Polylactose Exhibits Prebiotic Activity and Reduces Adiposity and Nonalcoholic Fatty Liver Disease in Rats Fed a High-Fat Diet.

BACKGROUND: Prebiotic dietary fibers change the intestinal microbiome favorably and provide a health benefit to the host. OBJECTIVES: Polylactose is a novel fiber, synthesized by extrusion of lactose. We evaluated its prebiotic activity by determining its fermentability, effect on the microbiota, and effects on adiposity and liver lipids in a diet-induced obesity animal model. METHODS: Male Wistar rats (4-5 wk old) were fed normal-fat (NF, 25% fat energy) or high-fat (HF, 51% fat energy) diets containing different fibers (6% fiber of interest and 3% cellulose, by weight), including cellulose (NFC and HFC, negative and positive controls, respectively), polylactose (HFPL), lactose matched to residual lactose in the HFPL diet, and 2 established prebiotic fibers: polydextrose (HFPD) and fructooligosaccharide (HFFOS). After 10 wk of feeding, organs were harvested and cecal contents collected. RESULTS: HFPL animals had greater cecum weight (3 times greater than HFC) and lower cecal pH (∼1 pH unit lower than HFC) than all other groups, suggesting that polylactose is more fermentable than other prebiotic fibers (HFPD, HFFOS; P < 0.05). HFPL animals also had increased taxonomic abundance of the probiotic species Bifidobacterium in the cecum relative to all other groups (P < 0.05). Epididymal fat pad weight was significantly decreased in the HFPL group (29% decrease compared with HFC) compared with all other HF groups (P < 0.05) and did not differ from the NFC group. Liver lipids and cholesterol were reduced in HFPL animals when compared with HFC animals (P < 0.05). CONCLUSIONS: Polylactose is a fermentable fiber that elicits a beneficial change in the gut microbiota as well as reducing adiposity in rats fed HF diets. These effects of polylactose were greater than those of 2 established prebiotics, fructooligosaccharide and polydextrose, suggesting that polylactose is a potent prebiotic.

Admission for Isolated Low-Grade Solid Organ Injury May Not Be Necessary in Pediatric Patients.

BACKGROUND: Recent publications indicate that blunt solid organ injuries can be safely managed with reduced length of stay using pathways focused on hemodynamics. We hypothesized that pediatric patients with isolated blunt Grade I or II solid organ injuries may be safely discharged after brief observation with appropriate outpatient follow-up. OBJECTIVE: The purpose of this study is to evaluate the need for admission of pediatric trauma patients with isolated low-grade solid organ injury resulting from blunt trauma. METHODS: We performed a retrospective cohort study of trauma registry data from 2011 to 2018 to identify isolated blunt Grade I or II solid organ injuries among children younger than 19 years. "Complication or intervention" was defined as transfusions, transfer to the intensive care unit, repeat imaging, decrease in Hgb greater than 2 g/dl, fluid bolus after initial resuscitation, operation or interventional radiology procedure, or readmission within 1 week. RESULTS: A total of 51 patients were admitted to the trauma service with isolated Grade I or II blunt solid organ injuries during the 8-year study period. The average age was 11 years. Among isolated Grade I or II injuries, seven (14%) had "complication or intervention" including greater than 2 g/dl drop in Hgb in four patients (8%), follow-up ultrasonography for pain in one patient (2%), readmission for pain in one patient (2%), or a fluid bolus in two patients (4%). None required transfusion or surgery. The most common mechanism of injury was sports related (45%), and the average length of stay was 1 day. CONCLUSION: Among a cohort of 51 patients with isolated blunt Grade I or II solid organ injuries, none required a significant intervention justifying need for admission. All "complication or intervention" patients observed were of limited clinical significance. We recommend that hemodynamically stable patients with isolated low-grade solid organ injuries may be discharged from the emergency department after a brief observation along with appropriate instructions and pain management.

Contrasting physiological responses to future ocean acidification among Arctic copepod populations.

