A Laboratory-Scale Evaluation of Smart Pebble Sensors Embedded in Geomaterials.

This paper introduces a novel approach to measure deformations in geomaterials using the recently developed 'Smart Pebble' sensors. Smart Pebbles were included in triaxial test specimens of unbound aggregates stabilized with geogrids. The sensors are equipped with an aggregate particle/position tracking algorithm that can manage uncertainty arising due to signal noise and random walk effects. Two Smart Pebbles were placed in each test specimen, one at specimen's mid-height, where a geogrid was installed in the mechanically stabilized specimen, and one towards the top of the specimen. Even with simple raw data processing, the trends on linear vertical acceleration indicated the ability of Smart Pebbles to assess the geomaterial configuration and applied stress states. Employing a Kalman filter-based algorithm, the Smart Pebble position coordinates were tracked during testing. The specimen's resilient deformations were simultaneously recorded. bender element shear wave transducer pairs were also installed on the specimens to further validate the Smart Pebble small-strain responses. The results indicate a close agreement between the BE sensors and Smart Pebbles estimates towards local stiffness enhancement quantification in the geogrid specimen. The study findings confirm the viability of using the Smart Pebbles in describing the resilient behavior of an aggregate material under repeated loading.

Discrepancies between phenotypic and genotypic identification methods of antibiotic resistant genes harboring Staphylococcusaureus.

Antimicrobial resistance is a global issue that limits therapeutic options for infections. S. aureus being a member of the ESKAPE group is capable of "escaping" the biocidal action of antimicrobial agents. There are phenotypic and genotypic methods used for the identification of antibiotic resistant genes harboring S. aureus but these methods do not always show concordant results. To address these discrepancies, a total of 335 equine nasal swab samples from four districts of Punjab were collected using a convenient sampling technique. These samples were first subjected to common microbial techniques to identify S. aureus. The disc diffusion assay was performed for the phenotypic identification of antibiotic resistant S. aureus by using discs of oxacillin, penicillin, vancomycin, gentamycin, and tetracycline. After this, PCR was performed by targeting mecA, blaZ, vanB, aaca-aphd, and tetK genes for genotypic identification of respective antibiotic-resistant S. aureus. Phenotypic discrepancies (number of antibiotic resistant isolates found from disc diffusion who appeared to be negative for the resistant gene), and genotypic discrepancies (number of antibiotic sensitive isolates found from disc diffusion who appeared to be positive for the resistant gene) were calculated. The discrepancy ratio for mecA, blaZ, vanB, aaca-aphd, and tetK genes were 3.09, 1.96, 2.67, 1.93, and 1.67 respectively. These discrepant results indicate that the absence or presence of only one gene is not a true marker of resistant or sensitive isolates. There are multiple resistance determinants and resistance mechanisms. This study also highlighted the phenomenon of silencing of antibiotic resistance determinants.

An Analysis of Motivating Factors in 1,725 Worldwide Cases of Mass Murder Between 1900-2019.

Mass murder, particularly mass shootings, constitutes a major, growing public health concern. Specific motivations for these acts are not well understood, often overattributed to severe mental illness. Identifying diverse factors motivating mass murders may facilitate prevention. We examined 1,725 global mass murders from 1900-2019, publicly described in English in print or online. We empirically categorized each into one of ten categories reflecting reported primary motivating factors, which were analyzed across mass murderers generally, as well as between U.S- and non-U.S.-based mass-shooters. Psychosis or disorganization related to mental illness were infrequently motivational factors (166; 9.6%), and were significantly more associated with mass murder committed using methods other than firearms. The vast majority (998, 57.86%) of incidents were impulsive and emotionally-driven, following adverse life circumstances. Most mass murderers prompted by emotional upset were found to be driven by despair or extreme sadness over life events (161, 16.13% within the category); romantic rejection or loss, or severe jealousy (204, 20.44% within the category); some specific non-romantic grudge (212, 21.24% within the category); or explosive, overwhelming rage following a dispute (266, 26.65% within the category). Results suggest that policies seeking to prevent mass murder should focus on criminal history, as well as subacute emotional disturbances not associated with severe mental illness in individuals with poor coping skills who have recently experienced negative life events.

Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression.

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, and the tobacco epidemic exacerbates kidney damage in patients with DN. However, the underlying molecular mechanisms remain unclear. METHOD: In the present study, we used a diabetic mouse model to investigate the molecular mechanisms for nicotine-exacerbated DN. Twelve-week-old female mice were injected with streptozotocin (STZ) to establish a hyperglycemic diabetic model. After four months, the control and hyperglycemic diabetic mice were further divided into four groups (control, nicotine, diabetic mellitus, nicotine + diabetic mellitus) by intraperitoneal injection of nicotine or PBS. After two months, urine and blood were collected for kidney injury assay, and renal tissues were harvested for further molecular assays using RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry. In vitro studies, we used siRNA to suppress Grem1 expression in human podocytes. Then we treated them with nicotine and high glucose to compare podocyte injury. RESULT: Nicotine administration alone did not cause apparent kidney injury, but it significantly increased hyperglycemia-induced albuminuria, BUN, plasma creatinine, and the kidney tissue mRNA expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry analysis revealed that, compared to hyperglycemia or nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and worsened DN. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury. CONCLUSION: Grem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN.

Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent.

Inflammation contributes to many chronic conditions. It is often associated with circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate with disease severity. They are often elevated and can serve as markers of inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-MSH and ACTH have receptor-mediated anti-inflammatory properties that can rescue cells from damage and death. These peptides have been studied well in the past century. In contrast, GLP-1 and its anti-inflammatory properties have been recognized only recently. GLP-1 has been proven to be a useful adjuvant therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It also lowers HbA1C and protects cells of the cardiovascular and nervous systems by reducing inflammation and apoptosis. In this review we have explored the link between GLP-1, inflammation, and sepsis.

Collagenase treatment decreases muscle stiffness in cerebral palsy: A preclinical ex vivo biomechanical analysis of hip adductor muscle fiber bundles.

AIM: To determine the dose-response relationship of collagenase Clostridium histolyticum (CCH) on collagen content and the change in muscle fiber bundle stiffness after ex vivo treatment of adductor longus biopsies with CCH in children with cerebral palsy (CP). METHOD: Biopsy samples of adductor longus from children with CP (classified in Gross Motor Function Classification System levels IV and V) were treated with 0 U/mL, 200 U/mL, 350 U/mL, or 500 U/mL CCH; percentage collagen reduction was measured to determine the dose-response. Peak and steady-state stresses were determined at 1%, 2.5%, 5%, and 7.5% strain increments; Young's modulus was calculated. RESULTS: Eleven patients were enrolled (nine males, two females, mean age at surgery 6 years 5 months; range: 2-16 years). A linear CCH dose-response relationship was determined. Peak and steady-state stress generation increased linearly at 5.9/2.3mN/mm2 , 12.4/5.3mN/mm2 , 22.2/9.7mN/mm2 , and 33.3/15.5mN/mm2 at each percentage strain increment respectively. After CCH treatment, peak and steady-state stress generation decreased to 3.2/1.2mN/mm2 , 6.5/2.9mN/mm2 , 12.2/5.7mN/mm2 , and 15.4/7.7mN/mm2 respectively (p < 0.004). Young's modulus decreased from 205 kPa to 100 kPa after CCH (p = 0.003). INTERPRETATION: This preclinical ex vivo study provides proof of concept for the use of collagenase to decrease muscle stiffness in individuals with CP.

Evidence and Molecular Characterization of Multidrug Resistant Staphylococcus aureus Isolated From Equines in Pakistan.

