Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues.

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in Caenorhabditis elegans We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

Mitotic checkpoint gene expression is tuned by codon usage bias.

The mitotic checkpoint (also called spindle assembly checkpoint, SAC) is a signaling pathway that safeguards proper chromosome segregation. Correct functioning of the SAC depends on adequate protein concentrations and appropriate stoichiometries between SAC proteins. Yet very little is known about the regulation of SAC gene expression. Here, we show in the fission yeast Schizosaccharomyces pombe that a combination of short mRNA half-lives and long protein half-lives supports stable SAC protein levels. For the SAC genes mad2+ and mad3+ , their short mRNA half-lives are caused, in part, by a high frequency of nonoptimal codons. In contrast, mad1+ mRNA has a short half-life despite a higher frequency of optimal codons, and despite the lack of known RNA-destabilizing motifs. Hence, different SAC genes employ different strategies of expression. We further show that Mad1 homodimers form co-translationally, which may necessitate a certain codon usage pattern. Taken together, we propose that the codon usage of SAC genes is fine-tuned to ensure proper SAC function. Our work shines light on gene expression features that promote spindle assembly checkpoint function and suggests that synonymous mutations may weaken the checkpoint.

Risk Factors for Lower Extremity Minor Amputation Conversion to Major Amputation.

BACKGROUND: Minor lower extremity amputations (LEAs) have become an important part of the limb salvage approach but are not as benign as previously thought. This study investigates the difference in outcome between toe/ray versus midfoot amputations and the risk factors for major amputation conversion associated with each procedure. METHODS: We performed retrospective chart review of foot amputation patients at a single tertiary care medical center with a primary end point of conversion to major amputation and secondary end points of 1-year wound healing and mortality rate. We collected data on relevant medical comorbidities, noninvasive vascular imaging, revascularization, repeat amputations, wound healing rate, and 1-year mortality. Patients were separated into toe/ray amputations versus midfoot amputation groups and compared using descriptive statistics, Chi-squared tests, Cox proportional hazards, and a multivariate logistic regression model. RESULTS: A total of 375 amputations were included in the analysis. 65.3% (245 patients) included toe/ray amputations and 34.7% (130 patients) included midfoot amputations. We compared these 2 cohorts with regard to their rate of conversion to repeat minor and/or major amputation in addition to overall mortality. The toe/ray group underwent more repeat minor amputations within 1 year after index amputation (34.7% vs. 21.5%, P = 0.008) and wound healing (epithelization) at 90 days was also higher in this group. The midfoot group had a higher conversion to major LEA within 1 year on univariate analysis (20.8 vs. 6.9%, P < 0.001). Overall 1-year mortality was 6.17% and there was no significant difference between groups. CONCLUSIONS: While there is a consistency with previous studies that found no significant overall difference in mortality between types of minor LEA, we have extended this previous work by demonstrating the independent risk factors for conversion to major amputation between types of minor LEA. Comparing these 2 groups will assist surgeons in choosing the appropriate level of amputations and will enhance patient's understanding of their chance of wound healing and risk of repeat amputation.

Characteristics and Outcomes of Patients Transferred for Treatment of Acute Limb Ischemia.

BACKGROUND: Patients requiring emergent vascular surgery often undergo transfer from one facility to another for definitive surgical care. In this study, we analyzed morbidity and mortality in patients presenting for emergent lower extremity thrombectomy and embolectomy in the transferred and nontransferred populations. METHODS: A retrospective analysis of prospectively collected data was performed utilizing the National Surgical Quality Improvement Program (NSQIP) database for all nonelective, emergent lower extremity embolectomy or thrombectomy (Current Procedural Terminology [CPT] 34,201 and 34,203) performed between 2011 and 2014. Demographics, comorbidities, and 30-day complications, and outcomes were compared among patients presenting from home versus those presenting from another hospital, emergency department, or nursing home. Multivariate analysis was performed to determine the association between mode of presentation, major complications, and death. RESULTS: We identified 1,954 patients who underwent emergent lower extremity embolectomy or thrombectomy. 40.7% (795 patients) were identified as transfer patients. Odds of transfer were significantly increased if a patient was functionally dependent (odds ratio OR 1.95, P < 0.001) or had a history of chronic obstructive pulmonary disease (COPD) (OR 1.348, P = 0.05). Odds of transfer were decreased if a patient was of a nonWhite race (OR 0.511, P < 0.001). 11.7% (229) patients in the described cohort died within 30 days of surgery. Those who died were more likely to present to the treating hospital as a transfer (56.3% vs. 38.6%, P < 0.001). In multivariate analysis, transfer status was significantly associated with 30-day mortality (OR 1.9: 95% confidence interval CI 1.40-2.64; P < 0.001). CONCLUSIONS: Patients transferred from an outside hospital or nursing home who present for emergent vascular procedures demonstrated increased mortality compared to those who present from home direct to the emergency department despite similar comorbid conditions. In addition, race was identified as an independent factor for transfer. Further studies are needed to understand the complex interactions between inter-hospital transfer patterns, emergency vascular surgery presentations, and racial biases to improve outcomes for this population.