Widespread ocean acidification (OA) is modifying the chemistry of the global ocean, and the Arctic is recognized as the region where the changes will progress at the fastest rate. Moreover, Arctic species show lower capacity for cellular homeostasis and acid-base regulation rendering them particularly vulnerable to OA. In the present study, we found physiological differences in OA response across geographically separated populations of the keystone Arctic copepod Calanus glacialis. In copepodites stage CIV, measured reaction norms of ingestion rate and metabolic rate showed severe reductions in ingestion and increased metabolic expenses in two populations from Svalbard (Kongsfjord and Billefjord) whereas no effects were observed in a population from the Disko Bay, West Greenland. At pHT 7.87, which has been predicted for the Svalbard west coast by year 2100, these changes resulted in reductions in scope for growth of 19% in the Kongsfjord and a staggering 50% in the Billefjord. Interestingly, these effects were not observed in stage CV copepodites from any of the three locations. It seems that CVs may be more tolerant to OA perhaps due to a general physiological reorganization to meet low intracellular pH during hibernation. Needless to say, the observed changes in the CIV stage will have serious implications for the C. glacialis population health status and growth around Svalbard. However, OA tolerant populations such as the one in the Disko Bay could help to alleviate severe effects in C. glacialis as a species.

Endotoxin rapidly desensitizes the gonads to kisspeptin-induced luteinizing hormone release in male Siberian hamsters (Phodopus sungorus).

Activation of the immune system induces rapid reductions in hypothalamic-pituitary-gonadal (HPG) axis activity, which in turn decreases secretion of sex steroids. This response is likely adaptive for survival by temporarily inhibiting reproduction to conserve energy; however, the physiological mechanisms controlling this response remain unclear. The neuropeptide kisspeptin is a candidate to mediate the decrease in sex hormones seen during sickness through its key regulation of the HPG axis. In this study, the effects of acute immune activation on the response to kisspeptin were assessed in male Siberian hamsters (Phodopus sungorus). Specifically, an immune response was induced in animals by a single treatment of lipopolysaccharide (LPS), and reproductive hormone concentrations were determined in response to subsequent injections of exogenous kisspeptin. Saline-treated controls showed a robust increase in circulating testosterone in response to kisspeptin; however, this response was blocked in LPS-treated animals. Circulating luteinizing hormone (LH) levels were elevated in response to kisspeptin in both LPS- and saline-treated groups and, thus, were unaffected by LPS treatment, suggesting gonad-level inhibition of testosterone release despite central HPG activation. In addition, blockade of glucocorticoid receptors by mifepristone did not attenuate the LPS-induced inhibition of testosterone release, suggesting that circulating glucocorticoids do not mediate this phenomenon. Collectively, these findings reveal that acute endotoxin exposure rapidly renders the gonads less sensitive to HPG stimulation, thus effectively inhibiting sex hormone release. More broadly, these results shed light on the effects of immune activation on the HPG axis and help elucidate the mechanisms controlling energy allocation and reproduction.

Effects of exogenous leptin on seasonal reproductive responses to interacting environmental cues in female Siberian hamsters.

Animals living in temperate climates respond to environmental cues that signal current and future resource availability to ensure that energy resources are available to support reproduction. Siberian hamsters (Phodopus sungorus) undergo robust gonadal regression in short, winter-like photoperiods as well as in response to mild food restriction in intermediate photoperiods. The goal of the present study was to investigate whether leptin is a relevant metabolic signal in regulating gonadal regression in response to diminishing food availability. Adult female hamsters housed in short-day (winter-like) or intermediate (fall-like) photoperiods received either ad libitum access to food or mild food restriction (90% of ad libitum intake) and were treated with either leptin or a vehicle for five weeks in order to determine the ability of leptin to inhibit gonadal regression. At the end of five weeks, vehicle-treated hamsters showed physiological signs associated with ongoing gonadal regression, such as decreases in body mass and food intake, cessation of estrous cycling, and small decreases in reproductive tissue mass. Leptin did not modify changes in body mass, food intake, hormone concentration, or tissue mass, but showed a tendency to support estrous cycling, particularly in response to food restriction in the intermediate photoperiod treatment. Overall, leptin appears to play a minor role in coordinating reproductive responses to multiple environmental cues, at least in the early stages of gonadal regression.

