Neuron-specific gene NSG1 binds to and positively regulates sortilin ectodomain shedding via a metalloproteinase-dependent mechanism.

Increasing evidence suggests that aberrant regulation of sortilin ectodomain shedding can contribute to amyloid-ß pathology and frontotemporal dementia, although the mechanism by which this occurs has not been elucidated. Here, we probed for novel binding partners of sortilin using multiple and complementary approaches and identified two proteins of the neuron-specific gene (NSG) family, NSG1 and NSG2, that physically interact and colocalize with sortilin. We show both NSG1 and NSG2 induce subcellular redistribution of sortilin to NSG1- and NSG2-enriched compartments. However, using cell surface biotinylation, we found only NSG1 reduced sortilin cell surface expression, which caused significant reductions in uptake of progranulin, a molecular determinant for frontotemporal dementia. In contrast, we demonstrate NSG2 has no effect on sortilin cell surface abundance or progranulin uptake, suggesting specificity for NSG1 in the regulation of sortilin cell surface expression. Using metalloproteinase inhibitors and A disintegrin and metalloproteinase 10 KO cells, we further show that NSG1-dependent reduction of cell surface sortilin occurred via proteolytic processing by A disintegrin and metalloproteinase 10 with a concomitant increase in shedding of sortilin ectodomain to the extracellular space. This represents a novel regulatory mechanism for sortilin ectodomain shedding that is regulated in a neuron-specific manner. Furthermore, this finding has implications for the development of strategies for brain-specific regulation of sortilin and possibly sortilin-driven pathologies.

SARS-CoV-2 Antibodies in Breastmilk Three and Six Months Postpartum in Relation to the Trimester of Maternal SARS-CoV-2 Infection-An Exploratory Study.

The immune system of neonates is immature and therefore knowledge of possible early-life protection against SARS-CoV-2 infection, such as breastfeeding, is of great importance. Few studies have investigated the presence and duration of SARS-CoV-2 antibodies in breastmilk in relation to the trimester of maternal infection during pregnancy, and none with successful participation from all three trimesters. This study has dual objectives (1) in relation to the trimester of infection to examine the frequency, concentration and duration of IgA and IgG antibodies in breastmilk and blood serum in the third and sixth month post-partum in former SARS-CoV-2-infected mothers and (2) to examine the association in pediatric emergency admission of children within the first six months of life compared to children of non-SARS-CoV-2-infected women. The first objective is based on a prospective cohort and the second is based on a nested case-control design. The study participants are women with a former SARS-CoV-2 infection during pregnancy, whose serology IgG tests at delivery were still positive. Maternal blood and breastmilk samples were collected at three and six months postpartum. Serum IgA frequency three months pp was 72.7% (50%, 90% and 60% in the first, second and third trimester) and 82% six months pp (67%, 91% and 82% in the first, second and third trimester). Breastmilk IgA frequency three months pp was 27% (16.6%, 36% and 20% in first, second and third trimester) and 28% six months pp (0%, 38% and 28% in the first, second and third trimester). The highest IgA concentration in breastmilk was found six months post-partum with infection in the third trimester. Serum IgA was detectable more than 400 days post infection, and serum IgG above threshold was found 430 days after date of infection. We found no correlation between serum IgA and breastmilk IgA, nor between serum IgG and breastmilk IgA regardless of the trimester of infection.

The impact of the Safe Delivery Application on knowledge and skills managing postpartum haemorrhage in a low resource setting: a cluster randomized controlled trial in West Wollega region, Ethiopia.

BACKGROUND: Postpartum haemorrhage is one of the leading causes of maternal mortality in low-income countries. Improving health workers' competencies in obstetric emergencies in low-income settings, has been recognized as an important factor in preventing maternal mortality and morbidity. mHealth interventions in maternal and newborn health care has shown the potential to improve health service delivery. Strong study designs such as randomized controlled trials are missing to estimate the effectiveness of the mHealth interventions. METHODS: Between August 2013 and August 2014, 70 health facilities in West Wollega Region, Ethiopia were included and randomized to intervention or control in a cluster randomized controlled trial. At intervention facilities birth attendants were provided with a smartphone with the SDA installed. Of 176 midwives and "health extension workers," 130 completed at 12 months follow-up. At baseline and after 6- and 12-months participants were assessed. Knowledge was tested by a Key Feature Questionnaire, skills by an Objective Structured Assessment of Technical Skills in a structured role-play scenario. RESULTS: Baseline skills scores were low and comparable with a median of 12/100 in the intervention and the control group. After 6 months skills had doubled in the intervention group (adjusted mean difference 29.6; 95% CI 24.2-35.1 compared to 1·8; 95% CI - 2.7 to 6.3 in the control group). At 12 months skills had further improved in the intervention group (adjusted mean difference 13.3; 95% CI 8.3-18.3 compared to 3.1; 95% CI - 1.0 to 7.3 in the control group). Knowledge scores also significantly improved in the intervention group compared to the control (adjusted mean difference after 12 months 8.5; 95% CI 2.0-15.0). CONCLUSION: The Safe Delivery App more than doubled clinical skills for managing postpartum haemorrhage among birth attendants making it an attractive tool to reduce maternal mortality. TRIAL REGISTRATION: Clinicaltrial.gov Identifier NCT01945931. September 5, 2013.

