The safety and efficacy of push dose vasopressors in critically ill adults.

PURPOSE: To evaluate practice patterns, efficacy, and safety of push dose pressors (PDP) in critically ill patients outside of the operating room (OR) at a large academic medical center. MATERIALS AND METHODS: This was a single-center, retrospective cohort study (June 2018 to July 2020) conducted at a 1273-bed academic medical center. The primary outcome was efficacy, defined as a 25% increase in systolic blood pressure, and the cohort was analyzed according to PDP response (i.e. responders versus non-responders). A logistic regression model was used to assess predictors of response to PDPs. Safety outcomes included the incidence of hypertension, bradycardia, and tachycardia. RESULTS: 1727 patients were included in the final analysis. The median doses of phenylephrine and epinephrine administered were 400 µg (IQR 200-888 µg) and 50 µg (IQR 20-100 µg). The primary outcome was achieved in 102 (71.8%) patients in the epinephrine group and 1140 (55.9%) of patients in the phenylephrine group. Adverse effects after PDP receipt were minimal, with the most common being hypertension in 6.6% and 13.4% of the phenylephrine and epinephrine groups respectively. CONCLUSIONS: This study demonstrates that PDP phenylephrine and epinephrine are safe and efficacious in treating the acute hypotensive period.

Anodal High-definition Transcranial Direct Current Stimulation over the Posterior Parietal Cortex Modulates Approximate Mental Arithmetic.

The representation and processing of numerosity is a crucial cognitive capacity. Converging evidence points to the posterior parietal cortex (PPC) as primary "number" region. However, the exact role of the left and right PPC for different types of numerical and arithmetic tasks remains controversial. In this study, we used high-definition transcranial direct current stimulation (HD-tDCS) to further investigate the causal involvement of the PPC during approximative, nonsymbolic mental arithmetic. Eighteen healthy participants received three sessions of anodal HD-tDCS at 1-week intervals in counterbalanced order: left PPC, right PPC, and sham stimulation. Results showed an improved performance during online parietal HD-tDCS (vs. sham) for subtraction problems. Specifically, the general tendency to underestimate the results of subtraction problems (i.e., the "operational momentum effect") was reduced during online parietal HD-tDCS. There was no difference between left and right stimulation. This study thus provides new evidence for a causal involvement of the left and right PPC for approximate nonsymbolic arithmetic and advances the promising use of noninvasive brain stimulation in increasing cognitive functions.

Impact of surface maintenance on BioSand filter performance and flow.

The BioSand filter (BSF) is a household scaled, intermittently operated, slow sand filter. The BSF requires maintenance to remove trapped sediments. This study evaluated the effects of maintenance on the filter's flow rate and performance. Four concrete BSFs received three styles of maintenance: surface agitation (SA), stirring method (SM), and sand removal (SR). Effluent water was collected from the filter between 0-2 L effluent (0-2 L effluent) and between 15-20 L effluent (15 L+ effluent). After maintenance, effluent at 15 L+ (no pause time) showed a significant decrease in thermotolerant coliform removal rates by 0.66-0.91 log (SA), 0.57-0.67 log (SM) and 0.32-0.83 log (RM) (<0.001). Effluent water at 0-2 L (with pause time) did not significantly decrease in thermotolerant coliform removal rates (>0.17) for any maintenance method. The recovery duration after maintenance for all methods at 0-2 L effluent had a median recovery of <1.2 days. The effluent at 15 L+ had a longer recovery period (at least 3.9, 3.0 and 12.75 days for the SA, SM, and SR method, respectively). The flow rate recovery for SA (76%) and SM (82%) was lower compared to SR (138%).

Clinical and haematological predictors of antibiotic prescribing for acute cough in adults in Swiss practices--an observational study.