Landscape and Socioeconomic Factors Determine Malaria Incidence in Tropical Forest Countries.

Deforestation, landscape dynamics, and socioeconomic factors within the tropical Americas, Africa, and Asia may have different impacts on malaria incidence. To evaluate how these drivers affect malaria incidence at the global and regional scale, we collected malaria incidence rates from 2000 to 2019 from 67 tropical countries, along with forest loss, land use change types, and socioeconomic elements. LASSO regression, linear mixed effect modeling, and k-fold cross validation were used to create and evaluate the models. Regionality plays a role in the significance of varying risk factors. The Tropical Americas model had the highest coefficient of determination (marginal R2 = 0.369), while the Africa model showed the highest predictive accuracy with only a 17.4% error rate. Strong associations between tree cover loss (ß = -4037.73, p < 0.001) and percentage forest area (ß = 5373.18, p = 0.012) in Africa, and percent of key biodiversity areas under protection (ß = 496.71, p < 0.001; ß = 1679.20, p < 0.001) in the tropical Americas and Asia with malaria incidence indicates that malaria risk should be considered during conservation policy development, and recommends that individual approaches to policy and investment be considered when implementing malaria interventions on different spatial scales.

Healthcare personnel with laboratory-confirmed mpox in California during the 2022 outbreak.

The California Department of Public Health (CDPH) reviewed 109 cases of healthcare personnel (HCP) with laboratory-confirmed mpox to understand transmission risk in healthcare settings. Overall, 90% of HCP with mpox had nonoccupational exposure risk factors. One occupationally acquired case was associated with sharps injury while unroofing a patient's lesion for diagnostic testing.

A population health approach to workplace mental health: rationale, implementation and engagement.

Objectives: To describe a population health-based program to support employee and dependent mental health and learn from engagement trends. Methods: Retrospective analysis of a program utilizing an assessment of mental health risk. For scoring "at risk," a Care Concierge is offered to connect users with resources. Results: Participation was offered to 56,442 employees and dependents. Eight thousand seven hundred thirty-one completed the assessment (15%). Of those, 4,644 (53%) scored moderate or higher. A total of 418 (9%) engaged the Care Concierge. Factors that negatively influenced the decision to engage care included bodily pain, financial concerns. Positive influences were younger age, high stress, anxiety, PTSD and low social support. Conclusion: Proactive assessment plus access to a Care Concierge facilitates mental healthcare utilization. Several factors influence likelihood to engage in care. A better understanding of these factors may allow for more targeted outreach and improved engagement.

Ocean acidification causes fundamental changes in the cellular metabolism of the Arctic copepod Calanus glacialis as detected by metabolomic analysis.

Using a targeted metabolomic approach we investigated the effects of low seawater pH on energy metabolism in two late copepodite stages (CIV and CV) of the keystone Arctic copepod species Calanus glacialis. Exposure to decreasing seawater pH (from 8.0 to 7.0) caused increased ATP, ADP and NAD+ and decreased AMP concentrations in stage CIV, and increased ATP and phospho-L-arginine and decreased AMP concentrations in stage CV. Metabolic pathway enrichment analysis showed enrichment of the TCA cycle and a range of amino acid metabolic pathways in both stages. Concentrations of lactate, malate, fumarate and alpha-ketoglutarate (all involved in the TCA cycle) increased in stage CIV, whereas only alpha-ketoglutarate increased in stage CV. Based on the pattern of concentration changes in glucose, pyruvate, TCA cycle metabolites, and free amino acids, we hypothesise that ocean acidification will lead to a shift in energy production from carbohydrate metabolism in the glycolysis toward amino acid metabolism in the TCA cycle and oxidative phosphorylation in stage CIV. In stage CV, concentrations of most of the analysed free fatty acids increased, suggesting in particular that ocean acidification increases the metabolism of stored wax esters in this stage. Moreover, aminoacyl-tRNA biosynthesis was enriched in both stages indicating increased enzyme production to handle low pH stress.

Getting Started with LINCS Datasets and Tools.