Maternal mortality caused by postpartum haemorrhage is a major public health concern in many low-income countries. Having access to skilled health care professionals during pregnancy and childbirth can prevent maternal deaths related to postpartum haemorrhage. mHealth interventions like the Safe Delivery App (SDA), a smartphone application, has shown the potential to improve the quality of care in emergency situations related to childbirth in low-income health system settings.This study examines the SDA as a training/education tool for improving health workers' competencies and performances in managing postpartum haemorrhage. The SDA contained animated instruction videos on how to prevent and treat postpartum haemorrhage and a list of essential drugs and basic equipment.In Ethiopia, 70 health facilities and 176 birth attendants were included in a randomized controlled trial. The intervention group received a smartphone with the SDA installed and half a day of introduction to the use of the app. Birth attendants' skills and knowledge in managing postpartum haemorrhage in the control and the intervention group were tested at baseline, 6 and 12 months after intervention.Our study found that the SDA is an effective tool to improve and sustain birth attendants' knowledge and skills in the management of postpartum haemorrhage in a rural, low-resource health system setting in Ethiopia, which confirms findings in other non-randomized studies examining the SDA on the management of postpartum haemorrhage.

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus-2 in the United States.

BACKGROUND: The evidence base for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is nascent. We sought to characterize SARS-CoV-2 transmission within US households and estimate the household secondary infection rate (SIR) to inform strategies to reduce transmission. METHODS: We recruited patients with laboratory-confirmed SARS-CoV-2 infection and their household contacts in Utah and Wisconsin during 22 March 2020-25 April 2020. We interviewed patients and all household contacts to obtain demographics and medical histories. At the initial household visit, 14 days later, and when a household contact became newly symptomatic, we collected respiratory swabs from patients and household contacts for testing by SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) and sera for SARS-CoV-2 antibodies testing by enzyme-linked immunosorbent assay (ELISA). We estimated SIR and odds ratios (ORs) to assess risk factors for secondary infection, defined by a positive rRT-PCR or ELISA test. RESULTS: Thirty-two (55%) of 58 households secondary infection among household contacts. The SIR was 29% (n = 55/188; 95% confidence interval [CI], 23%-36%) overall, 42% among children (aged <18 years) of the COVID-19 patient and 33% among spouses/partners. Household contacts to COVID-19 patients with immunocompromised conditions and household contacts who themselves had diabetes mellitus had increased odds of infection with ORs 15.9 (95% CI, 2.4-106.9) and 7.1 (95% CI: 1.2-42.5), respectively. CONCLUSIONS: We found substantial evidence of secondary infections among household contacts. People with COVID-19, particularly those with immunocompromising conditions or those with household contacts with diabetes, should take care to promptly self-isolate to prevent household transmission.

A Prospective Cohort Study in Nonhospitalized Household Contacts With Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Symptom Profiles and Symptom Change Over Time.

BACKGROUND: Improved understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spectrum of disease is essential for clinical and public health interventions. There are limited data on mild or asymptomatic infections, but recognition of these individuals is key as they contribute to viral transmission. We describe the symptom profiles from individuals with mild or asymptomatic SARS-CoV-2 infection. METHODS: From 22 March to 22 April 2020 in Wisconsin and Utah, we enrolled and prospectively observed 198 household contacts exposed to SARS-CoV-2. We collected and tested nasopharyngeal specimens by real-time reverse-transcription polymerase chain reaction (rRT-PCR) 2 or more times during a 14-day period. Contacts completed daily symptom diaries. We characterized symptom profiles on the date of first positive rRT-PCR test and described progression of symptoms over time. RESULTS: We identified 47 contacts, median age 24 (3-75) years, with detectable SARS-CoV-2 by rRT-PCR. The most commonly reported symptoms on the day of first positive rRT-PCR test were upper respiratory (n = 32 [68%]) and neurologic (n = 30 [64%]); fever was not commonly reported (n = 9 [19%]). Eight (17%) individuals were asymptomatic at the date of first positive rRT-PCR collection; 2 (4%) had preceding symptoms that resolved and 6 (13%) subsequently developed symptoms. Children less frequently reported lower respiratory symptoms (21%, 60%, and 69% for <18, 18-49, and ≥50 years of age, respectively; P = .03). CONCLUSIONS: Household contacts with laboratory-confirmed SARS-CoV-2 infection reported mild symptoms. When assessed at a single timepoint, several contacts appeared to have asymptomatic infection; however, over time all developed symptoms. These findings are important to inform infection control, contact tracing, and community mitigation strategies.