The purpose of the current study was to investigate the nasal colonization and drug resistance profile of Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant S. aureus (VRSA) in donkeys (n =63), mules (n = 42), and horses (n = 98). MRSA and VRSA were confirmed based on phenotypic and molecular methods, followed by phylogenetic analysis. Furthermore, the association of various animal and management-based risk factors with S. aureus colonization was also evaluated. The presence of nuc gene on polymerase chain reaction showed an overall prevalence of 42.86% of S. aureus in equines. Based on Kirby-Bauer disc diffusion test, 26.44% of isolates showed resistance to vancomycin. Further, mecA and vanB genes were targeted which showed an overall 14.94% and 13.79% prevalence of methicillin and vancomycin-resistant isolates, respectively. The phylogenetic analysis revealed a significant variation of the study isolates with each other and with already reported sequences of mecA and vanB genes. Risk factor analysis revealed that raising purpose (P = .011), work intensity (P < .001), stocking density (P = .006), presence of other livestock animals in surroundings (P = .043), and common drinking water source (P = .023) as significant. Antimicrobial susceptibility testing of MRSA and VRSA isolates showed high resistance to various commonly used antibiotics. Furthermore, all the tested isolates showing resistance to three or more than three antibiotics were considered multiple drug-resistant. The current study manifests the molecular evidence of MRSA and VRSA isolated from equines in Pakistan which will help to address the emerging issue of multidrug resistance in S. aureus in equines and emphasizes the need for possible measures to tackle this issue.

Victimology of Mass Shootings and Mass Murders Not Involving Firearms.

Most research to date has focused on perpetrators of mass murder incidents. Hence, there is little information on victims. We examined 973 mass murders that occurred in the United States between 1900 and 2019 resulting in 5,273 total fatalities and 4,498 nonfatal injuries for a total of 9,771 victims (on average 10 victims per incident). Approximately 64% of victims of mass murder were White individuals, 13% were Black individuals, 6% were Asian individuals, and 14% were Latinx individuals. Given the higher number of nonfatal injuries per non-firearm mass murder event (11.0 vs. 2.8, p < .001), the total number of victims was only 50% higher for mass shootings (5,855 victims) vs. non-firearm mass murder events (3,916 victims). Among the 421 incidents of mass murder in the United States since 2000, Black, Asian, and Native American individuals were overrepresented among victims of mass shootings compared with their representation in the general U.S. population, and White individuals were underrepresented (all p ≤ .002). Findings of racial/ethnic differences were similar among victims of mass murder committed with means other than firearms for Black, Asian, and White individuals. These findings highlight different areas of victimology within the context of these incidents.

Predictive Factors of Outcomes in Acute Subdural Hematoma Evacuation.

OBJECTIVE: This comparative cross-sectional study was conducted in the Departments of Trauma and Neurosurgery, Ayub Teaching Hospital, Abbottabad, Pakistan from September 2021 to February 2022 to study predictive factors of outcomes in acute subdural hematoma evacuation. METHODOLOGY: A total of 101 patients with confirmed diagnosis of acute subdural hematoma (ASDH) who underwent surgical evacuation by consultant neurosurgeon were included in the study. A detailed clinical proforma was designed to document all the clinical and demographic details of these patients at the time of admission. Glasgow Coma Scale outcome score (GOS) was used to assess the outcome of patients after the surgery. Sociodemographic and clinical parameters were associated with outcome of surgery in our study participants. RESULTS: Out of 101 patients, 55 (54.5%) were males and 46 (45.5%) were females. Mean age was 43.66±19.66 years with 7.39 as mean Glasgow Coma Scale (GCS) at presentation. Road traffic accident (RTA) 62 (61.4%) was most frequent mechanism of injury followed by fall from height (19.8%) and history of assault (13.9%). In our study, 59 patients had poor outcomes while 42 had good outcomes. Elder age, low GCS at presentation, and use of oral anticoagulant were associated with poor outcomes while pupillary reaction had no effect on the outcome after application of test of significance. CONCLUSION: More than half of the patients managed with surgical evacuation for acute subdural hematoma as per guidelines at our neurosurgical unit had poor outcomes according to Glasgow Coma Scale. In this study, advancing age (>60 years), low GCS score at presentation, and use of oral anticoagulation therapy emerged as significant risk factors for poor outcomes in participants. Pupillary reaction had no effect on outcomes as per this study but this needs further evaluation in future studies.

Neonatal venolymphatic malformation with spontaneous parotid duct rupture: first case report.

