the primary prophylactic effect of hydroxychloroquine against SARS-CoV-2, does not support any prophylactic benefit of hydroxychloroquine in the prevention of infection with SARS-CoV-2.

For many vaccine-preventable diseases like influenza, vaccination rates are lower than optimal to achieve community protection. Those at high risk for infection and serious complications are especially advised to be vaccinated to protect themselves. Using influenza as a model, we studied one method of increasing vaccine uptake: informing high-risk patients, identified by a machine learning model, about their risk status. Patients (N=39,717) were evenly randomized to (1) a control condition (exposure only to standard direct mail or patient portal vaccine promotion efforts) or to be told via direct mail, patient portal, and/or SMS that they were (2) at high risk for influenza and its complications if not vaccinated; (3) at high risk according to a review of their medical records; or (4) at high risk according to a computer algorithm analysis of their medical records. Patients in the three treatment conditions were 5.7% more likely to get vaccinated during the 112 days post-intervention (p < .001), and did so 1.4 days earlier (p < .001), on average, than those in the control group. There were no significant differences among risk messages, suggesting that patients are neither especially averse to nor uniquely appreciative of learning their records had been reviewed or that computer algorithms were involved. Similar approaches should be considered for COVID-19 vaccination campaigns.

This survey study queried employees of a health care system before COVID-19 vaccine distribution to assess their intentions to receive a vaccine and to understand their reasons for hesitancy to do so.

Background. There has been a steady increase in the use of electronic media and instant messaging among healthcare professionals, where it has been almost universally adopted in the workplace. The use of WhatsApp and its perceived benefits in healthcare have been extensively studied; however, there are concerns regarding the potential for ethical breaches in confidentiality through shared electronic patient information. Objectives. To identify the usage characteristics and incidence of shared patient information with WhatsApp use in a team of medical doctors in an unobserved and unregulated setting. Methods. We conducted a retrospective cross-sectional content analysis of WhatsApp messages ( n =3 340) among a team of 20 doctors in a South African district hospital over 6 months. All messages found within this time period were allocated unique identifiers. The text and image messages were thematically grouped into four categories, i.e. clinical care, resource allocation, social and administrative. Messages that contained patient-identifying information were included in the analysis. Results. Of a total of 3 340 messages sent, 220 (6.6%) contained patient-identifying information. Of these, 109 (3.3%) contained non-anonymised patient information, while in 111 (3.3%) messages, the information was anonymised. The likelihood of sharing patient identifiers was proportionally much higher in shared images (odds ratio (OR) 5.1; 95% confidence interval (CI) 3.2 - 8.2; p

We partnered with Walmart to test 22 nudges designed to boost vaccination rates in their pharmacies. Nudges were delivered via text message to over 650,000 Walmart pharmacy patients in the fall of 2020 and encouraged patients to visit Walmart for a flu vaccine. We demonstrate that behaviorally informed messages increase pharmacy vaccination rates by an average of 6.7% over a roughly three-month follow-up period. The most effective messages in our field experiment matched the tone of typical pharmacy communications and reminded patients that a flu shot was waiting for them. These insights suggest that carefully crafted messages informed by the results of this study could nudge the adoption of other vaccines for other infectious diseases, including COVID-19.

Healthcare workers (HCWs) have been recommended to receive first priority for limited COVID-19 vaccines. They have also been identified as potential ambassadors of COVID-19 vaccine acceptance, helping to ensure that sufficient members of a hesitant public accept COVID-19 vaccines to achieve population immunity. Yet HCWs themselves have shown vaccine hesitancy in other contexts and the few prior surveys of U.S. HCW intentions to receive a COVID-19 vaccine report acceptance rates of only 28% to 34%. However, it is unknown whether HCW acceptance remains low following mid-November announcements of the efficacy of the first COVID-19 vaccines and the issuance of two emergency use authorizations (EUA) in December. We report the results of a December 2020 survey (N= 16,158; response rate 61%) administered by a large Pennsylvania health system to determine the intentions of its employees to receive a vaccine when it is offered to them. In a mixed sample of individuals serving in patient-facing and other roles, 55% would decide to receive a COVID-19 vaccine when offered, 16.4% would not, and 28.5% reported being undecided. The distribution of responses varied little across hospital campuses, between those in patient-facing roles and other HCWs, or by area or department of work. The higher rate of COVID-19 vaccine acceptance we observe may reflect the framing and timing of our survey. Among hesitant respondents, an overwhelming majority (90.3%) reported concerns about unknown risks and insufficient data. Other commonly reported concerns included known side effects (57.4%) and wanting to wait until they see how it goes with others (44.4%). We observed a substantial increase in self-reported intent to receive a COVID-19 vaccine after an FDA advisory committee voted to recommend an EUA. Among respondents who completed the survey after that point in time, 79% intend to receive a COVID-19 vaccine (n= 1155). Although only suggestive, this trend offers hope that rates of COVID-19 vaccine acceptance may be higher among HCWs and, perhaps, the general public than more hypothetical survey results have indicated.