Palliative Care Consultation is Associated with Decreased Rates of In-Hospital Mortality Among Patients Undergoing Major Amputation.

BACKGROUND: Despite advancements in medical care and surgical techniques, major amputation continues to be associated with risks for morbidity and mortality. Palliative care programs may help alleviate symptoms and align patients' goals and the care they receive with their treatment plan. Access to specialty palliative medicine among vascular surgery patients is limited. Here, we aim to describe utilization and impact of formal palliative care consultation for patients receiving major amputations. METHODS: This is a retrospective, secondary data analysis project examining the records of patients who received major amputations by the vascular surgery team between 2016 and 2021. Demographics, operative, and postoperative outcomes were recorded. The primary outcome variable was palliative care consultation during index admission (the admission in which the patient received their first major amputation). Secondary outcomes were in-hospital mortality and code status at the time of death, if death occurred during the index admission, location of death, and discharge destination. RESULTS: The cohort comprised of 292 patients (39% female, 53% Black, mean age 63), who received a lower extremity major amputation. Most patients (65%) underwent amputation for limb ischemia. One-year mortality after first major amputation was 29%. Average length of stay was 20 days. Thirty-five (12%) patients received a palliative care consultation during the hospitalization in which they received their first major amputation. On multivariable analysis, patients were more likely to receive a palliative care consult during their index admission if they had undergone a thorough knee amputation (OR = 2.89, P = 0.039) or acute limb ischemia (OR = 4.25, P = 0.005). A formal palliative care consult was associated with lower likelihood of in-hospital death and increased likelihood of discharge to hospice (OR = 0.248, P = 0.0167, OR = 1.283, P < 0.001).There were no statistically significant differences in the code status of patients who received a palliative care consultation. CONCLUSIONS: In a large academic medical center, palliative medicine consultation was associated with lower in-hospital mortality among patients with advanced vascular disease and major limb amputation. These data will hopefully stimulate much needed prospective research to develop and test tools to identify patients in need and derive evidence about the impact of palliative care services.

An outbreak of Salmonella Saintpaul gastroenteritis after attending a school camp in the Northern Territory, Australia.

An outbreak of salmonellosis occurred following attendance at a school camp between 5 and 8 August 2014 in a remote area of the Northern Territory, Australia. We conducted a retrospective cohort study via telephone interviews, using a structured questionnaire that recorded symptoms and exposures to foods and activities during the camp. A case was anyone with laboratory confirmed Salmonella Saintpaul infection or a clinically compatible illness after attending the camp. Environmental health officers from the Environmental Health Branch undertook an investigation and collected water and environmental samples. We interviewed 65 (97%) of the 67 people who attended the camp. There were 60 students and 7 adults. Of the 65 people interviewed, 30 became ill (attack rate 46%); all were students; and 4 had laboratory confirmed S. Saintpaul infection. The most commonly reported symptoms were diarrhoea (100% 30/30), abdominal pain (93% 28/30), nausea (93% 28/30) and fever (70% 21/30). Thirteen people sought medical attention but none required hospitalisation. Illness was significantly associated with drinking cordial at lunch on 7 August (RR 3.8, 95% CI 1.3-11, P < 0.01), as well as drinking cordial at lunch on 8 August (RR 2.1, 95% CI 1.1-4.2, P=0.01). Salmonella spp. was not detected in water samples or wallaby faeces collected from the camp ground. The epidemiological investigation suggests the outbreak was caused by environmental contamination of food or drink and could have occurred during ice preparation or storage, preparation of the cordial or from inadequate sanitising of the cooler from which the cordial was served. This outbreak highlights the risks of food or drink contamination with environmental Salmonella. Those preparing food and drink in campground settings should be vigilant with cleaning, handwashing and disinfection to prevent outbreaks of foodborne disease.