Disorders of salivary glands especially the parotid gland very rare among neonates and children other than cytomegaly and parotitis epidermica. Venolymphatic malformations are very rare in children. Such presentation around the parotid region yet to be reported. This case report describes a rare presentation of a neonatal venolymphatic malformation on the parotid duct. A 4-week-old termly delivered male infant referred to by a general practitioner bruising over the left buccal area for 1 day from non-consanguine healthy parents. On examination a bluish discoloration in the buccal mucosa over a firm mildly tender area without signs of inflammation was seen. Ultrasound examination of the lesion showed fluid and solid soft tissue suggestive of haematoma and magnetic resonance imaging scan confirmed the rupture of the parotid duct with venolymphatic malformation. The child has been referred to the vascular malformation clinic and plastic surgical clinic in a tertiary care hospital for follow-up.

Oxytocin and Related Peptide Hormones: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.

Zinc and hypoxic preconditioning: a strategy to enhance the functionality and therapeutic potential of bone marrow-derived mesenchymal stem cells.

The therapeutic use of bone marrow mesenchymal stem cells (BM-MSCs) requires a large number of cells (1-100 × 106 cells/kg of body weight). Extensive in vitro growth is limited due to the aging of cultured BM-MSCs which leads to abnormal morphology and senescence. Hypoxia increases BM-MSC proliferation, but the question of whether hypoxia preconditioning is safe for clinical application of BM-MSCs remains to be answered. Zinc is essential for cell proliferation and differentiation, especially for the regulation of DNA synthesis and mitosis. It is a structural constituent of numerous proteins on a molecular level, including transcription factors and enzymes of cellular signaling machinery. All the tissues, fluids, and organs of the human body contain zinc. More than 95% of zinc is intracellular, of which 44% is involved in the transcription of DNA. We investigated the effects of ZnCl2 on proliferation, morphology, migration, population doubling time (PDT), and gene expression of BM-MSCs under hypoxic (1% O2) and normoxic (21% O2) environments. BM-MSCs were preconditioned with optimized concentrations of ZnCl2 under normoxic and hypoxic environments and further examined for morphology by the phase-contrast inverted microscope, cell proliferation by MTT assay, PDT, cell migration ability, and gene expression analysis. Zinc significantly enhanced the proliferation of BM-MSCs, and it decreases PDT under hypoxic and normoxic environments as compared to control cells. Migration of BM-MSCs toward the site of injury increased and expression of HIF1-α significantly decreased under hypoxic conditions as compared to non-treated hypoxic cells and control. At late passages (P9), the morphology of normoxic BM-MSCs was transformed into large, wide, and flat cells, and they became polygonal and lost their communication with other cells. Conversely, zinc-preconditioned BM-MSCs retained their spindle-shaped, fibroblast-like morphology at P9. The expression of proliferative genes was found significantly upregulated, while downregulation of genes OCT4 and CCNA2 was observed in zinc-treated BM-MSCs under both normoxic and hypoxic conditions. ZnCl2 treatment can be used for extensive expansion of BM-MSCs in aged populations to obtain a large number of cells required for systemic administration to produce therapeutic efficacy.

Bihemispheric ischemic strokes in patients with COVID-19.

BACKGROUND: There is emerging evidence that COVID-19 can trigger thrombosis because of a hypercoagulable state, including large-vessel occlusion ischemic strokes. Bihemispheric ischemic stroke is uncommon and is thought to indicate an embolic source. Here, we examine the findings and outcomes of patients with bihemispheric stroke in the setting of COVID-19. METHODS: We performed a retrospective cohort study at a quaternary academic medical center between March 1, 2020, and April 30, 2020. We identified all patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who presented with simultaneous bihemispheric ischemic strokes. RESULTS: Of 637 COVID-19 admissions during the 2-month period, 13 had a diagnosis of acute ischemic stroke, including 5 who developed bihemispheric cerebral infarction. Three of those 5 (60%) were female, median age was 54 (range 41-67), and all five were being managed for severe COVID-19-related pneumonia complicated by acute kidney injury and liver failure before the diagnosis of cerebral infarction was established. Five presented with elevated ferritin, lactate dehydrogenase, and interleukin-6 (IL-6) levels, and four had lymphopenia and elevated D-dimer levels. All patients underwent neuroimaging with computed tomography for persistent depressed mentation, with or without a focal neurologic deficit, demonstrating multifocal ischemic strokes with bihemispheric involvement. Outcome was poor in all patients: two were discharged to a rehabilitation facility with moderate-to-severe disability and three (60%) patients died. CONCLUSIONS: Stroke is implicated in SARS-CoV-2 infection. Although causality cannot be established, we present the imaging and clinical findings of patients with COVID-19 and simultaneous bihemispheric ischemic strokes. Multifocal ischemic strokes with bihemispheric involvement should be considered in COVID-19 patients with severe infection and poor neurologic status and may be associated with poor outcomes.