BACKGROUND: Acute cough is a common problem in general practice and is often caused by a self-limiting, viral infection. Nonetheless, antibiotics are often prescribed in this situation, which may lead to unnecessary side effects and, even worse, the development of antibiotic resistant microorganisms worldwide. This study assessed the role of point-of-care C-reactive protein (CRP) testing and other predictors of antibiotic prescription in patients who present with acute cough in general practice. METHODS: Patient characteristics, symptoms, signs, and laboratory and X-ray findings from 348 patients presenting to 39 general practitioners with acute cough, as well as the GPs themselves, were recorded by fourth-year medical students during their three-week clerkships in general practice. Patient and clinician characteristics of those prescribed and not-prescribed antibiotics were compared using a mixed-effects model. RESULTS: Of 315 patients included in the study, 22% were prescribed antibiotics. The two groups of patients, those prescribed antibiotics and those treated symptomatically, differed significantly in age, demand for antibiotics, days of cough, rhinitis, lung auscultation, haemoglobin level, white blood cell count, CRP level and the GP's license to self-dispense antibiotics. After regression analysis, only the CRP level, the white blood cell count and the duration of the symptoms were statistically significant predictors of antibiotic prescription. CONCLUSIONS: The antibiotic prescription rate of 22% in adult patients with acute cough in the Swiss primary care setting is low compared to other countries. GPs appear to use point-of-care CRP testing in addition to the duration of clinical symptoms to help them decide whether or not to prescribe antibiotics.

General practitioner teachers' job satisfaction and their medical students' wish to join the field - a correlational study.

BACKGROUND: There will be increasing competition for young physicians worldwide as more and more physicians retire. While enthusiasm towards GP work is important for GP teachers as role models, satisfaction within the profession has declined. This study aims to determine if medical students' desire to become GPs is related to the job satisfaction of their teaching GPs and explore the factors tied to this job satisfaction. METHODS: In this cross-sectional, correlational study, teaching GPs of the University of Bern and the fourth year medical students completing internships with them filled in separate questionnaires. RESULTS: Whether or not the GP teacher is perceived by a student to be satisfied with her/his job is correlated to that student's satisfaction with the internship, which in turn, is correlated with student's wish to be a GP after the internship. Results show which factors are most related to GP job satisfaction and the effect of working hours and their composition. CONCLUSIONS: Medical students' perception of their GP teachers' job satisfaction positively affect their wish to become GPs, and their satisfaction with their internships adds to this. Enhancing the positive aspects of GP work, such as recognition, and improving negative ones, such as administrative duties, are necessary to attract medical students into the GP field.

A PLURIPOTENT STEM CELL PLATFORM FOR IN VITRO SYSTEMS GENETICS STUDIES OF MOUSE DEVELOPMENT.

The directed differentiation of pluripotent stem cells (PSCs) from panels of genetically diverse individuals is emerging as a powerful experimental system for characterizing the impact of natural genetic variation on developing cell types and tissues. Here, we establish new PSC lines and experimental approaches for modeling embryonic development in a genetically diverse, outbred mouse stock (Diversity Outbred mice). We show that a range of inbred and outbred PSC lines can be stably maintained in the primed pluripotent state (epiblast stem cells -- EpiSCs) and establish the contribution of genetic variation to phenotypic differences in gene regulation and directed differentiation. Using pooled in vitro fertilization, we generate and characterize a genetic reference panel of Diversity Outbred PSCs (n = 230). Finally, we demonstrate the feasibility of pooled culture of Diversity Outbred EpiSCs as "cell villages", which can facilitate the differentiation of large numbers of EpiSC lines for forward genetic screens. These data can complement and inform similar efforts within the stem cell biology and human genetics communities to model the impact of natural genetic variation on phenotypic variation and disease-risk.

General practitioner involvement in follow-up of childhood cancer survivors: a systematic review.

BACKGROUND: An increasing number of childhood cancer survivors need long-term follow-up care. Different models address this problem, including that of follow-up by general practitioners (GP). We describe models that involve GPs in follow-up for childhood cancer survivors, their advantages and disadvantages, clinics that employ these models, and the elements essential to high-quality, GP-led follow-up care. PROCEDURE: We searched four databases (PubMed [including Medline], Embase, Cochrane, and CINAHL) without language restrictions. RESULTS: We found 26 publications, which explicitly mentioned GP-led follow-up. Two models were commonly described: GP-only, and shared care between GP and pediatric oncology or late effects clinic. The shared care model appears to have advantages over GP-only follow-up. We found four clinics using models of GP-led follow-up, described in five papers. We identified well-organized transition, treatment summary, survivorship care plan, education of GPs and guidelines as necessary components of successful follow-up. CONCLUSION: Scarcity of literature necessitated a review rather than a meta-analysis. More research on the outcomes of GP-led care is necessary to confirm the model for follow-up of childhood cancer survivors in the long term. However, with the necessary elements in place, the model of GP-led follow-up, and shared care in particular, holds promise.