Translating a Fall Prevention Intervention Into Practice: A Randomized Community Trial.

OBJECTIVES: We examined whether community translation of an effective evidence-based fall prevention program via standard monetary support can produce a community-wide reduction in fall injuries in older adults and evaluated whether an enhanced version with added technical support and capacity building amplified the fall reduction effect. METHODS: We completed a randomized controlled community trial among adults aged 65 and older in (1) 10 control communities receiving no special resources or guidance on fall prevention, (2) 5 standard support communities receiving modest funding to implement Stepping On, and (3) 5 enhanced support communities receiving funding and technical support. The primary outcome was hospital inpatient and emergency department discharges for falls, examined with Poisson regression. RESULTS: Compared with control communities, standard and enhanced support communities showed significantly higher community-wide reductions (9% and 8%, respectively) in fall injuries from baseline (2007-2008) to follow-up (2010-2011). No significant difference was found between enhanced and standard support communities. CONCLUSIONS: Population-based fall prevention interventions can be effective when implemented in community settings. More research is needed to identify the barriers and facilitators that influence the successful adoption and implementation of fall prevention interventions into broad community practice.

Effectiveness of an adaptive, multifaceted intervention to enhance care for patients with complex multimorbidity in general practice: protocol for a pragmatic cluster randomised controlled trial (the MM600 trial).

INTRODUCTION: Patients with complex multimorbidity face a high treatment burden and frequently have low quality of life. General practice is the key organisational setting in terms of offering people with complex multimorbidity integrated, longitudinal, patient-centred care. This protocol describes a pragmatic cluster randomised controlled trial to evaluate the effectiveness of an adaptive, multifaceted intervention in general practice for patients with complex multimorbidity. METHODS AND ANALYSIS: In this study, 250 recruited general practices will be randomly assigned 1:1 to either the intervention or control group. The eligible population are adult patients with two or more chronic conditions, at least one contact with secondary care within the last year, taking at least five repeat prescription drugs, living independently, who experience significant problems with their life and health due to their multimorbidity. During 2023 and 2024, intervention practices are financially incentivised to provide an extended consultation based on a patient-centred framework to eligible patients. Control practices continue care as usual. The primary outcome is need-based quality of life. Outcomes will be evaluated using linear and logistic regression models, with clustering considered. The analysis will be performed as intention to treat. In addition, a process evaluation will be carried out and reported elsewhere. ETHICS AND DISSEMINATION: The trial will be conducted in compliance with the protocol, the Helsinki Declaration in its most recent form and good clinical practice recommendations, as well as the regulation for informed consent. The study was submitted to the Danish Capital Region Ethical Committee (ref: H-22041229). As defined by Section 2 of the Danish Act on Research Ethics in Research Projects, this project does not constitute a health research project but is considered a quality improvement project that does not require formal ethical approval. All results from the study (whether positive, negative or inconclusive) will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05676541.

A model to translate evidence-based interventions into community practice.

There is a tension between 2 alternative approaches to implementing community-based interventions. The evidence-based public health movement emphasizes the scientific basis of prevention by disseminating rigorously evaluated interventions from academic and governmental agencies to local communities. Models used by local health departments to incorporate community input into their planning, such as the community health improvement process (CHIP), emphasize community leadership in identifying health problems and developing and implementing health improvement strategies. Each approach has limitations. Modifying CHIP to formally include consideration of evidence-based interventions in both the planning and evaluation phases leads to an evidence-driven community health improvement process that can serve as a useful framework for uniting the different approaches while emphasizing community ownership, priorities, and wisdom.

Consistency of the counting talk test for exercise prescription.