An outbreak of salmonellosis associated with duck prosciutto at a Northern Territory restaurant.

In June 2015, an outbreak of salmonellosis occurred among people who had eaten at a restaurant in Darwin, Northern Territory over 2 consecutive nights. We conducted a retrospective cohort study of diners who ate at the restaurant on 19 and 20 June 2015. Diners were telephoned and a questionnaire recorded symptoms and menu items consumed. An outbreak case was defined as anyone with laboratory confirmed Salmonella Typhimurium PT9 (STm9) or a clinically compatible illness after eating at the restaurant. Environmental health officers inspected the premises and collected food samples. We contacted 79/83 of the cohort (response rate 95%); 21 were cases (attack rate 27%), and 9 had laboratory confirmed STm9 infection. The most commonly reported symptoms were diarrhoea (100%), abdominal pain (95%), fever (95%) and nausea (95%). Fifteen people sought medical attention and 7 presented to hospital. The outbreak was most likely caused by consumption of duck prosciutto, which was consumed by all cases (OR 18.6, CI 3.0-∞, P < 0.01) and was prepared on site. Salmonella was not detected in any food samples but a standard plate count of 2 x 107 colony forming units per gram on samples of duck prosciutto demonstrated bacterial contamination. The restaurant used inappropriate methodology for curing the duck prosciutto. Restaurants should consider purchasing pre-made cured meats, or if preparing them on site, ensure that they adhere to safe methods of production.

Evaluating Operative Exposure for Medical Students in the Era of Virtual Learning: A Single-Institution Experience.

INTRODUCTION: Training at a tertiary center offers clerkship students the opportunity to rotate through a wide range of surgical specialties that may not be otherwise available. At our institution, students rotate through general surgery for 3 out of 9 weeks, with the remainder offering electives. As a result, students may have limited experience with core general surgery cases which are necessary to complete by the end of the clerkship to demonstrate competency. In efforts to standardize clinical training, students must log 11 core general surgery cases either in the operating room or modules via Wise-MD. Wise-MD is used in place of participating in the operating room when students do not have the opportunity to see certain cases during their surgical rotation. The purpose of the study is to ascertain what proportion of third year medical students experience core general surgery cases in the operating room versus Wise-MD, providing insight into ways to improve the surgical clerkship. METHODS: Clerkship students recorded whether surgical cases are completed via Wise-MD or experienced in the operating room. Forms submitted by students who completed surgical clerkship between January 2018 to September 2022 were analyzed. For each core surgical case (anorectal, appendicitis, bowel obstruction, breast cancer, cholecystitis, colon cancer, diverticulitis, inguinal hernia, lung cancer, skin cancer, and trauma) students were stratified based on their reported experience. The proportion of Wise-MD versus operating room cases was calculated. RESULTS: Between January 2018 and September 2022 a total of 411 students submitted completed case logs. Among all surgical cases, 60% were experienced by students in the operating room. The surgical cases with the highest proportion of operating room experience included appendicitis (78%), cholecystitis (85%), inguinal hernia (79%), and trauma (76%). The surgical cases with the lowest proportion of operating room experience included lung cancer (34%) and skin cancer (44%). CONCLUSION: Despite enforcing a general surgery block, about 40% of students are not experiencing most "bread and butter" surgical cases. Clerkship directors should be mindful about the distribution of medical students among surgical teams as this may affect which cases are observed. Moreover, the opportunity for surgical electives may influence general surgery exposure.

Soil micronutrients linked to human health in India.

Trace soil minerals are a critical determinant of both crop productivity and the mineral concentration of crops, therefore potentially impacting the nutritional status of human populations relying on those crops. We link health data from nearly 0.3 million children and one million adult women across India with over 27 million soil tests drawn from a nationwide soil health program. We find that soil zinc availability is positively associated with children's linear height growth, and soil iron availability is positively associated with hemoglobin levels. The link between soil zinc and childhood stunting is particularly robust-a one standard deviation increase in satisfactory soil zinc tests is associated with approximately 11 fewer children stunted per 1000. We also find that this zinc-stunting relationship is strongest in wealthier households. Our results suggest that soil mineral availability impacts human nutritional status and health in at least some areas of India, and that agronomic fortification may be a beneficial intervention.

Predictive Factors for Mortality Following Major Lower Extremity Amputation.