Achieving Flow: An Exploratory Investigation of Elite College Athletes and Musicians.

While studies on the characteristics of flow states and their relation to peak performance exist, little is known about the dynamics by which flow states emerge and develop over time. The current paper qualitatively explores the necessary pre-conditions to enter flow, and the development of flow over time until its termination. Using an elicitation interview, participants (10 athletes and 12 musicians) were asked to recall their flow experiences in sports or music performances. The analysis resulted in the identification of the following three phases that athletes and musicians experience during flow: (1) Preparation to enter flow; (2) Entry into the flow state and; (3) Exit from the flow state. These three phases are characterized by several sub-themes contributing to the experience of flow. The function of emotions is crucial, as they play a core role across all three phases and regulate flow over time. The findings provide insights into the phenomenological characteristics of the transition and maintenance of the three proposed phases and the temporal dynamics of flow.

Plasma host protein biomarkers correlating with increasing Mycobacterium tuberculosis infection activity prior to tuberculosis diagnosis in people living with HIV.

BACKGROUND: Biomarkers correlating with Mycobacterium tuberculosis infection activity/burden in asymptomatic individuals are urgently needed to identify and treat those at highest risk for developing active tuberculosis (TB). Our main objective was to identify plasma host protein biomarkers that change over time prior to developing TB in people living with HIV (PLHIV). METHODS: Using multiplex MRM-MS, we investigated host protein expressions from 2 years before until time of TB diagnosis in longitudinally collected (every 3-6 months) and stored plasma from PLHIV with incident TB, identified within a South African (SA) and US cohort. We performed temporal trend and discriminant analyses for proteins, and, to assure clinical relevance, we further compared protein levels at TB diagnosis to interferon-gamma release assay (IGRA; SA) or tuberculin-skin test (TST; US) positive and negative cohort subjects without TB. SA and US exploratory data were analyzed separately. FINDINGS: We identified 15 proteins in the SA (n=30) and 10 in the US (n=24) incident TB subjects which both changed from 2 years prior until time of TB diagnosis after controlling for 10% false discovery rate, and were significantly different at time of TB diagnosis compared to non-TB subjects (p<0.01). Five proteins, CD14, A2GL, NID1, SCTM1, and A1AG1, overlapped between both cohorts. Furthermore, after cross-validation, panels of 5 - 12 proteins were able to predict TB up to two years before diagnosis. INTERPRETATION: Host proteins can be biomarkers for increasing Mycobacterium tuberculosis infection activity/burden, incipient TB, and predict TB development in PLHIV. FUNDING: NIH/NIAID AI117927, AI146329, and AI127173 to JMA.

Development of an Innovative Digital Data Collection System for Routine Mental Health Care Delivery in Rural Haiti.

INTRODUCTION: Effective digital health management information systems (HMIS) support health data validity, which enables health care teams to make programmatic decisions and country-level decision making in support of international development targets. In 2015, mental health was included within the Sustainable Development Goals, yet there are few applications of HMIS of any type in the practice of mental health care in resource-limited settings. Zanmi Lasante (ZL), one of the largest providers of mental health care in Haiti, developed a digital data collection system for mental health across 11 public rural health facilities. PROGRAM INTERVENTION: We describe the development, implementation, and evaluation of the digital system for mental health data collection at ZL. To evaluate system reliability, we assessed the number of missing monthly reports. To evaluate data validity, we calculated concordance between the digital system and paper charts at 2 facilities. To evaluate the system's ability to inform decision making, we specified and then calculated 4 priority indicators. RESULTS: The digital system was missing 5 of 143 monthly reports across all facilities and had 74.3% (55/74) and 98% (49/50) concordance with paper charts. It was possible to calculate all 4 indicators, which led to programmatic changes in 2 cases. In response to implementation challenges, it was necessary to use strategies to increase provider buy-in and ultimately to introduce dedicated data clerks to keep pace with data collection and protect time for clinical work. LESSONS LEARNED: While demonstrating the potential of collecting mental health data digitally in a low-resource rural setting, we found that it was necessary to consider the ongoing roles of paper records alongside digital data collection. We also identified the challenge of balancing clinical and data collection responsibilities among a limited staff. Ongoing work is needed to develop truly sustainable and scalable models for mental health data collection in resource-limited settings.

Flow States and Associated Changes in Spatial and Temporal Processing.

