Practical quality improvement changes for a low-resourced pediatric unit.

Background: This work describes a sustainable and replicable initiative to optimize multi-disciplinary care and uptake of clinical best practices for patients in a pediatric intensive care unit in Low/Middle Income Countries and to understand the various factors that may play a role in the reduction in child mortality seen after implementation of the Quality Improvement Initiative. Methods: This was a longitudinal assessment of a quality improvement program with the primary outcome of intubated pediatric patient mortality. The program was assessed 36 months following implementation of the quality improvement intervention using a t-test with linear regression to control for co-variates. An Impact Pathway model was developed to describe potential pathways for improvement, and context was added with an exploratory analysis of adoption of the intervention and locally initiated interventions. Results: 147 patients were included in the sustainability cohort. Comparing the initial post-implementation cohort to the sustainability cohort, the overall PICU unexpected extubations per 100 days mechanical ventilation decreased significantly from baseline (6.98) to the first year post intervention (3.52; p < 0.008) but plateaued without further significant decrease in the final cohort (3.0; p = 0.73), whereas the mortality decreased from 22.4 (std 0.42) to 9.5% (std 0.29): p value: 0.002 (confidence intervals: 0.05;0.21). The regression model that examined age, sex, diagnosis and severity of illness (via aggregate Pediatric Risk of Mortality (PRISM) scores between epochs) yielded an adjusted R-squared (adjusting for the number of predictors) value of 0.046, indicating that approximately 4.6% of the variance in mortality was explained by the predictors included in the model. The overall significance of the regression model was supported by an F-statistic of 3.198 (p = 0.00828). age, weight, diagnosis, and severity of illness. 15 new and locally driven quality practices were observed in the PICU compared to the initial post-implementation time period. The Impact Pathway model suggested multiple unique potential pathways connecting the improved patient outcomes with the intervention components. Conclusion: Sustained improvements were seen in the care of intubated pediatric patients. While some of this improvement may be attributable to the intervention, it appears likely that the change is multifactorial, as evidenced by a significant number of new quality improvement projects initiated by the local clinical team. Although currently limited by available data, the use of Driver Diagram and Impact Pathway models demonstrates several proposed causal pathways and holds potential for further elucidating the complex dynamics underlying such improvements.

Oil and Gas Extraction Industry Workers' Compensation Claims and Proposed Safety Interventions.

OBJECTIVE: This study analyzed Ohio workers' compensation data to identify potential prevention strategies for common oil and gas extraction industry claims. METHODS: Claim rates for 2001-2018 were calculated per full-time equivalent employee. Descriptive analyses on free-text descriptions of lost-time (LT) claims (>7 days away from work) identified common characteristics among claims and injured workers. RESULTS: Among 3134 claims, 860 (27%) were LT. The industry group, drilling contractors, experienced the highest LT claims rate, whereas the cost from servicing contractors was the highest. Contact with objects and equipment caused the highest LT claims rate. The most frequent LT occupation was roustabout, and the most frequent LT work activity was material handling. Transportation incidents caused most fatalities and hospitalizations. Over half of LT claims were from short-tenured workers. CONCLUSIONS: Both proven and innovative approaches are needed to reduce severe workers' compensation claims in this industry.

The wildland firefighter exposure and health effect (WFFEHE) study: cohort characteristics and health behavior changes in context.