The purpose of this study was to assess the consistency of the counting talk test (CTT) method for estimating exercise intensity across various modes of exercise in healthy young adults. Thirty-six individuals completed the study, which required participation in 3 separate sessions within a 2-week time period. During the first session, the individuals completed a maximal effort treadmill test from which each individual's heart rate reserve (HRR) was calculated. During the second and third sessions, the subjects participated in 2 modes of exercise in each session for a total of 4 different modes of exercise. The individuals exercised at 40% HRR, 50% HRR, 60% HRR, 75% HRR, and 85% HRR. The heart rate (HR), CTT, and rating of perceived exertion (RPE) were recorded at each workload. Based on the individual's resting CTT (CTT(rest)), the %CTT for each exercise stage was then calculated. Pearson correlations demonstrated moderate to good correlations between the CTT and HRR methods and the CTT and RPE methods for estimating exercise intensity. This study found that for the individuals with CTT(rest) <25, moderate to vigorous intensity exercise as recommended by the American College of Sports Medicine HRR guidelines could be achieved by exercising at a level of 40-50% CTT(rest). Individuals with a CTT(rest) ≥25, exercising at a level of 30-40% CTT(rest) would place them in the moderate to vigorous exercise intensity range. A high degree of reliability was demonstrated using the CTT method across the various modes of aerobic exercise. As such, independent of the exercise mode, the CTT was found to be an easy and consistent method for prescribing moderate to vigorous aerobic exercise intensity.

A multidisciplinary course on injury prevention and control for medical students.

PURPOSE: Medical student education has begun to embrace integration across specialties in order to improve understanding of diseases. The Medical College of Wisconsin's Trauma and Injury Control course was developed to expose students to the science, principles, and practice of injury prevention and control, with emphasis on collaboration among disciplines. This paper describes the development, implementation, and evaluation of that course. METHODS: This retrospective study evaluated learner satisfaction and knowledge gained during a fourth-year selective from March 2007 to 2009. The educational experience provided unique activities developed through an interprofessional approach. Student assessment included oral presentations, small-group discussions, and participation in activities. Students evaluated the quality of the experience using written narrative evaluations. Two independent, blinded raters analyzed student narratives using the constant comparative method associated with grounded theory. RESULTS: Thirty-seven students completed the course and provided comments. Evaluations demonstrated high satisfaction. Five themes emerged as strengths and outcomes: (1) recognition of injury as preventable, (2) variety of interactive educational experiences, (3) understanding physician's role in injury policy, (4) opportunity to see the system of injury care, (5) recognition of injury as a disease. Criticisms of the course related to problems with coordination. CONCLUSION: Horizontal integration of the teaching of injury is feasible and should be promoted as a valued instructional technique.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns.

OBJECTIVE: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes. METHODS: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available. RESULTS: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies. CONCLUSION: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection.

Symptoms and Transmission of SARS-CoV-2 Among Children - Utah and Wisconsin, March-May 2020.

BACKGROUND AND OBJECTIVES: Limited data exist on severe acute respiratory syndrome coronavirus 2 in children. We described infection rates and symptom profiles among pediatric household contacts of individuals with coronavirus disease 2019. METHODS: We enrolled individuals with coronavirus disease 2019 and their household contacts, assessed daily symptoms prospectively for 14 days, and obtained specimens for severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction and serology testing. Among pediatric contacts (<18 years), we described transmission, assessed the risk factors for infection, and calculated symptom positive and negative predictive values. We compared secondary infection rates and symptoms between pediatric and adult contacts using generalized estimating equations. RESULTS: Among 58 households, 188 contacts were enrolled (120 adults; 68 children). Secondary infection rates for adults (30%) and children (28%) were similar. Among households with potential for transmission from children, child-to-adult transmission may have occurred in 2 of 10 (20%), and child-to-child transmission may have occurred in 1 of 6 (17%). Pediatric case patients most commonly reported headache (79%), sore throat (68%), and rhinorrhea (68%); symptoms had low positive predictive values, except measured fever (100%; 95% confidence interval [CI]: 44% to 100%). Compared with symptomatic adults, children were less likely to report cough (odds ratio [OR]: 0.15; 95% CI: 0.04 to 0.57), loss of taste (OR: 0.21; 95% CI: 0.06 to 0.74), and loss of smell (OR: 0.29; 95% CI: 0.09 to 0.96) and more likely to report sore throat (OR: 3.4; 95% CI: 1.04 to 11.18). CONCLUSIONS: Children and adults had similar secondary infection rates, but children generally had less frequent and severe symptoms. In two states early in the pandemic, we observed possible transmission from children in approximately one-fifth of households with potential to observe such transmission patterns.

Developing a global research agenda on violence and injury prevention: a modest proposal.