Improved perception during high performance is a commonly reported phenomenon. However, it is difficult to determine whether these reported changes experienced during flow states reflect veridical changes in perceptual processing, or if instead are related to some form of memory or response bias. Flow is a state in which an individual experiences high focus and involvement in a specific task, and typically experiences a lack of distractibility, a disordered sense of time, great enjoyment, and increased levels of performance. The present pre-registered study investigated 27 athletes and musicians using a temporal order judgement (TOJ) task before and after a sports or music performance over three sessions. Participants' flow experiences were surveyed in order to measure how modulations of flow over successive performances potentially modulates spatiotemporal perception and processing. Hierarchical linear modeling showed a positive moderation of subjectively experienced flow and performance on post-measures of a TOJ task. Specifically, the higher the subjective flow experience of the sport or music performance was rated, the better the participant performed in the post-performance TOJ task compared to the pre-performance TOJ task. The findings of the present study provide a more comprehensive explanation of human perception during flow at high level performances and suggest important insights regarding the possibility of modulated temporal processing and spatial attention.

Consanguinity and genetic diseases among the Bedouin population in the Negev.

Arab Bedouins (AB) in Israel are traditionally a semi-nomadic population. Their average birth rate is extremely high (birth rate of 5.43, as well is their high consanguinity rate (44%), despite having decreased from 60% in 1992. Additionally, their mean inbreeding coefficient is 0.0238.The high rate of consanguinity results in a high prevalence of recessive genetic and multifactorial disorders as well as high infant mortality rate (11 per 1000 live births). Various genetic diseases are prevalent in AB, exemplifying how extensive the impact of consanguinity is on the community. Targeted screening programs are provided for prevalent severe genetic diseases. However, despite initial success, genetic screening is still underutilized in AB. AB, the Ministry of Health, the Ministry of Education, and different social associations should plan and manage programmed interventions. These programs should work intensively to further educate and raise awareness regarding consanguinity and its potential harms, to increase trust and collaboration between the community and the public health system, to expand screening and premarital consultations, and to create a genetic bank (specific mutations/whole genome) for the AB community.

Capsular glycan recognition provides antibody-mediated immunity against tuberculosis.

A better understanding of all immune components involved in protecting against Mycobacterium tuberculosis infection is urgently needed to inform strategies for novel immunotherapy and tuberculosis (TB) vaccine development. Although cell-mediated immunity is critical, increasing evidence supports that antibodies also have a protective role against TB. Yet knowledge of protective antigens is limited. Analyzing sera from 97 US immigrants at various stages of M. tuberculosis infection, we showed protective in vitro and in vivo efficacy of polyclonal IgG against the M. tuberculosis capsular polysaccharide arabinomannan (AM). Using recently developed glycan arrays, we established that anti-AM IgG induced in natural infection is highly heterogeneous in its binding specificity and differs in both its reactivity to oligosaccharide motifs within AM and its functions in bacillus Calmette-Guérin vaccination and/or in controlled (latent) versus uncontrolled (TB) M. tuberculosis infection. We showed that anti-AM IgG from asymptomatic but not from diseased individuals was protective and provided data suggesting a potential role of IgG2 and specific AM oligosaccharides. Filling a gap in the current knowledge of protective antigens in humans, our data support the key role of the M. tuberculosis surface glycan AM and suggest the importance of targeting specific glycan epitopes within AM in antibody-mediated immunity against TB.

Early life stress alters adult serotonin 2C receptor pre-mRNA editing and expression of the alpha subunit of the heterotrimeric G-protein G q.