Human Chorionic Gonadotropin and Related Peptides: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Sepsis continues to be a major cause of morbidity, mortality, and post-recovery disability in patients with a wide range of non-infectious and infectious inflammatory disorders, including COVID-19. The clinical onset of sepsis is often marked by the explosive release into the extracellular fluids of a multiplicity of host-derived cytokines and other pro-inflammatory hormone-like messengers from endogenous sources ("cytokine storm"). In patients with sepsis, therapies to counter the pro-inflammatory torrent, even when administered early, typically fall short. The major focus of our proposed essay is to promote pre-clinical studies with hCG (human chorionic gonadotropin) as a potential anti-inflammatory therapy for sepsis.

Psychotic symptoms in mass shootings v. mass murders not involving firearms: findings from the Columbia mass murder database.

BACKGROUND: Mass shootings account for a small fraction of annual worldwide murders, yet disproportionately affect society and influence policy. Evidence suggesting a link between mass shootings and severe mental illness (i.e. involving psychosis) is often misrepresented, generating stigma. Thus, the actual prevalence constitutes a key public health concern. METHODS: We examined global personal-cause mass murders from 1900 to 2019, amassed by review of 14 785 murders publicly described in English in print or online, and collected information regarding perpetrator, demographics, legal history, drug use and alcohol misuse, and history of symptoms of psychiatric or neurologic illness using standardized methods. We distinguished whether firearms were or were not used, and, if so, the type (non-automatic v. semi- or fully-automatic). RESULTS: We identified 1315 mass murders, 65% of which involved firearms. Lifetime psychotic symptoms were noted among 11% of perpetrators, consistent with previous reports, including 18% of mass murderers who did not use firearms and 8% of those who did (χ2 = 28.0, p < 0.01). US-based mass shooters were more likely to have legal histories, use recreational drugs or misuse alcohol, or have histories of non-psychotic psychiatric or neurologic symptoms. US-based mass shooters with symptoms of any psychiatric or neurologic illness more frequently used semi-or fully-automatic firearms. CONCLUSIONS: These results suggest that policies aimed at preventing mass shootings by focusing on serious mental illness, characterized by psychotic symptoms, may have limited impact. Policies such as those targeting firearm access, recreational drug use and alcohol misuse, legal history, and non-psychotic psychopathology might yield more substantial results.

Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension.

Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic target of rapamycin complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.

A novel rapamycin analog is highly selective for mTORC1 in vivo.

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

Is metformin poised for a second career as an antimicrobial?

Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo.

Obesity paradox, obesity orthodox, and the metabolic syndrome: An approach to unity.

Obesity and the accompanying metabolic syndrome are strongly associated with heightened morbidity and mortality in older adults. In our review of more than 20 epidemiologic studies of major infectious diseases, including leaders such as tuberculosis, community-acquired pneumonia, and sepsis, obesity was associated with better outcomes. A cause-and-effect relationship between over-nutrition and survival with infection is suggested by results of two preliminary studies of infections in mice, where high fat feeding for 8-10 weeks provided much better outcomes. The better outcomes of infections with obesity are reminiscent of many recent studies of "sterile" non-infectious medical and surgical conditions where outcomes for obese patients are better than for their thinner counterparts --- and given the tag "obesity paradox". Turning to the history of medicine and biological evolution, we hypothesize that the metabolic syndrome has very ancient origins and is part of a lifelong metabolic program. While part of that program (the metabolic syndrome) promotes morbidity and mortality with aging, it helps infants and children as well as adults in their fight against infections and recovery from injuries, key roles in the hundreds of centuries before the public health advances of the 20th century. We conclude with speculation on how understanding the biological elements that protect obese patients with infections or injuries might be applied advantageously to thin patients with the same medical challenges.

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health.

Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.