OBJECTIVES: Work is an under-recognized social determinant of health. There is limited research describing US wildland firefighter (WFF) workforce demographics or how to work associates with WFF health behaviors. In this study researchers characterized a WFF cohort and tested hypotheses that WFFs used tobacco, alcohol, and sugar-sweetened beverages (SSBs) differently over the course of the fire season and that different fire crews may exhibit different behavior patterns. METHODS: Researchers collected data in the field with 6 WFF crews during 2 consecutive fire seasons (2018 and 2019). WFF crews completed questionnaires before and after each season. WFFs with an initial preseason questionnaire and at least 1 follow-up questionnaire were included (n = 138). Descriptive statistics summarized WFFs' baseline demographic, employment, and health characteristics. Linear mixed models were used to test for changes in WFFs' substance use over time and assess crew-level differences. A meta-analysis of WFF longitudinal studies' population characteristics was attempted to contextualize baseline findings. RESULTS: WFFs were predominately male, less than 35 yr of age, non-Hispanic White, and had healthy weight. Smokeless tobacco use and binge drinking were prevalent in this cohort (52% and 78%, respectively, among respondents). Longitudinal analyses revealed that during the fire season WFFs' use of tobacco and SSBs increased and the number of days they consumed alcohol decreased. Crew-level associations varied by substance. The meta-analysis was not completed due to cross-study heterogeneity and inconsistent reporting. DISCUSSION: WFF agencies can promote evidence-based substance use prevention and management programs and modify working conditions that may influence WFF stress or substance use.

Risk factors for heat-related illness resulting in death or hospitalization in the oil and gas extraction industry.

Many oil and gas extraction (OGE) activities occur in high-heat environments, resulting in a significant risk of heat-related illness among outdoor workers in this industry. This report highlights cases of occupational heat-related illness that resulted in death and identifies common risk factors for heat-related fatalities and hospitalizations among OGE workers. Two databases maintained by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) were reviewed to identify heat-related fatalities, hospitalizations, and associated risk factors among OGE workers. Nine fatalities and associated risk factors were identified during 2014-2019 from NIOSH's Fatalities in Oil and Gas Extraction (FOG) Database. Risk factors identified included those commonly associated with heat-related fatalities: new workers not acclimatized to heat, inadequate heat stress training, and underlying hypertension or cardiovascular disease. Of particular note, substance use was identified as a significant risk factor as more than half of the fatalities included a positive postmortem test for amphetamines or methamphetamines. Fifty heat-related hospitalizations were identified from OSHA's Severe Injury Report Database during January 2015-May 2021. Heat stress has been and will continue to be an important cause of fatality and adverse health effects in OGE as hot outdoor working conditions become more common and extreme. More emphasis on heat stress training, acclimatization regimens, medical screening, and implementation of workplace-supportive recovery programs may reduce heat-related fatalities and injuries in this industry.

Risky driving behaviors and employer motor vehicle safety policies among U.S. oil and gas extraction workers.

INTRODUCTION: Over half of fatal occupational injuries in the oil and gas extraction (OGE) industry are due to transportation incidents. While driving for work is common in this industry and risky driving behaviors have been identified as contributing factors to fatal crashes among OGE workers, limited information is available on the frequency of risky driving behaviors and employer policies to reduce these behaviors. METHODS: Researchers conducted a cross-sectional survey of OGE workers in three states. Responses from 363 OGE workers who drive as a part of their work duties were analyzed to evaluate relationships between self-reported risky driving behaviors (i.e., speeding, cell phone use, and driving unbelted) and awareness of motor vehicle safety policies by their employers. RESULTS: Hands-free cell phone use was the most common risky driving behavior among participants (59.8%), while a hands-free cell phone ban was the least commonly reported employer motor vehicle safety policy (34.7%). Multiple logistic regression results identified longer work and commuting hours, lack of employer motor vehicle safety policies, having ever been in a work crash, and being employed by an operator to be significantly associated with risky driving behaviors. CONCLUSIONS: Workers whose employers lacked motor vehicle safety policies were more likely to engage in risky driving behaviors. PRACTICAL APPLICATIONS: Results of this survey support the implementation of motor vehicle safety interventions such as bans on texting and handheld and hands-free cell phone use, speed management, and in-vehicle monitoring systems by OGE employers as well as research focusing on the effectiveness of these interventions in OGE. Additional research could examine worker driving behaviors through self-reported data in combination with objective measures.

Fatalities in Oil and Gas Extraction Database, an Industry-Specific Worker Fatality Surveillance System - United States, 2014-2019.