Infant maternal separation, a paradigm of early life stress in rodents, elicits long-lasting changes in gene expression that persist into adulthood. In BALB/c mice, an inbred strain with spontaneously elevated anxiety and stress reactivity, infant maternal separation led to increased depression-like behavioral responses to adult stress and robustly increased editing of serotonin 2C receptor pre-mRNA. Chronic fluoxetine treatment of adult BALB/c mice exposed to early life stress affected neither their behavioral responses to stress nor their basal 5-HT2C pre-mRNA editing phenotype. However, when fluoxetine was administered during adolescence, depression-like behavioral responses to stress were significantly diminished in these mice, and their basal and stress-induced 5-HT2C pre-mRNA editing phenotypes were significantly lower. Moreover, when BALB/c mice exposed to early life stress were raised in an enriched postweaning environment, their depression-like behavioral responses to adult stress were also significantly diminished. However, their 5-HT2C pre-mRNA editing phenotype remained unaltered. Hence, the similar behavioral effects of enrichment and fluoxetine treatment during adolescence were not accompanied by similar changes in 5-HT2C pre-mRNA editing. Enriched and nonenriched BALB/c mice exposed to early life stress also exhibited significantly increased expression of mRNA and protein encoding the G alpha q subunit of G-protein that couples to 5-HT2A/2C receptors. In contrast, G alpha q expression levels were significantly lower in fluoxetine-treated mice. These findings suggest that compensatory changes in G alpha q expression occur in mice with persistently altered 5-HT2C pre-mRNA editing and provide an explanation for the dissociation between 5-HT2C receptor editing phenotypes and behavioral stress responses.

Advancing Pre-Health Humanities as Intensive Research Practice: Principles and Recommendations from a Cross-Divisional Baccalaureate Setting.

This essay argues that pre-health humanities programs should focus on intensive research practice for baccalaureate students and provides three guiding principles for implementing it. Although the interdisciplinary nature of health humanities permits baccalaureate students to use research methods from the natural sciences, social sciences, and humanities, pre-health humanities coursework tends to force students to adopt only one of many disciplinary identities. Alternatively, an intensive research approach invites students to critically select and combine methods from multiple (and seemingly opposing) disciplines to ask and answer questions about health problems more innovatively. Using the authors' experiences with implementing health humanities baccalaureate research initiatives at The University of North Carolina at Chapel Hill, the authors contend that pre-health humanities programs should teach and study multiple disciplinary research methods and their values; examine how health humanities research might transfer across disciplines; and focus on mentoring opportunities for funding, presenting, and publishing research. These recommendations have the potential to create unprecedented research experiences for baccalaureate students as they prepare to enter careers within and beyond the allied health professions.

Thalidomide use in the US : experience with pregnancy testing in the S.T.E.P.S. programme.

INTRODUCTION: In 1998, thalidomide (Thalomid), a known human teratogen, was approved by the US FDA for the treatment of erythema nodosum leprosum. To prevent fetal exposure to thalidomide, a restricted distribution risk management programme, the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.), was implemented. All clinicians, pharmacists and patients who prescribe, dispense and receive thalidomide, respectively, are required to enroll in S.T.E.P.S. Sexually active females of childbearing potential must use two methods of birth control before, during and after treatment. These patients must also have a negative pregnancy test within 24 hours before beginning therapy and periodically while on therapy. The objective of this report is to summarise the patterns of thalidomide use and to describe the occurrence of positive pregnancy tests in females of childbearing potential while they were using thalidomide in the S.T.E.P.S. programme in the US. STUDY DESIGN/METHODS: A retrospective review of patients receiving thalidomide within the S.T.E.P.S. programme from September 1998 to 31 December 2004 to determine the occurrence of positive pregnancy tests whilst on treatment. RESULTS: Approximately 124,000 (43% female) patients were registered within the S.T.E.P.S. programme between September 1998 and 31 December 2004. Approximately 6,000 patients were females of childbearing potential, representing 5% of all patients and 11% of all female patients. Between 30 July 2001 and 31 December 2004, >88% of thalidomide use was for oncological conditions. There were 72 females of childbearing potential who had positive pregnancy tests. Sixty-nine of these patients had false positive pregnancy tests. Of the remaining three, one woman was pregnant while on thalidomide. This patient had an initial negative test and received thalidomide. Therapy was stopped when she had a positive pregnancy test. This pregnancy resulted in a miscarriage. Two additional patients were determined to be pregnant before receiving thalidomide. CONCLUSIONS: The S.T.E.P.S. programme is critical to managing the risks of thalidomide-associated teratogenicity. Sustained vigilance among health care providers and patients receiving thalidomide is essential to its continued success. Health care providers should be aware of the occurrence of false-positive pregnancy tests in females of childbearing potential receiving thalidomide.

Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System.

In this case series, we examined concomitant risk factors mentioned in reports of torsades de pointes, a rare ventricular arrhythmia, that occurred in association with administration of macrolide antimicrobials (e.g., azithromycin, clarithromycin, dirithromycin, and erythromycin). Increasing age, female sex, and concomitant diseases and drug administration believed to increase risks for torsades de pointes were commonly reported.