Background There is an urgent need for treatments that can shorten hospitalization and lower the risk of secondary infection and death in patients with corona disease. The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease. Methods The ProPAC-COVID is a multi-center, randomized, placebo-controlled, double-blinded clinical trial. The primary outcome is number of days spent alive and out of hospital within 14 days from randomization. Randomization will be in blocks of unknown size, and the final allocation will be stratified for age, site of recruitment, and whether the patient has any chronic lung diseases. Data is analyzed using intention-to-treat (ITT) principles, and main analyses will also be subject to modified ITT analysis and per protocol analysis. Discussion This paper describes the detailed statistical analysis plan for the evaluation of primary and secondary endpoints of the ProPAC-COVID study. Enrolment of patients to the ProPAC-COVID study is still ongoing. The purpose of this paper is to provide primary publication of study results to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Trial registration ClinicalTrials.gov NCT04322396. Registered on 26 March 2020.

Background: In Peru, anemia has been a persistent health problem that is known to lead to irreversible cognitive and developmental deficits in children. The Peruvian government has recently made anemia a primary health concern by passing legislation in 2017 that makes anemia an intersectoral priority. This new legislation fortifies previous programs while creating new programs that target specific age groups. Objectives: Evaluate the effectiveness of government programs in Madre de Dios, Peru to reduce anemia prevalence and increase hemoglobin levels among children ages 2–11 years old. Methods: Propensity scores are used to match 688 children enrolled in 2018, after the legislation, and 2,140 children enrolled in previous studies our team conducted in the region between 2014 and 2017, based on sex, age (years), intervention status (prior/post), community income, presence of a health post in the community (yes/no), community type (indigenous, non-indigenous rural, non-indigenous urban) and road access (fraction of the number of months out of the year with road access). A pseudo matched case-control analysis to evaluate changes in anemia prevalence and hemoglobin was conducted using t-tests and multivariate models. Program effectiveness is evaluated overall, by age groups (2–4, 5–7 and 8–11 years old), and community type (indigenous vs. urban). Findings: The adjusted odds ratio indicated lower odds of anemia (OR = 0.31, 95%CI 0.17–0.54) for children exposed to the anemia prevention programs vs. those not exposed. The effect was not significantly different across age groups; however, the intervention effects significantly differed by community type among children 8–11 years old, with urban children less likely to benefit from anemia interventions (OR = 0.69, 95% CI 0.38–1.25) compared to indigenous children (OR = 0.21, 95% CI 0.08–0.56). Conclusion: Government programs to reduce anemia in Madre de Dios were found to be associated with reduced anemia prevalence in the study communities. However, the lack of program monitoring precludes the attribution of anemia decline to specific interventions or program components. In addition, regional anemia prevalence remains high according to the 2019 Demographic and Health Survey, suggesting impaired population impact. Program monitoring and evaluation is a key component of health interventions to improve program implementation effectiveness.

Background Exome and genome sequencing are routinely used in clinical care and research. These technologies allow for the detection of pathogenic/likely pathogenic variants in clinically actionable genes. However, fueled in part by a lack of empirical evidence, controversy surrounds the provision of genetic results for adult-onset conditions to minors and their parents. We have designed a mixed-methods, longitudinal cohort study to collect empirical evidence to advance this debate. Methods Pediatric participants in the Geisinger MyCode® Community Health Initiative with available exome sequence data will have their variant files assessed for pathogenic/likely pathogenic variants in 60 genes designated as actionable by MyCode. Eight of these genes are associated with adult-onset conditions (Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Lynch syndrome, MUTYH-associated polyposis, HFE-Associated Hereditary Hemochromatosis), while the remaining genes have pediatric onset. Prior to clinical confirmation of results, pediatric MyCode participants and their parents/legal guardians will be categorized into three study groups: 1) those with an apparent pathogenic/likely pathogenic variant in a gene associated with adult-onset disease, 2) those with an apparent pathogenic/likely pathogenic variant in a gene associated with pediatric-onset disease or with risk reduction interventions that begin in childhood, and 3) those with no apparent genomic result who are sex- and age-matched to Groups 1 and 2. Validated and published quantitative measures, semi-structured interviews, and a review of electronic health record data conducted over a 12-month period following disclosure of results will allow for comparison of psychosocial and behavioral outcomes among parents of minors (ages 0–17) and adolescents (ages 11–17) in each group. Discussion These data will provide guidance about the risks and benefits of informing minors and their family members about clinically actionable, adult-onset genetic conditions and, in turn, help to ensure these patients receive care that promotes physical and psychosocial health. Trial registration ClinicalTrials.gov Identifier: NCT03832985. Registered 6 February 2019

