Public health emergency preparedness for infectious disease emergencies: a scoping review of recent evidence.

BACKGROUND: The COVID-19 pandemic continues to demonstrate the risks and profound health impacts that result from infectious disease emergencies. Emergency preparedness has been defined as the knowledge, capacity and organizational systems that governments, response and recovery organizations, communities and individuals develop to anticipate, respond to, or recover from emergencies. This scoping review explored recent literature on priority areas and indicators for public health emergency preparedness (PHEP) with a focus on infectious disease emergencies. METHODS: Using scoping review methodology, a comprehensive search was conducted for indexed and grey literature with a focus on records published from 2017 to 2020 onward, respectively. Records were included if they: (a) described PHEP, (b) focused on an infectious emergency, and (c) were published in an Organization for Economic Co-operation and Development country. An evidence-based all-hazards Resilience Framework for PHEP consisting of 11 elements was used as a reference point to identify additional areas of preparedness that have emerged in recent publications. The findings were analyzed deductively and summarized thematically. RESULTS: The included publications largely aligned with the 11 elements of the all-hazards Resilience Framework for PHEP. In particular, the elements related to collaborative networks, community engagement, risk analysis and communication were frequently observed across the publications included in this review. Ten emergent themes were identified that expand on the Resilience Framework for PHEP specific to infectious diseases. Planning to mitigate inequities was a key finding of this review, it was the most frequently identified emergent theme. Additional emergent themes were: research and evidence-informed decision making, building vaccination capacity, building laboratory and diagnostic system capacity, building infection prevention and control capacity, financial investment in infrastructure, health system capacity, climate and environmental health, public health legislation and phases of preparedness. CONCLUSION: The themes from this review contribute to the evolving understanding of critical public health emergency preparedness actions. The themes expand on the 11 elements outlined in the Resilience Framework for PHEP, specifically relevant to pandemics and infectious disease emergencies. Further research will be important to validate these findings, and expand understanding of how refinements to PHEP frameworks and indicators can support public health practice.

Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants.

Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1-null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL/6J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.

Spatial and temporal dynamics of the cardiac mitochondrial proteome.

Mitochondrial proteins alter in their composition and quantity drastically through time and space in correspondence to changing energy demands and cellular signaling events. The integrity and permutations of this dynamism are increasingly recognized to impact the functions of the cardiac proteome in health and disease. This article provides an overview on recent advances in defining the spatial and temporal dynamics of mitochondrial proteins in the heart. Proteomics techniques to characterize dynamics on a proteome scale are reviewed and the physiological consequences of altered mitochondrial protein dynamics are discussed. Lastly, we offer our perspectives on the unmet challenges in translating mitochondrial dynamics markers into the clinic.

Diet1 is a regulator of fibroblast growth factor 15/19-dependent bile acid synthesis.

BACKGROUND: A fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and hepatic bile acid synthesis. In response to bile acid uptake in enterocytes, farnesoid X receptor is activated and induces transcription of fibroblast growth factor (FGF)15 in mice, or FGF19 in humans. FGF15/19 is secreted into the enterohepatic circulation, and through activation of hepatic receptors, leads to repression of Cyp7a1, a rate-limiting enzyme for bile acid synthesis. Using a genetic approach, we identified a novel protein, Diet1, as a control point for FGF15/19 production. KEY MESSAGES: Mice with a Diet1-null mutation have reduced FGF15 secretion, causing impaired feedback repression of hepatic bile acid synthesis, and increased fecal bile acid excretion. As a result, Diet1-deficient mice constitutively convert cholesterol to bile acids and are resistant to diet-induced hypercholesterolemia and atherosclerosis. Diet1 affects FGF15/19 production at the posttranscriptional level, and the proteins appear to have overlapping subcellular localization in enterocytes. Diet1 appears to be a control point for the production of FGF15/19 in enterocytes, and thus a regulator of bile acid and lipid homeostasis. Studies to evaluate the role of common and rare DIET1 genetic variants in human health and disease are warranted. CONCLUSIONS: Further elucidation of the Diet1-FGF15/19 interaction will provide new insights into the intricate regulatory mechanisms underlying bile acid metabolism.

Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum.

The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2-deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2-deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2-deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.

Regulation of bile acid homeostasis by the intestinal Diet1-FGF15/19 axis.

PURPOSE OF REVIEW: Hepatic bile acid synthesis is controlled, in part, by a complex enterohepatic feedback regulatory mechanism. In this review, we focus on the role of the intestinal FGF15/19 hormone in modulating bile acid levels, and additional metabolic effects on glucose metabolism, nonalcoholic liver disease (NAFLD), and liver regeneration. We also highlight the newly identified intestinal protein, Diet1, which is a modulator of FGF15/19 levels. RECENT FINDINGS: Low FGF19 levels are associated with bile acid diarrhea and NAFLD. In contrast, high FGF19 levels are associated with diabetes remission following Roux-en-Y gastric bypass surgery, suggesting new therapeutic approaches against type 2 diabetes. The effect of FGF15/19 on liver plasticity is a double-edged sword: whereas elevated FGF15/19 levels improve survival of mice after partial hepatectomy, FGF19 mitogenic activity is associated with liver carcinoma. Finally, a recent study has identified Diet1, an intestinal factor that influences FGF15/19 levels in mouse intestine and human enterocytes. Diet1 represents the first factor shown to influence FGF15/19 levels at a post-transcriptional level. SUMMARY: The biological effects of FGF15/19 make it an attractive target for treating metabolic dysregulation underlying conditions such as fatty liver and type 2 diabetes. Further elucidation of the role of Diet1 in FGF15/19 secretion may provide a control point for the pharmacological modulation of FGF15/19 levels.

Pupillary effects of high-dose opioid quantified with infrared pupillometry.

BACKGROUND: The pupillary light reflex is a critical component of the neurologic examination, yet whether it is present, depressed, or absent is unknown in patients with significant opioid toxicity. Although opioids produce miosis by activating the pupillary sphincter muscle, these agents may induce significant hypercarbia and hypoxia, causing pupillary constriction to be overcome via sympathetic activation. The presence of either "pinpoint pupils" or sympathetically mediated pupillary dilation might prevent light reflex assessment. This study was designed to determine whether the light reflex remains quantifiable during opioid-induced hypercarbia and hypoxia. METHODS: Ten volunteers were administered remifentanil with a gradually increasing infusion rate and intermittent boluses, until the increasing respiratory depression produced an oxyhemoglobin saturation of 85% or less with associated hypercarbia. Subjects' heart rate, blood pressure, respiration, and transcutaneous carbon dioxide level were continuously recorded. Arterial blood gases and pupillary measures were taken before opioid administration, at maximal desaturation, and 15 min after recovery. RESULTS: The opioid-induced oxygen desaturation (≤ 85%) was associated with significant hypercarbia and evidence of sympathetic activation. During maximal hypoxia and hypercarbia, the pupil displayed parasympathetic dominance (2.5 ± 0.2 mm diameter) with a robust quantifiable light reflex. The reflex amplitude was linearly related to pupil diameter. CONCLUSIONS: Opioid administration with significant accompanying hypercarbia and hypoxia results in pupil diameters of 2 to 3 mm and a reduced but quantifiable pupillary light reflex. The authors conclude that the pupillary examination and evaluation of the light reflex remain useful for neurologic assessment during opioid toxicity.

A Path to High-Value Gastric Cancer Surgery Care Delivery.