Problem/Condition: The U.S. oil and gas extraction (OGE) industry faces unique safety and health hazards and historically elevated fatality rates. The lack of existing surveillance data and occupational safety and health research called for increased efforts to better understand factors contributing to worker fatalities in the OGE industry. This report describes the creation of the Fatalities in Oil and Gas Extraction (FOG) database, presents initial findings from the first 6 years of data collection (2014-2019), highlights ways that FOG data have been used, and describes the benefits and challenges of maintaining the surveillance system. Period Covered: 2014-2019. Description of System: In 2013, the National Institute for Occupational Safety and Health (NIOSH) created the FOG database, a surveillance system comprising an industry-specific worker fatality database. NIOSH researchers worked with OGE partners to establish inclusion criteria for the database and develop unique database variables to elucidate industry-specific factors related to each fatality (e.g., phase of operation, worker activity, and working alone). FOG cases are identified through various sources, such as Occupational Safety and Health Administration (OSHA) reports, media reports, and notifications from professional contacts. NIOSH researchers compile source documents; OGE-specific database variables are coded by multiple researchers to ensure accuracy. Data collection ceased in 2019 because grant funding ended. Results: During 2014-2019, a total of 470 OGE worker fatalities were identified in the FOG database. A majority of these fatalities (69.4%) were identified from OSHA reports and Google Alerts (44.7% and 24.7%, respectively). Unique database variables created to characterize fatalities in the OGE industry (i.e., phase of operation, worker activity, working alone, and working unobserved) were identified in approximately 85% of OGE worker fatality cases. The most frequent fatal events were vehicle incidents (26.8%), contact injuries (21.7%), and explosions (14.5%). The event type was unknown among 5.7% of worker fatalities. Approximately three fourths of fatalities identified through the FOG database were among contractors. Approximately 20% of cases included workers who were working alone. Interpretation: The FOG database is a resource for identifying safety and health trends and emerging issues among OGE workers (e.g., exposure to hydrocarbon gases and vapors and fatalities resulting from cardiac events) that might not be available in other surveillance systems. The FOG database also helps researchers better identify groups of workers that are at increased risk for injury in an already high-risk industry. Challenges exist when maintaining an industry-specific surveillance system, including labor-intensive data collection, the need for researchers with substantial knowledge of the industry, delays in access to timely data, and missing source file data. Public Health Actions: Continued surveillance of worker fatalities in the OGE industry is recommended to help identify new safety and health hazards and guide research and prevention activities. Industry, academic institutions, and government can use findings from the FOG database to identify factors contributing to fatal injuries in OGE and develop interventions to improve worker safety and health. The findings in this report also can be used by other industries with high fatality rates to support the development of worker fatality surveillance systems.

Working Alone and/or in Remote Locations: Opportunities to Prevent the Risk of Fatality From Cardiovascular Events in Oil and Gas Extraction Workers.

OBJECTIVE: The aim of the study is to explore personal and work factors related to fatal cardiac events among oil and gas extraction (OGE) workers. METHODS: The National Institute for Occupational Safety and Health Fatalities in Oil and Gas Extraction database was reviewed to identify fatal cardiac events among OGE workers from 2014 through 2019. A case series design was used to review case files, provide descriptive statistics, and summarize the findings. RESULTS: There were 75 fatalities identified, including 55 (73%) with sufficient information for review. Of the 55 workers, 18 (33%) worked alone. Thirty-six fatal cardiac events (66%) were unwitnessed by a coworker. Toxicology findings suggested some possible exposures to hydrogen sulfide or hydrocarbon gases or vapors. Missing data were common. CONCLUSIONS: This study identified the need for cardiovascular disease prevention and treatment, emergency preparedness, lone worker programs, medical screening, and enhanced exposure control in the OGE industry.

Fatalities Involving Substance Use Among US Oil and Gas Extraction Workers Identified Through an Industry Specific Surveillance System (2014-2019).