No abstract available.

Background Immunosuppressive medications are widely used for the prevention of allograft rejection in transplantation and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Despite their clinical utility, these medications are accompanied by multiple off-target effects, some of which may be mediated by their effects on mitochondria. Methods We examined the effect of commonly used immunosuppressive reagents, mycophenolate mofetil (MMF), cyclosporine A (CsA), rapamycin, and tacrolimus on mitochondrial function in human T-cells. T-cells were cultured in the presence of immunosuppressive medications in a range of therapeutic doses. After incubation, mitochondrial membrane potential, reactive oxygen species (ROS) production, and apoptotic cell death were measured by flow cytometry after staining with DiOC6, MitoSOX Red, and Annexin V and 7-AAD, respectively. Increases in cytosolic cytochrome c were demonstrated by Western blot. T-cell basal oxygen consumption rates were measured using a Seahorse bioanalyzer. Results T-cells demonstrated significant levels of mitochondrial depolarization after treatment with therapeutic levels of MMF but not after treatment with CsA, tacrolimus, or rapamycin. Only MMF induced T-cell ROS production and induced significant levels of apoptotic cell death that were associated with increased levels of cytosolic cytochrome c. MMF decreased T-cell basal oxygen consumption within its therapeutic range, and CsA demonstrated a trend toward this result. Conclusions The impairment of mitochondrial function by commonly used immunosuppressive reagents may impair T-cell differentiation and function by decreasing energy production, producing toxic ROS, and inducing apoptotic cell death.

Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).

Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychological disorder of childhood. Medication and cognitive behavioral therapy are effective treatments for many children; however, adherence to medication and therapy regimens is low. Thus, identifying effective adjunct treatments is imperative. Previous studies exploring computerized training programs as supplementary treatments have targeted working memory or attention. However, many lines of research suggest inhibitory control (IC) plays a central role in ADHD pathophysiology, which makes IC a potential intervention target. In this randomized control trial (NCT03363568), we target IC using a modified stop-signal task (SST) training designed by NeuroScouting, LLC in 40 children with ADHD, aged 8 to 11 years. Children were randomly assigned to adaptive treatment (n = 20) or non-adaptive control (n = 20) with identical stimuli and task goals. Children trained at home for at least 5 days a week (about 15m/day) for 4-weeks. Relative to the control group, the treatment group showed decreased relative theta power in resting EEG and trending improvements in parent ratings of attention (i.e. decreases in inattentive behaviors). Both groups showed improved SST performance. There was not evidence for treatment effects on hyperactivity or teacher ratings of symptoms. Results suggest training IC alone has potential to positively impact symptoms of ADHD and provide evidence for neural underpinnings of this impact (change in theta power; change in N200 latency). This shows promising initial results for the use of computerized training of IC in children with ADHD as a potential adjunct treatment option for children with ADHD.

Purpose The clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility. Methods Whole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient–participants and their clinicians. We queried patient–participants’ electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient–participants of eligible age who had begun risk management. Results Thirty-seven MyCode patient–participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer—including a stage 1C fallopian tube cancer—via these procedures. Conclusion Screening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