Objective: To evaluate the feasibility, safety, and effectiveness of a comprehensive regional program, including the Minimally Invasive Recovery and Empowerment Care (MIREC) pathway, that can significantly reduce hospital stays after laparoscopic gastrectomy without increasing adverse events. Background: Cost-effectiveness and improving patient outcomes are crucial in providing quality gastric cancer care worldwide. Methods: To compare the outcomes of gastric cancer surgery using 2 different models of care within an integrated healthcare system from February 2012 to March 2023. The primary endpoint was the length of hospital stay. The secondary endpoints were the need for intensive care unit care, emergency room (ER) visits, readmission, reoperation, and death within 30 days after surgery. Results: There were 553 patients, 167 in the pre-(February 2012-April 2016) and 386 in the post-MIREC period (May 2016-March 2023). Perioperative chemotherapy utilization increased from 31.7% to 76.4% (P < 0.0001). Laparoscopic gastrectomy increased from 17.4% to 97.7% (P < 0.0001). Length of hospitalization decreased from 7 to 2 days (P < 0.0001), with 32.1% and 88% of patients discharged home on postoperative day 1 and postoperative day 2, respectively. When comparing pre- and post-MIREC, intensive care unit utilization (10.8% vs. 2.9%, P < 0.0001), ER visits (34.7% vs. 19.7%, P = 0.0002), and readmission (18.6% vs. 11.1%, P = 0.019) at 30 days were also considerably lower. In addition, more patients received postoperative adjuvant chemotherapy (31.4% to 63.5%, P < 0.0001), and the time between gastrectomy and starting adjuvant chemotherapy was also less (49-41 days; P = 0.002). Conclusion: This comprehensive regional program, which encompasses regionalization care, laparoscopic approach, modern oncologic care, surgical subspecialization, and the MIREC pathway, can potentially improve gastric cancer surgery outcomes. These benefits include reduced hospital stays and lower complication rates. As such, this program can revolutionize how gastric cancer surgery is delivered, leading to a higher quality of care and increased value to patients.

Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Glucarpidase (voraxaze), a carboxypeptidase enzyme for methotrexate toxicity.

Glucarpidase (Voraxaze) for methotrexate toxicity.

Nursery origin of yellowfin tuna in the western Atlantic Ocean: significance of Caribbean Sea and trans-Atlantic migrants.

Natural geochemical markers in the otolith of yellowfin tuna (Thunnus albacares) were used to establish nursery-specific signatures for investigating the origin of fish captured in the western Atlantic Ocean (WAO). Two classes of chemical markers (trace elements, stable isotopes) were used to first establish nursery-specific signatures of age-0 yellowfin tuna from four primary production zones in the Atlantic Ocean: Gulf of Mexico, Caribbean Sea, Cape Verde, and Gulf of Guinea. Next, mixture and individual assignment methods were applied to predict the origin of sub-adult and adult yellowfin tuna from two regions in the WAO (Gulf of Mexico, Mid Atlantic Bight) by relating otolith core signatures (corresponding to age-0 period) to baseline signatures of age-0 fish from each nursery. Significant numbers of migrants from Caribbean Sea and eastern Atlantic Ocean (EAO) production zones (Gulf of Guinea, Cape Verde) were detected in the WAO, suggesting that fisheries in this region were subsidized by outside spawning/nursery areas. Contributions from local production (Gulf of Mexico) were also evident in samples from both WAO fisheries, but highly variable from year to year. High levels of mixing by yellowfin tuna from the different production zones and pronounced interannual trends in nursery-specific contribution rates in the WAO emphasize the complex and dynamic nature of this species' stock structure and population connectivity. Given that geographic shifts in distribution across national or political boundaries leads to governance and management challenges, this study highlights the need for temporally resolved estimates of nursery origin to refine assessment models and promote the sustainable harvest of this species.

Trimer IgG and neutralising antibody response to COVID-19 mRNA vaccination in individuals with sarcoidosis.