OBJECTIVE: Characteristics of oil and gas extraction (OGE) work, including long hours, shiftwork, fatigue, physically demanding work, and job insecurity are risk factors for substance use among workers. Limited information exists examining worker fatalities involving substance use among OGE workers. METHODS: The National Institute for Occupational Safety and Health's Fatalities in Oil and Gas Extraction database was screened for fatalities involving substance use from 2014 through 2019. RESULTS: Twenty-six worker deaths were identified as involving substance use. Methamphetamine or amphetamine was the most common substances (61.5%) identified. Other contributing factors were lack of seatbelt use (85.7%), working in high temperatures (19.2%), and workers' first day with the company (11.5%). CONCLUSIONS: Employer recommendations to mitigate substance use-related risks in OGE workers include training, medical screening, drug testing, and workplace supported recovery programs.

Outcomes at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults in the USA: a follow-up surveillance study.

BACKGROUND: Data on medium-term outcomes in indivduals with myocarditis after mRNA COVID-19 vaccination are scarce. We aimed to assess clinical outcomes and quality of life at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults. METHODS: In this follow-up surveillance study, we conducted surveys in US individuals aged 12-29 years with myocarditis after mRNA COVID-19 vaccination, for whom a report had been filed to the Vaccine Adverse Event Reporting System between Jan 12 and Nov 5, 2021. A two-component survey was administered, one component to patients (or parents or guardians) and one component to health-care providers, to assess patient outcomes at least 90 days since myocarditis onset. Data collected were recovery status, cardiac testing, and functional status, and EuroQol health-related quality-of-life measures (dichotomised as no problems or any problems), and a weighted quality-of-life measure, ranging from 0 to 1 (full health). The EuroQol results were compared with published results in US populations (aged 18-24 years) from before and early on in the COVID-19 pandemic. FINDINGS: Between Aug 24, 2021, and Jan 12, 2022, we collected data for 519 (62%) of 836 eligible patients who were at least 90 days post-myocarditis onset: 126 patients via patient survey only, 162 patients via health-care provider survey only, and 231 patients via both surveys. Median patient age was 17 years (IQR 15-22); 457 (88%) patients were male and 61 (12%) were female. 320 (81%) of 393 patients with a health-care provider assessment were considered recovered from myocarditis by their health-care provider, although at the last health-care provider follow-up, 104 (26%) of 393 patients were prescribed daily medication related to myocarditis. Of 249 individuals who completed the quality-of-life portion of the patient survey, four (2%) reported problems with self-care, 13 (5%) with mobility, 49 (20%) with performing usual activities, 74 (30%) with pain, and 114 (46%) with depression. Mean weighted quality-of-life measure (0·91 [SD 0·13]) was similar to a pre-pandemic US population value (0·92 [0·13]) and significantly higher than an early pandemic US population value (0·75 [0·28]; p<0·0001). Most patients had improvements in cardiac diagnostic marker and testing data at follow-up, including normal or back-to-baseline troponin concentrations (181 [91%] of 200 patients with available data), echocardiograms (262 [94%] of 279 patients), electrocardiograms (240 [77%] of 311 patients), exercise stress testing (94 [90%] of 104 patients), and ambulatory rhythm monitoring (86 [90%] of 96 patients). An abnormality was noted among 81 (54%) of 151 patients with follow-up cardiac MRI; however, evidence of myocarditis suggested by the presence of both late gadolinium enhancement and oedema on cardiac MRI was uncommon (20 [13%] of 151 patients). At follow-up, most patients were cleared for all physical activity (268 [68%] of 393 patients). INTERPRETATION: After at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination, most individuals in our cohort were considered recovered by health-care providers, and quality of life measures were comparable to those in pre-pandemic and early pandemic populations of a similar age. These findings might not be generalisable given the small sample size and further follow-up is needed for the subset of patients with atypical test results or not considered recovered. FUNDING: US Centers for Disease Control and Prevention.