BACKGROUND: Despite advances in techniques and care, major amputation bears a high risk for mortality. Previously identified factors associated with increased risk of mortality include amputation level, renal function, and pre-operative white cell count. METHODS: A single center retrospective chart review was conducted identifying patients who had undergone a major amputation. Chi-squared, t-testing, and Cox proportional hazard modeling were performed examining death at 6 months and 12 months. RESULTS: Factors associated with an increased risk of six-month mortality include age (OR 1.01-1.05, P < .001), sex (OR 1.08-3.24, P < .01), minority race (OR 1.18-18.19, P < .01), chronic kidney disease (OR 1.40-6.06, P < .001), and use of pressors at the induction of anesthesia for index amputation (OR 2.09-7.85, P < .000). Factors associated with increased risk of 12 month mortality were similar. DISCUSSION: Patients undergoing major amputation continue to suffer high mortality. Those patients who received their amputation under physiologically stressful conditions were more likely to die within 6 months. Reliably predicting six-month mortality can assist surgeons and patients in making appropriate care decisions.

Lessons in liability: Examining medical malpractice suits against general surgeons in Maryland.

BACKGROUND: Although medical malpractice lawsuits pose a significant burden, there is a paucity of research on physician-specific characteristics influencing lawsuits against surgeons. Our objective was to identify factors associated with general surgeons being named in malpractice cases. METHODS: This was a cross sectional study of Maryland general surgeons, using malpractice data from a publicly accessible judiciary database. Case number per decade and lifetime lawsuit status were modeled with linear and logistic regression. RESULTS: Male surgeons had a higher average lawsuit volume (p = 0.002) and were more likely to be named in a malpractice case (p < 0.001). In regression analysis, a second graduate degree was a predictor of average cases per 10 years (p = 0.008) and male gender predicted lifetime lawsuit status (OR = 1.73, p = 0.046). CONCLUSIONS: Male gender was associated with increased odds of being named in a malpractice lawsuit. Identifying this difference is a preliminary step in developing interventions to reduce lawsuits amongst surgeons.

Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues.

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in C. elegans. We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, a functional homolog of mammalian peroxisome proliferator-activated receptor alpha (PPARα), regulates stress resilience and proteostasis downstream of embryo integrity and other pathways that influence lipid homeostasis, and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing inter-tissue pathway in somatic tissues, also triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49 together with its co-activator MDT-15 contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer as well as by other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting. Further, we show that increased NHR-49 activity is sufficient to suppress polyglutamine aggregation and improve stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

Temporal Trends of Racial and Socioeconomic Disparities in Population Exposures to Upstream Oil and Gas Development in California.

People living near oil and gas development are exposed to multiple environmental stressors that pose health risks. Some studies suggest these risks are higher for racially and socioeconomically marginalized people, which may be partly attributable to disparities in exposures. We examined whether racially and socioeconomically marginalized people in California are disproportionately exposed to oil and gas wells and associated hazards. We longitudinally assessed exposure to wells during three time periods (2005-2009, 2010-2014, and 2015-2019) using sociodemographic data at the census block group-level. For each block group and time period, we assessed exposure to new, active, retired, and plugged wells, and cumulative production volume. We calculated risk ratios to determine whether marginalized people disproportionately resided near wells (within 1 km). Averaged across the three time periods, we estimated that 1.1 million Californians (3.0%) lived within 1 km of active wells. Nearly 9 million Californians (22.9%) lived within 1 km of plugged wells. The proportion of Black residents near active wells was 42%-49% higher than the proportion of Black residents across California, and the proportion of Hispanic residents near active wells was 4%-13% higher than their statewide proportion. Disparities were greatest in areas with the highest oil and gas production, where the proportion of Black residents was 105%-139% higher than statewide. Socioeconomically marginalized residents also had disproportionately high exposure to wells. Though oil and gas production has declined in California, marginalized communities persistently had disproportionately high exposure to wells, potentially contributing to health disparities.

Ruptured Iliac Arteriovenous Fistula Presenting With Thigh Pain and Swelling: Case Report.

The presentation of abdominal arteriovenous fistulas is classically described as a triad of a pulsatile abdominal mass with a bruit, high-output heart failure, and regional venous hypertension with primarily open operative therapy. In the following case, we present the treatment of a patient who arrived with acute right heart failure and renal failure due to an arteriovenous fistula and who was successfully treated with endovascular repair.

Mood, Activity Participation, and Leisure Engagement Satisfaction (MAPLES): a randomised controlled pilot feasibility trial for low mood in acquired brain injury.