Background: Individuals with sarcoidosis are at higher risk for infection owing to underlying disease pathogenesis and need for immunosuppressive treatment. Current knowledge as to how subjects with sarcoidosis respond to different forms of vaccination is limited. We examined quantitative and functional antibody response to COVID-19 vaccination in infection-naive subjects with and without sarcoidosis. Methods: Our prospective cohort study recruited 14 subjects with biopsy-proven sarcoidosis and 27 age-sex matched controls who underwent a two-shot series of the BNT162b2 mRNA vaccine at the University of Illinois at Chicago. Baseline, 4-week and 6-month trimer spike protein IgG and neutralising antibody (nAb) titres were assessed. Correlation and multivariate regression analysis was conducted. Results: Sarcoidosis subjects had a significant increase in short-term antibody production to a level comparable to controls; however, IgG titres significantly declined back to baseline levels by 6 months. Corresponding neutralising assays revealed robust nAb titres in sarcoidosis subjects that persisted at 6 months. A significant and strong correlation between IgG and nAb titres across all time points was observed in the control group. However within the sarcoidosis group, a significant but weak correlation between antibody levels was found. Overall, IgG levels were poor predictors of nAb titres at short- or long-term time points. Conclusions: Sarcoidosis subjects exhibit nAb induced by the BNT162b2 mRNA SARS-CoV-2 vaccine at levels comparable to controls that persists at 6 months indicating conferred immunity. Trimer IgG levels are poor predictors of nAb in subjects with sarcoidosis. Studies of further antibody immunoglobulins and subtypes warrant investigation.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: A transcriptomic analysis of the immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells (PBMCs) was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p < 0.05). Anti-spike IgG remained elevated above baseline at six months in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) and identify transcriptomic and clinical predictors of anti-Spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of end stage renal disease (ESRD). Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Catheter-directed embolectomy for massive pulmonary embolism in a pediatric patient.

Pulmonary embolisms can affect 0.9 in 100,000 children and carry high risk for mortality. However, management of pediatric pulmonary embolism is largely derived from adult studies and treatment often includes local or systemic thrombolytics or anticoagulation, which may pose unique bleeding risks in children and adolescents compared with adults. This report describes a case in which catheter-directed embolectomy was used to successfully manage a pediatric patient with high-risk/massive pulmonary embolism. This case suggests that catheter-directed embolectomy is an effective therapy in patients outside the adult population and more research is required to expand inclusion criteria for current catheter-directed embolectomy treatment paradigms. Moreover, this case emphasizes the need for dedicated pediatric pulmonary embolism response teams to best serve the pediatric population.

Quality of ICU Discharge Summaries Produced by Pediatric Residents: The Memorial Health University Medical Center Experience.

Background: Discharging intensive care unit (ICU) patients directly home is becoming more common. High-quality ICU discharge summaries are crucial in the transition of patient care. Currently, at Memorial Health University Medical Center (MHUMC), there exists no standardized ICU discharge summary template or consistency when discharge documentation is completed. Investigators evaluated the timeliness and completeness of ICU discharge summaries at MHUMC produced by pediatric residents. Methods: A single-center retrospective chart review of pediatric patients discharged directly from a 10-bed Pediatric ICU to home was conducted. Charts were evaluated pre- and post-intervention. The intervention included the implementation of a standardized ICU discharge template, formal resident training in writing discharge summaries, and a new policy mandating documentation completion within 48 hours of patient discharge. Timeliness was based on documentation completion within 48 hours. Completeness was evaluated on the presence of the Joint Commission on Accreditation of Healthcare Organizations' (JCAHO) recommendations of specific components that should be included in all discharge summaries. Results were reported as proportions, with differences calculated using Fisher's exact and chi-square tests. Patient descriptive characteristics were recorded. Results: Thirty-nine total patients, 13 pre-intervention and 26 post-intervention were included in the study. In the pre-intervention group, 38.5% (5/13) had discharge summaries completed in less than 48 hours from patient discharge compared to 88.5% (23/26) in the post-intervention group (P=.002). Post-intervention discharge documentation was more likely than pre-intervention to contain the discharge diagnosis (100% vs. 69.2%, P=.009) and to provide follow-up care instructions for the outpatient physician (100% vs. 75%, P=.031). Conclusion: Standardizing discharge summary templates and encouraging stricter institutional policies regarding the timely completion of discharge summaries can improve the ICU discharge process. Formal resident training in medical documentation is important and should be incorporated into graduate medical education curricula.