Self-reported exposure to hazards and mitigation strategies among oil and gas extraction workers in three U.S. states.

Numerous health and safety hazards exist at U.S. onshore oil and gas extraction worksites. Higher fatal injury rates have been reported among drilling and servicing companies, which are more likely to employ workers in construction and extraction occupations, compared to operators that employ more workers in management and office and administrative support roles. However, there is little information describing the extent to which workers encounter these hazards, are provided hazard mitigation strategies by their employers, or use personal protective equipment (PPE). A cross-sectional survey of 472 U.S. oil and gas extraction workers was conducted to identify and characterize factors related to on-the-job fatalities, injuries, and illnesses and determine workers' health and safety concerns. Workers were employed by servicing companies (271/472, 57.4%), drilling contractors (106/472, 22.5%), and operators (95/472, 20.1%). The likelihood of contact with hazardous substances varied by substance and company type. Drilling and servicing employees had significantly higher odds of self-reported contact with pipe dope (ORdrilling = 10.07, 95% CI: 1.74-63.64; ORservicing = 5.95, 95% CI: 2.18-18.34), diesel exhaust (ORdrilling = 2.28, 95% CI: 1.15-5.05; ORservicing = 4.93, 95% CI: 2.73-10.32), and drilling mud (ORdrilling = 24.36, 95% CI: 4.45-144.69; ORservicing = 3.48, 95% CI: 1.24-12.20), compared to operators. Safety policies, programs, and trainings were commonly reported by workers, although substance-specific training (e.g., respirable crystalline silica hazards) was less common. Differences in self-reported employer PPE requirements and worker use of PPE when needed or required for safety highlight a need for novel strategies to improve the use of PPE. Overall, this study highlights differences in work conditions by company type and uncovers gaps in employer administrative controls and PPE use.

On the road again: A cross-sectional survey examining work schedules, commuting time, and driving-related outcomes among U.S. oil and gas extraction workers.

BACKGROUND: Oil and gas extraction (OGE) workers in the United States experience high fatality rates, with motor vehicle crashes the leading cause of death. Land-based OGE workers drive frequently to remote and temporary worksites. Limited information is available on factors that may influence crash risk for this workforce. METHODS: A cross-sectional survey of 500 land-based OGE workers examined work schedules and hours, commuting, sleep, employer policies, and their relationship to potentially harmful events while driving. RESULTS: Over 60% of participants worked 12 or more hours per day. The mean daily roundtrip commuting time was 1.82 h. Longer daily commutes, nonstandard work schedules, less sleep on workdays, and lack of employer policies were associated with one or more risky driving-related outcomes. CONCLUSIONS: Implementation and evaluation of OGE employer policies and programs to limit long work hours, reduce long daily commutes, promote sufficient sleep, and reduce drowsy driving among U.S. OGE workers are needed.

The Wildland Firefighter Exposure and Health Effect (WFFEHE) Study: Rationale, Design, and Methods of a Repeated-Measures Study.

The wildland firefighter exposure and health effect (WFFEHE) study was a 2-year repeated-measures study to investigate occupational exposures and acute and subacute health effects among wildland firefighters. This manuscript describes the study rationale, design, methods, limitations, challenges, and lessons learned. The WFFEHE cohort included fire personnel ages 18-57 from six federal wildland firefighting crews in Colorado and Idaho during the 2018 and 2019 fire seasons. All wildland firefighters employed by the recruited crews were invited to participate in the study at preseason and postseason study intervals. In 2019, one of the crews also participated in a 3-day midseason study interval where workplace exposures and pre/postshift measurements were collected while at a wildland fire incident. Study components assessed cardiovascular health, pulmonary function and inflammation, kidney function, workplace exposures, and noise-induced hearing loss. Measurements included self-reported risk factors and symptoms collected through questionnaires; serum and urine biomarkers of exposure, effect, and inflammation; pulmonary function; platelet function and arterial stiffness; and audiometric testing. Throughout the study, 154 wildland firefighters participated in at least one study interval, while 144 participated in two or more study interval. This study was completed by the Centers for Disease Control and Prevention's National Institute for Occupational Safety and Health through a collaborative effort with the U.S. Department of Agriculture Forest Service, Department of the Interior National Park Service, and Skidmore College. Conducting research in the wildfire environment came with many challenges including collecting study data with study participants with changing work schedules and conducting study protocols safely and operating laboratory equipment in remote field locations. Forthcoming WFFEHE study results will contribute to the scientific evidence regarding occupational risk factors and exposures that can impact wildland firefighter health over a season and across two wildland fire seasons. This research is anticipated to lead to the development of preventive measures and policies aimed at reducing risk for wildland firefighters and aid in identifying future research needs for the wildland fire community.