BACKGROUND: Acquired brain injury (ABI) affects approximately 79.3 million individuals annually and is linked with elevated rates of depression and low mood. Existing methods for treating depression in ABI have shown mixed efficacy. Behavioural activation (BA) is a potentially promising intervention. Its premise is that individuals with low mood avoid planning and engaging in activities due to low expectations of a positive outcome. Consequently, their exposure to positive reinforcement is reduced, exacerbating low mood. BA aims to break this cycle by encouraging activity planning and engagement. It is unknown whether cognitive demands of traditional BA may undermine efficacy in ABI. Here, we assess the feasibility and acceptability of two groups designed to increase activity engagement. In the activity planning group (traditional BA), the importance of meaningful and positive activity will be discussed and participants encouraged to plan/engage in activities in everyday life. The activity engagement group (experiential BA) instead focuses on engagement in positive experiences (crafts, games, discussion) within the group. The primary aims are to evaluate the feasibility and acceptability of the two groups in ABI. A secondary aim is to explore relative efficacy of the groups compared to an equivalent period of waitlist controls. METHOD: This study outlines a parallel-arm pilot feasibility trial for individuals with low mood and ABI that compares a traditional vs experiential BA group vs waitlist controls. Adults (≥ 18 years) will be recruited from local ABI services and randomised to condition. Feasibility and acceptability will be assessed via recruitment, retention, attendance and participant feedback. Groups will be compared (pre- and post-intervention and 1 month follow-up) by assessing self-reported activity engagement. Secondary outcomes include self-report measures of depression, anxiety, post-traumatic distress related to the ABI, motivation, participation and sense of control over one's life. ETHICS AND DISSEMINATION: The trial has been approved by the Health Research Authority of the NHS in the UK (East of England-Cambridge Central, REF 18/EE/0305). Results will inform future research on interventions for mood in ABI and be disseminated broadly via peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03874650 pre-results. Protocol version 2.1, March 5, 2019.

Production and Use of Hymenolepis diminuta Cysticercoids as Anti-Inflammatory Therapeutics.

Helminthic therapy has shown considerable promise as a means of alleviating some inflammatory diseases that have proven resistant to pharmaceutical intervention. However, research in the field has been limited by a lack of availability to clinician scientists of a helminth that is relatively benign, non-communicable, affordable, and effectively treats disease. Previous socio-medical studies have found that some individuals self-treating with helminths to alleviate various diseases are using the rat tapeworm (cysticercoid developmental stage of Hymenolepis diminuta; HDC). In this study, we describe the production and use of HDCs in a manner that is based on reports from individuals self-treating with helminths, individuals producing helminths for self-treatment, and physicians monitoring patients that are self-treating. The helminth may fit the criteria needed by clinical scientists for clinical trials, and the methodology is apparently feasible for any medical center to reproduce. It is hoped that future clinical trials using this organism may shed light on the potential for helminthic therapy to alleviate inflammatory diseases. Further, it is hoped that studies with HDCs may provide a stepping stone toward population-wide restoration of the biota of the human body, potentially reversing the inflammatory consequences of biota depletion that currently affect Western society.

Herbal Supplement Sales in US Increase 8.5% in 2017, Topping $8 Billion. Strongest sales growth in more than 15 years bolstered by continued popularity of Ayurvedic herbs and new formulations of botanicals with general health and nutrition benefits

In 2017, retail sales of herbal dietary supplements in the United States surpassed $8 billion for the first time, reaching an estimated total of $8.085 billion. Consumer spending increased by approximately $633 million, or 8.5%, from 2016 ­ the strongest US sales growth for herbal supplements in more than 15 years. Total US retail sales have increased every year since 2004, and since then, consumer spending on herbal supplements has nearly doubled.

Frontal sinus mucoceles presenting in the upper eyelid: an easily missed diagnosis.

Frontal sinus mucoceles are epithelium-lined mucus-containing sacs that are capable of bony expansion causing a spectrum of ophthalmological symptoms. If left untreated, they can erode the thin sinus wall causing life-threatening complications such as meningitis. We would like to alert the clinicians to this diagnosis that can be easily misdiagnosed. The first patient appeared to have an allergic blepharo-conjunctivitis that was not responding to topical and systemic medications. The second patient presented with recurrent preseptal cellulitis unresponsive to oral antibiotics. CT imaging of both patients revealed frontal sinus mucoceles. Both patients recovered well with sinus surgery. Management of these patients needed a close liaison with our ENT and radiology colleagues to warrant a good outcome.