The Library of Integrated Network-based Cellular Signatures (LINCS) was an NIH Common Fund program that aimed to expand our knowledge about human cellular responses to chemical, genetic, and microenvironment perturbations. Responses to perturbations were measured by transcriptomics, proteomics, cellular imaging, and other high content assays. The second phase of the LINCS program, which lasted 7 years, involved the engagement of six data and signature generation centers (DSGCs) and one data coordination and integration center (DCIC). The DSGCs and the DCIC developed several digital resources, including tools, databases, and workflows that aim to facilitate the use of the LINCS data and integrate this data with other publicly available data. The digital resources developed by the DSGCs and the DCIC can be used to gain new biological and pharmacological insights that can lead to the development of novel therapeutics. This protocol provides step-by-step instructions for processing the LINCS data into signatures, and utilizing the digital resources developed by the LINCS consortia for hypothesis generation and knowledge discovery. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Navigating L1000 tools and data in CLUE.io Basic Protocol 2: Computing signatures from the L1000 data with the CD method Basic Protocol 3: Analyzing lists of differentially expressed genes and querying them against the L1000 data with BioJupies and the Bulk RNA-seq Appyter Basic Protocol 4: Utilizing the L1000FWD resource for drug discovery Basic Protocol 5: KINOMEscan and the KINOMEscan Appyter Basic Protocol 6: LINCS P100 and GCP Proteomics Assays Basic Protocol 7: The LINCS Joint Project (LJP) Basic Protocol 8: The LINCS Data Portals and SigCom LINCS Basic Protocol 9: Creating and analyzing signatures with iLINCS.

Effects of exercise and physical activity on knee osteoarthritis.

Exercise is one of the most discussed and controversial nonpharmacologic management strategies for osteoarthritis (OA) of the knee. Health care providers and patients share varied and often pseudoscientific beliefs regarding the effects of exercise on knee OA formulated on outdated notions of the etiology, pathophysiology, and progression of the condition. Based on the contemporary literature, regular light to moderate physical activity has both preventive and therapeutic benefits for individuals with knee OA. Exercise regimens with strong evidence of benefit include those that focus on aerobic/cardiovascular conditioning and lower extremity strength training. Health care providers should confidently incorporate exercise recommendations into clinical management and offer patients evidence-based and individually tailored exercise prescriptions to help manage the painful and often disabling symptoms of this condition.

Food restriction during development delays puberty but does not affect adult seasonal reproductive responses to food availability in Siberian hamsters (Phodopus sungorus).

Seasonally breeding animals respond to environmental cues to determine optimal conditions for reproduction. Siberian hamsters (Phodopus sungorus) primarily rely on photoperiod as a predictive cue of future energy availability. When raised in long-day photoperiods (>14 h light), supplemental cues such as food availability typically do not trigger the seasonal reproductive response of gonadal regression, which curtails reproduction in unsuitable environments. We investigated whether recognition of food availability as a cue could be altered by a nutritional challenge during development. Specifically, we predicted that hamsters receiving restricted food during development would be sensitized to food restriction (FR) as adults and undergo gonadal regression in response. Male and female hamsters were given either ad libitum (AL) food or FR from weaning until d60. The FR treatment predictably limited growth and delayed puberty in both sexes. For 5 weeks after d60, all hamsters received an AL diet to allow FR hamsters to gain mass equal to AL hamsters. Then, adult hamsters of both juvenile groups received either AL or FR for 6 weeks. Juvenile FR had lasting impacts on adult male body mass and food intake. Adult FR females exhibited decreased estrous cycling and uterine horn mass indiscriminately of juvenile food treatment, but there was little effect on male reproductive measurements. Overall, we observed a delay in puberty in response to postweaning FR, but this delay appeared not to affect seasonal reproductive responses in the long term. These findings increase our understanding of seasonal reproductive responses in a relevant environmental context.

Workplace Mental Health: Application of a Population Health Approach of Proactive Screening to Identify Risk and Engage in Care.