COVID-19 mortality among Amalgamated Transit Union (ATU) and Transport Workers Union (TWU) workers-March-July 2020, New York City metro area.

BACKGROUND: Transit workers have jobs requiring close public contact for extended periods of time, placing them at increased risk for severe acute respiratory syndrome coronavirus 2 infection and more likely to have risk factors for coronavirus disease 2019 (COVID-19)-related complications. Collecting timely occupational data can help inform public health guidance for transit workers; however, it is difficult to collect during a public health emergency. We used nontraditional epidemiological surveillance methods to report demographics and job characteristics of transit workers reported to have died from COVID-19. METHODS: We abstracted demographic and job characteristics from media scans on COVID-19 related deaths and reviewed COVID-19 memorial pages for the Amalgamated Transit Union (ATU) and Transport Workers Union (TWU). ATU and TWU provided a list of union members who died from COVID-19 between March 1-July 7, 2020 and a total count of NYC metro area union members. Peer-reviewed publications identified through a scientific literature search were used to compile comparison demographic statistics of NYC metro area transit workers. We analyzed and reported characteristics of ATU and TWU NYC metro area decedents. RESULTS: We identified 118 ATU and TWU NYC metro area transit worker COVID-19 decedents with an incidence proportion of 0.3%. Most decedents were male (83%); median age was 58 years (range: 39-71). Median professional tenure was 20 years (range: 2-41 years). Operator (46%) was the most reported job classification. More than half of the decedents (57%) worked in positions associated with close public contact. CONCLUSION: Data gathered through nontraditional epidemiological surveillance methods provided insight into risk factors among this workforce, demonstrating the need for mitigation plans for this workforce and informing transit worker COVID-19 guidance as the pandemic progressed.

Familial hypercholesterolemia in Mexico: Initial insights from the national registry.

BACKGROUND: Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated. OBJECTIVE: Report the results of the first years (2017-2019) of the Mexican FH registry. METHODS: There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations. RESULTS: To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C <100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033). CONCLUSION: The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.

The development of the Mexican Familial Hypercholesterolemia (FH) National Registry.

BACKGROUND AND AIMS: In Mexico, familial hypercholesterolemia (FH) is, as in other parts of the world, largely underdiagnosed and undertreated, and represents a significant burden to the healthcare system. However, there is not enough information to design public policies against the disease. Genetic studies have shown that LDLR mutations are the most common cause, but in a large percentage of the cases, no mutation has been identified in the FH genes. METHODS: In accordance with the procedures of the European Atherosclerosis Society (EAS) FH registries network, the Mexican FH registry (www.fhmexico.org.mx) was launched in December 2017 to address the gaps in knowledge regarding this disease. Reference centres and the main nationwide public health providers have been invited to participate. RESULTS: To date, 142 cases have been registered. The mean age at diagnosis of probands is 36.42 ±â€¯19.9 years (adults and children). Tendon xanthomas or premature corneal arcus were present in 40% and 17.6%, respectively. Molecular analysis was present in 70%, with over 95% of alterations located on the LDL receptor gene. The median untreated LDL-C is 6.5 (5.6-8.4) mmol/l and the median on treatment LDL-C level is 4.3 ±â€¯1.7 mmol/l. CONCLUSIONS: The Mexican FH registry aims to obtain real world information regarding the management of patients in this country. By participating in this global call to action, we hope to improve both short and long term outcomes for all FH patients in Mexico.