Biological sex modifies aldosterone's secretion at a cellular level.

Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues' levels. This study's goal was to determine whether ALDO's biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO's biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG's MR (thereby activating the ultrashort feedback loop) reduced CYP11B2's activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO's biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO's circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.

mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner.

The mechanistic target of the rapamycin (mTOR) pathway plays a role in features common to both excess salt/aldosterone and cardiovascular/renal diseases. Dietary sodium can upregulate mTORC1 signaling in cardiac and renal tissue, and the inhibition of mTOR can prevent aldosterone-associated, salt-induced hypertension. The impact of sex and age on mTOR's role in volume homeostasis and the regulation of aldosterone secretion is largely unknown. We hypothesize that both age and sex modify mTOR's interaction with volume homeostatic mechanisms. The activity of 3 volume homeostatic mechanisms-cardiovascular, renal, and hormonal (aldosterone [sodium retaining] and brain natriuretic peptide [BNP; sodium losing])-were assessed in mTORC1 deficient (Raptor+/-) and wild-type male and female littermates at 2 different ages. The mice were volume stressed by being given a liberal salt (LibS) diet. Raptor+/-mice of both sexes when they aged: (1) reduced their blood pressure, (2) increased left ventricular internal diameter during diastole, (3) decreased renal blood flow, and (4) increased mineralocorticoid receptor expression. Aldosterone levels did not differ by sex in young Raptor+/- mice. However, as they aged, compared to their littermates, aldosterone decreased in males but increased in females. Finally, given the level of Na+ intake, BNP was inappropriately suppressed, but only in Raptor+/- males. These data indicate that Raptor+/- mice, when stressed with a LibS diet, display inappropriate volume homeostatic responses, particularly with aging, and the mechanisms altered, differing by sex.

Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses.

Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/-) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/- mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/- mice had normal ALDO levels but lacked normal renovascular responses. In humans, ERAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels.

Integrated omics dissection of proteome dynamics during cardiac remodeling.

Transcript abundance and protein abundance show modest correlation in many biological models, but how this impacts disease signature discovery in omics experiments is rarely explored. Here we report an integrated omics approach, incorporating measurements of transcript abundance, protein abundance, and protein turnover to map the landscape of proteome remodeling in a mouse model of pathological cardiac hypertrophy. Analyzing the hypertrophy signatures that are reproducibly discovered from each omics data type across six genetic strains of mice, we find that the integration of transcript abundance, protein abundance, and protein turnover data leads to 75% gain in discovered disease gene candidates. Moreover, the inclusion of protein turnover measurements allows discovery of post-transcriptional regulations across diverse pathways, and implicates distinct disease proteins not found in steady-state transcript and protein abundance data. Our results suggest that multi-omics investigations of proteome dynamics provide important insights into disease pathogenesis in vivo.

A reference set of curated biomedical data and metadata from clinical case reports.

Clinical case reports (CCRs) provide an important means of sharing clinical experiences about atypical disease phenotypes and new therapies. However, published case reports contain largely unstructured and heterogeneous clinical data, posing a challenge to mining relevant information. Current indexing approaches generally concern document-level features and have not been specifically designed for CCRs. To address this disparity, we developed a standardized metadata template and identified text corresponding to medical concepts within 3,100 curated CCRs spanning 15 disease groups and more than 750 reports of rare diseases. We also prepared a subset of metadata on reports on selected mitochondrial diseases and assigned ICD-10 diagnostic codes to each. The resulting resource, Metadata Acquired from Clinical Case Reports (MACCRs), contains text associated with high-level clinical concepts, including demographics, disease presentation, treatments, and outcomes for each report. Our template and MACCR set render CCRs more findable, accessible, interoperable, and reusable (FAIR) while serving as valuable resources for key user groups, including researchers, physician investigators, clinicians, data scientists, and those shaping government policies for clinical trials.