Exercise and caloric restriction improve health, including reducing risk of cardiovascular disease, neurological disease, and cancer. However, molecular mechanisms underlying these protections are poorly understood, partly due to the cost and time investment of mammalian long-term diet and exercise intervention studies. We subjected Caenorhabditis elegans nematodes to a 6-day, twice daily swimming exercise regimen, during which time the animals also experienced brief, transient food deprivation. Accordingly, we included a non-exercise group with the same transient food deprivation, a non-exercise control with ad libitum access to food, and a group that exercised in food-containing medium. Following these regimens, we assessed mitochondrial health and sensitivity to mitochondrial toxicants. Exercise protected against age-related decline in mitochondrial morphology in body-wall muscle. Food deprivation increased organismal basal respiration; however, exercise was the sole intervention that increased spare respiratory capacity and proton leak. We observed increased lifespan in exercised animals compared to both control and transiently food-deprived nematodes. Finally, exercised animals (and to a lesser extent, transiently food-deprived animals) were markedly protected against lethality from acute exposures to the mitotoxicants rotenone and arsenic. Thus, swimming exercise and brief food deprivation provide effective intervention in C. elegans, protecting from age-associated mitochondrial decline and providing resistance to mitotoxicant exposures.

The first opportunities to field test interventions to increase COVID-19 vaccination were among health care workers (HCWs), who were among the first to be offered COVID-19 vaccines. After 1 large Pennsylvania health system sent 36 vaccine-related mass emails to employees over 5 weeks (eAppendix in Supplement 1), 9723 of 23 700 HCWs (41%) had still not scheduled their vaccination. We sought to determine whether individually addressed emails designed with behaviorally informed features1,2,3,4,5 could increase vaccination registration compared with a delayed control group.

Many software development organizations strive to enhance the productivity of their developers. All too often, efforts aimed at improving developer productivity are undertaken without knowledge about how developers spend their time at work and how it influences their own perception of productivity. To fill in this gap, we deployed a monitoring application at 20 computers of professional software developers from four companies for an average of 11 full work day in situ . Corroborating earlier findings, we found that developers spend their time on a wide variety of activities and switch regularly between them, resulting in highly fragmented work. Our findings extend beyond existing research in that we correlate developers’ work habits with perceived productivity and also show productivity is a personal matter. Although productivity is personal, developers can be roughly grouped into morning, low-at-lunch and afternoon people. A stepwise linear regression per participant revealed that more user input is most often associated with a positive, and emails, planned meetings and work unrelated websites with a negative perception of productivity. We discuss opportunities of our findings, the potential to predict high and low productivity and suggest design approaches to create better tool support for planning developers’ work day and improving their personal productivity.

Background High blood pressure is increasing worldwide, disproportionately so in developing countries. Inadequate health care systems and adoption of unhealthy lifestyles have been linked to this emergent pattern. To better understand this trend, it is imperative we measure prevalence of hypertension, and examine specific risk factors, at a local level. This study provides a cross-sectional view of urban residents of Arusha City to determine prevalence and associated risk factors. Methods Blood pressure was measured using a digital sphygmomanometer. Interviews were conducted using the WHO STEPwise survey questionnaire to assess lifestyle factors. Dietary intake information was collected by a standardized Food Frequency Questionnaire (FFQ). Descriptive statistics were used to analyze demographic characteristics. Means and standard deviations were calculated for continuous variables and percentages for categorical variables. Pearson’s Chi Square (χ 2) tests were used to determine significant risk factors for hypertension, and multivariate log binomial regression was used to reveal potential predictors of hypertension. Dietary patterns were analyzed by principal component analysis. Results Approximately 45% of the study population was found to be hypertensive. The mean arterial blood pressure (MABP) of the sample was 102.3 mmHg (SD = 18.3). Mean systolic and diastolic blood pressure were 136.3 (SD = 30.5) and 85.3 (SD = 16.1) mmHg, respectively. Through multivariate analysis, age and body mass index were found to be independently, positively, associated with hypertension. Adherence to ‘healthy’ dietary pattern was negatively independently associated with hypertension. Conclusions With nearly half of participants being hypertensive, this study suggests that hypertension is a significant health risk in Arusha, Tanzania. Obesity, healthy diet, and age were found to be positively associated with hypertension risk. This study did not establish any significant association between increased blood pressure and Western-dietary pattern, cigarette smoking, alcohol intake, and physical activities.