OBJECTIVE: To evaluate a proactive, voluntary screening program designed to identify employees with emerging mental health risk and engage them in care. METHODS: Risk was proactively identified through online screening of 344 participants. At-risk participants were offered a mental health care concierge to provide support, develop a care plan, and connect to care. RESULTS: Risk for common mental health conditions was identified in 244 (71%) participants, of whom 66 (27%) connected with a care concierge. Compared with participants who did not connect to a care concierge, those who did were more likely to report a financial crisis (68.2% vs 50.8%) and less likely to report verbal abuse (9.1% vs 19.6%) and difficulty meeting daily needs (12.1% vs 25.1%). CONCLUSION: Implementation of this screening program identified employees at risk for mental health conditions and facilitated connection to care.

Gene Set Knowledge Discovery with Enrichr.

Profiling samples from patients, tissues, and cells with genomics, transcriptomics, epigenomics, proteomics, and metabolomics ultimately produces lists of genes and proteins that need to be further analyzed and integrated in the context of known biology. Enrichr (Chen et al., 2013; Kuleshov et al., 2016) is a gene set search engine that enables the querying of hundreds of thousands of annotated gene sets. Enrichr uniquely integrates knowledge from many high-profile projects to provide synthesized information about mammalian genes and gene sets. The platform provides various methods to compute gene set enrichment, and the results are visualized in several interactive ways. This protocol provides a summary of the key features of Enrichr, which include using Enrichr programmatically and embedding an Enrichr button on any website. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Analyzing lists of differentially expressed genes from transcriptomics, proteomics and phosphoproteomics, GWAS studies, or other experimental studies Basic Protocol 2: Searching Enrichr by a single gene or key search term Basic Protocol 3: Preparing raw or processed RNA-seq data through BioJupies in preparation for Enrichr analysis Basic Protocol 4: Analyzing gene sets for model organisms using modEnrichr Basic Protocol 5: Using Enrichr in Geneshot Basic Protocol 6: Using Enrichr in ARCHS4 Basic Protocol 7: Using the enrichment analysis visualization Appyter to visualize Enrichr results Basic Protocol 8: Using the Enrichr API Basic Protocol 9: Adding an Enrichr button to a website.

Predicting Lyme Disease From Patients' Peripheral Blood Mononuclear Cells Profiled With RNA-Sequencing.

Although widely prevalent, Lyme disease is still under-diagnosed and misunderstood. Here we followed 73 acute Lyme disease patients and uninfected controls over a period of a year. At each visit, RNA-sequencing was applied to profile patients' peripheral blood mononuclear cells in addition to extensive clinical phenotyping. Based on the projection of the RNA-seq data into lower dimensions, we observe that the cases are separated from controls, and almost all cases never return to cluster with the controls over time. Enrichment analysis of the differentially expressed genes between clusters identifies up-regulation of immune response genes. This observation is also supported by deconvolution analysis to identify the changes in cell type composition due to Lyme disease infection. Importantly, we developed several machine learning classifiers that attempt to perform various Lyme disease classifications. We show that Lyme patients can be distinguished from the controls as well as from COVID-19 patients, but classification was not successful in distinguishing those patients with early Lyme disease cases that would advance to develop post-treatment persistent symptoms.

Recent Progress in Lyme Disease and Remaining Challenges.

Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.

Contrasting responses to salinity and future ocean acidification in arctic populations of the amphipod Gammarus setosus.

Climate change is leading to alterations in salinity and carbonate chemistry in arctic/sub-arctic marine ecosystems. We examined three nominal populations of the circumpolar arctic/subarctic amphipod, Gammarus setosus, along a salinity gradient in the Kongsfjorden-Krossfjorden area of Svalbard. Field and laboratory experiments assessed physiological (haemolymph osmolality and gill Na+/K+-ATPase activity, NKA) and energetic responses (metabolic rates, MO2, and Cellular Energy Allocation, CEA). In the field, all populations had similar osmregulatory capacities and MO2, but lower-salinity populations had lower CEA. Reduced salinity (S = 23) and elevated pCO2 (~1000 µatm) in the laboratory for one month increased gill NKA activities and reduced CEA in all populations, but increased MO2 in the higher-salinity population. Elevated pCO2 did not interact with salinity and had no effect on NKA activities or CEA, but reduced MO2 in all populations. Reduced CEA in lower-rather than higher-salinity populations may have longer term effects on other energy demanding processes (growth and reproduction).

A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH.

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50-80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.