Frequency and clinical and molecular aspects of familial hypercholesterolemia in an endocrinology unit in Ciudad Bolívar, Venezuela. / Frecuencia, aspectos clínicos y moleculares de la hipercolesterolemia familiar en una unidad de endocrinología de Ciudad Bolívar, Venezuela.

OBJECTIVE: To assess the frequency and the clinical, biochemical, and molecular aspects of familial hypercholesterolemia (FH) in subjects attending an endocrinology unit. METHODS: An observational, descriptive study evaluating 3,140 subjects attending the endocrinology unit of Centro Médico Orinoco in Ciudad Bolívar, Venezuela, from 7 January 2013 to 9 December 2016. The index cases were selected using the Dutch Lipid Clinic Network criteria. Plasma lipid levels were measured, and a molecular analysis was performed by DNA sequencing of the LDLR and APOB genes. RESULTS: Ten (0.32%) of the 3,140 study patients had clinical and biochemical characteristics consistent with FH. All but one were female. Three had first-degree relatives with prior premature coronary artery; and none had a personal history of this condition. Three patients were obese; three had high blood pressure; and no one suffered from diabetes. Three patients had a history of tendon xanthomas, and one of corneal arcus. LDL-C levels ranged from 191 to 486mg/dL. Two patients were on statin therapy. The genetic causes of FH were identified in four patients, and were LDLR gene mutations in three of them and an APOB gene mutation in exon 26 in the other. CONCLUSION: Approximately, one out of every 300 people attending this endocrinology unit in those four years had FH, and LDLR gene mutations were the most prevalent cause.

PRKCI promotes immune suppression in ovarian cancer.

A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNFα to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNFα and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.

Dioxins and related environmental contaminants increase TDP-43 levels.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor. Recently, exposure to these toxicants was identified as a risk factor for ALS. METHODS: We examined levels of TDP-43 reporter activity, transcript and protein. Quantification was done using cell lines, induced pluripotent stem cells (iPSCs) and mouse brain. The target samples were treated with AHR agonists, including 6-Formylindolo[3,2-b]carbazole (FICZ, a potential endogenous ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, and benzo(a)pyrene, an abundant carcinogen in cigarette smoke). The action of the agonists was inhibited by concomitant addition of AHR antagonists or by AHR-specific shRNA. RESULTS: We now report that AHR agonists induce up to a 3-fold increase in TDP-43 protein in human neuronal cell lines (BE-M17 cells), motor neuron differentiated iPSCs, and in murine brain. Chronic treatment with AHR agonists elicits over 2-fold accumulation of soluble and insoluble TDP-43, primarily because of reduced TDP-43 catabolism. AHR antagonists or AHR knockdown inhibits agonist-induced increases in TDP-43 protein and TARDBP transcription demonstrating that the ligands act through the AHR. CONCLUSIONS: These results provide the first evidence that environmental AHR ligands increase TDP-43, which is the principle pathological protein associated with ALS. These results suggest novel molecular mechanisms through which a variety of prevalent environmental factors might directly contribute to ALS. The widespread distribution of dioxins, PCBs and PAHs is considered to be a risk factor for cancer and autoimmune diseases, but could also be a significant public health concern for ALS.

High Prevalence of Pneumocystis jirovecii Dihydropteroate Synthase Gene Mutations in Patients with a First Episode of Pneumocystis Pneumonia in Santiago, Chile, and Clinical Response to Trimethoprim-Sulfamethoxazole Therapy.

Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.

The panorama of familial hypercholesterolemia in Latin America: a systematic review.

The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.