Background Student-Run Free Clinics (SRFCs) have been an integral part of US medical schools since the 1960s and provide health care to underserved populations. In 2018, we established an SRFC in Hamburg, Germany, a major city in Northern Europe. The aim of this study was to describe the central problems and to investigate the usefulness of an SRFC in a country with free access to medical care, such as Germany. Methods All consecutive patients treated at the SRFC Hamburg between February 2018 and March 2019 that consented to this study were analyzed regarding clinical characteristics, diagnosis, readmission rate and country of origin. Results Between February 2018 and March 2019, 229 patients were treated at the SRFC in Hamburg. The patients came from 33 different countries with a majority (n = 206, 90%) from countries inside the European Union. The most common reasons for visiting the SRFC were infections (23.2%), acute or chronic wounds (13.5%) and fractures (6.3%). Conclusion Our multicultural patients suffer mainly from infections and traumatological and dermatological diseases. We find similarities to published Canadian SRFC patient cohorts but differences in diseases and treatment modalities compared to US SRFCs. Importantly, we demonstrate the relevance and necessity of the SRFC in a major city in Northern Europe.

Prostate cancer affects hundreds of thousands of men and families throughout the world. Although chemotherapy, radiation, surgery, and androgen deprivation therapy are applied, these therapies do not cure metastatic prostate cancer. Patients treated by androgen deprivation often develop castration resistant prostate cancer which is incurable. Novel approaches of treatment are clearly necessary. We have previously shown that prostate cancer originates as a stem cell disease. A prostate cancer patient sample, #87, obtained from prostatectomy surgery, was collected and frozen as single cell suspension. Cancer stem cell cultures were grown, single cell-cloned, and shown to be tumorigenic in SCID mice. However, outside its natural niche, the cultured prostate cancer stem cells lost their tumor-inducing capability and stem cell marker expression after approximately 8 transfers at a 1:3 split ratio. Tumor-inducing activity could be restored by inducing the cells to pluripotency using the method of Yamanaka. Cultures of human prostate-derived normal epithelial cells acquired from commercial sources were similarly induced to pluripotency and these did not acquire a tumor phenotype in vivo. To characterize the iPS87 cell line, cells were stained with antibodies to various markers of stem cells including: ALDH7A1, LGR5, Oct4, Nanog, Sox2, Androgen Receptor, and Retinoid X Receptor. These markers were found to be expressed by iPS87 cells, and the high tumorigenicity in SCID mice of iPS87 was confirmed by histopathology. This research thus characterizes the iPS87 cell line as a cancer-inducing, stem cell-like cell line, which can be used in the development of novel treatments for prostate cancer.

The inverse Spin Hall effect offers a promising approach for the generation of intense broadband terahertz radiation from optically driven ultrathin magnetic samples. Here, we present our approach for tailoring the spatial and spectral emission properties of such spintronic thin film systems, utilizing terahertz resonator designs.

Exercise can protect against cardiovascular disease, neurodegenerative disease, diabetes, cancer, and age-associated declines in muscle, immune, and cognitive function. In fact, regular physical exercise is the most powerful intervention known to enhance robustness of health and aging. Still, the molecular and cellular mechanisms that mediate system-wide exercise benefits remain poorly understood, especially as applies to “off target” tissues that do not participate directly in training activity. Elaborating molecular mechanisms of whole-animal exercise benefits is therefore of considerable importance to human health. The development of exercise protocols for short-lived genetic models holds great potential for deciphering fundamental mechanisms of exercise trans-tissue signaling during the entire aging process. Here, we report on the optimization of a long-term swim exercise protocol for C. elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase during early adulthood. We found that multiple daily swim sessions are essential for exercise adaptation in C. elegans, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters such as mitochondrial respiration and mid-life survival and increases the functional healthspan of pharynx and intestine. Importantly, we show that swim exercise also enhances nervous system health: exercise increases learning ability of adult animals and protects against neurodegeneration in C. elegans models of tauopathy, Alzheimer’s disease, and Huntington’s disease. An important point is that swim training only during C. elegans early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into mid-life. Overall, our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health (even after cessation of exercise), and establish the foundation for exploiting the powerful advantages of this genetic model to dissect the exercise-dependent molecular circuitry that confers long-lasting system-wide health benefits to aging or diseased adults.

To overcome the ever-growing demand for software, software development organizations strive to enhance the productivity of their developers. But what does productivity mean in the context of software development? A substantial amount of work on developer productivity has been undertaken over the past four decades. The majority of this work considered productivity from a top-down perspective (the manager view) in terms of the artifacts and code created per unit of time. Common examples of such productivity measures are the lines of source code modified per hour, the resolution time for modification requests, or function points created per month. These productivity measures focus on a single, output-oriented factor for quantifying productivity, and do not take into account developers’ individual work roles, practices and other factors that might affect their productivity, such as work fragmentation, the tools used, or the work/office environment. In our research, we investigated how productivity could be quantified from the bottom-up, following a mixed-methods approach that involved more than 800 software developers. By investigating developers’ individual productivity, it is possible to better understand the individual work habits and patterns, how they relate to the productivity perceptions and also which factors are most relevant for a developer’s productivity.