The need for the development of a global injury prevention research agenda is examined. Literature was reviewed in public health and selected policy strategies outside of public health that address the development of research agendas both for specific injury topics as well as for other health related areas; the benefits of creating a global research agenda are highlighted. There are examples of successful strategies where the development of a global research agenda on an injury specific topic has improved knowledge and prevention activities in that subfield. There are also examples that consolidate larger health topics and follow an agenda. Such efforts can benefit from wider governmental and institutional support. It is concluded that the development of a global injury prevention research agenda focused on collaborative efforts and with emphasis in implementation and dissemination research could be a useful tool to improve the quantity and quality of research in the field.

Different Dosages of Corticosteroid and Routes of Administration in Mandibular Third Molar Surgery: a Systematic Review.

OBJECTIVES: The objective of the present systematic review was to test the hypothesis of no difference in facial swelling, pain and trismus after surgical removal of mandibular third molar with different dosages of corticosteroids and administration routes. MATERIAL AND METHODS: A MEDLINE (PubMed), Embase database and Cochrane Library search in combination with a hand-search of relevant journals was conducted by including randomized controlled trials published in English until 1st December 2017. RESULTS: Seven studies fulfilled the inclusion criteria. Considerable variation in the included studies prevented meta-analysis from being performed. Preoperative submucosal injection of corticosteroids significantly diminishes facial swelling, pain and trismus compared with placebo. However, different dosages of corticosteroid and administration routes reveal contrary results indicating that administration of a higher dosage of corticosteroids do not necessarily cause a further decrease in facial swelling, pain and trismus. CONCLUSIONS: Consequently, the optimal dosage of corticosteroids and administration route for diminishing postsurgical morbidity and improve quality of life after surgical removal of mandibular third molar is presently unknown. Therefore, further well-designed randomized clinical trials including a standardised protocol, patient-reported outcome measures and three-dimensional analysis of facial swelling is needed.

Research on the Translation and Implementation of Stepping On in Three Wisconsin Communities.

OBJECTIVE: Falls are a leading cause of injury death. Stepping On is a fall prevention program developed in Australia and shown to reduce falls by up to 31%. The original program was implemented in a community setting, by an occupational therapist, and included a home visit. The purpose of this study was to examine aspects of the translation and implementation of Stepping On in three community settings in Wisconsin. METHODS: The investigative team identified four research questions to understand the spread and use of the program, as well as to determine whether critical components of the program could be modified to maximize use in community practice. The team evaluated program uptake, participant reach, program feasibility, program acceptability, and program fidelity by varying the implementation setting and components of Stepping On. Implementation setting included type of host organization, rural versus urban location, health versus non-health background of leaders, and whether a phone call could replace the home visit. A mixed methodology of surveys and interviews completed by site managers, leaders, guest experts, participants, and content expert observations for program fidelity during classes was used. RESULTS: The study identified implementation challenges that varied by setting, including securing a physical therapist for the class and needing more time to recruit participants. There were no implementation differences between rural and urban locations. Potential differences emerged in program fidelity between health and non-health professional leaders, although fidelity was high overall with both. Home visits identified more home hazards than did phone calls and were perceived as of greater benefit to participants, but at 1 year no differences were apparent in uptake of strategies discussed in home versus phone visits. CONCLUSION: Adaptations to the program to increase implementation include using a leader who is a non-health professional, and omitting the home visit. Our research demonstrated that a non-health professional leader can conduct Stepping On with adequate fidelity, however non-health professional leaders may benefit from increased training in certain aspects of Stepping On. A phone call may be substituted for the home visit, although short-term benefits are greater with the home visit.

Clean indoor air policies in Wisconsin workplaces.

OBJECTIVE: To describe the nature and extent of workplace environmental tobacco smoke exposures in Wisconsin. METHODS: Descriptive data and confidence intervals from the Current Population Survey tobacco supplements of 1995-1996 and 1998-1999 are presented. RESULTS: The percent of indoor workers working under a smoke-free policy increased slightly, from 62% in 1995-1996 to 65% in 1998-1999. Respondents with a college degree were more likely to work under a smoke-free policy than those with a high school education or less. Among respondents with a work policy in 1998-1999, a complete ban on smoking reduced any workplace exposure in the past 2 weeks (4%) compared to a partial ban (26%) or an unrestricted policy (30%). CONCLUSION: Wisconsin has seen a small increase in workplace policies that ban smoking in the workplace. These policies are more likely to protect workers of higher socioeconomic status and may increase health disparities in tobacco-related diseases in the future.