Interruptions at the workplace can consume a lot of time and cause frustration, especially if they happen at moments of high focus. To reduce costly interruptions, we developed the FlowLight, a small LED Lamp mounted at a worker's desk that computes a worker's availability for interruptions based on computer interaction and indicates it to her coworkers with colors, similar to a traffic light. In a large study with 449 participants, we found that the FlowLight reduced interruptions by 46%. We also observed an increased awareness of the potential harm of interruptions and an increased feeling of productivity. In this chapter, we present our insights from developing and evaluating FlowLight, and reflect on the key factors that contributed to its success.

Recently, we have seen an explosion in the number of devices and apps that we can use to track various aspects of our lives, such as the steps we walk, the quality of our sleep, or the calories we consume. People use devices such as the Fitbit activity tracker to increase and maintain their physical activity level by tracking their behavior, setting goals (e.g. 10'000 steps a day) and competing with friends. Many of these approaches have been shown to successfully encourage users to change their behaviors, often motivated through persuasive technologies, such as goal-setting, social encouragement and sharing mechanisms. We explored how we can map the tremendous success of these smart devices to the workplace, with the aim to increase software developers' self-awareness about productivity through self-monitoring. Yet, little is known about expectations of, the experience with, and the impact of self-monitoring in the workplace. From a mixed-methods approach we inferred design elements for building workplace self-monitoring tools, which we then implemented as a technology probe called WorkAnalytics. We field-tested these design elements during a three-week study with software development professionals. In the field study, we found that self-monitoring paired with experience sampling increases developers' awareness about work and motivates many to improve their behaviors, and that a wide variety of different metrics is needed to fulfill developers' expectations. Our work can serve as a starting point for researchers and practitioners to build self-monitoring tools for the workplace.

Traditional cooking using biomass is associated with ill health, local environmental degradation, and regional climate change. Clean stoves (liquefied petroleum gas (LPG), biogas, and electric) are heralded as a solution, but few studies have demonstrated their environmental health benefits in field settings. We analyzed the impact of mainly biogas (as well as electric and LPG) stove use on social, environmental, and health outcomes in two districts in Odisha, India, where the Indian government has promoted household biogas. We established a cross-sectional observational cohort of 105 households that use either traditional mud stoves or improved cookstoves (ICS). Our multidisciplinary team conducted surveys, environmental air sampling, fuel weighing, and health measurements. We examined associations between traditional or improved stove use and primary outcomes, stratifying households by proximity to major industrial plants. ICS use was associated with 91% reduced use of firewood (p0.01), substantial time savings for primary cooks, a 72% reduction in PM

The use of assisted reproductive technology, specifically in vitro fertilization, has been shown to increase the risk for the fetus having a congenital malformation as compared with a fetus conceived naturally. Congenital malformations can be effectively diagnosed prenatally through the use of sonography and fetal echocardiography. This case study presents the sonographic prenatal detection of a vascular ring in the heart of a fetus conceived through in vitro fertilization. A right aortic arch with a left ductus arteriosus was identified in the three-vessel view during a detailed fetal echocardiogram. The use of prenatal sonography, specifically fetal echocardiography, led to the accurate diagnosis and appropriate treatment for the fetus.

Silver nanoparticles (AgNPs) are extensively used for their antibacterial properties in a diverse set of applications, ranging from the treatment of municipal wastewater to infection control in hospitals. However, the properties of AgNPs that render them conducive to bactericidal use in commerce may influence their potential toxicity to non-bacterial organisms. Based on the physiological and phylogenetic similarities between bacteria and mitochondria within eukaryotic cells, mitochondria are a likely intracellular target of AgNP toxicity. Mitochondria-specific outcomes of AgNP exposures have been identified in multiple cell types, including (but not limited to) loss of membrane potential, inhibition of enzymes involved in oxidative phosphorylation, and changes in calcium sequestration. However, the biological significance of mitochondrial toxicity due to AgNP exposure is currently incompletely understood. This review examines the existing evidence of mitochondrial toxicity induced by AgNP exposure, with discussions of the role of the physicochemical properties of the nanoparticles themselves in mitochondrial toxicity. The impacts of potentially differential cell- and tissue-specific significance of AgNP-induced mitochondrial dysfunction are also discussed.