Ophthalmology Residency Program Director Survey on Pass/Fail U.S. Medical Licensing Exam Step 1 Scoring.

Background Beginning January 26, 2022, the U.S. Medical Licensing Exam (USMLE) Step 1 changed from a numerical score to pass/fail (P/F). The purpose of this study was to determine the perspective of ophthalmology program directors regarding this change in evaluating applicants. Methods After institutional review board approval, a survey was sent out to program directors of all 125 ophthalmology programs accredited by the Accreditation Council for Graduate Medical Education. Survey questions asked for program demographics, the utility of USMLE Step 1 and 2 Clinical Knowledge scores in assessing applicants, and the importance of 16 different applicant metrics before and after Step 1 becomes P/F. The metrics examined were: letters of recommendation; clerkship grades; class ranking; Alpha Omega Alpha Membership; Gold Humanism Honor Society Membership; Dean's Letter; involvement and leadership; personal statement; number of abstracts, presentations, and publications; mean number of research experiences in the specialty; Step 2 Clinical Knowledge score; volunteering; preclinical grades; away rotation in the specialty; the applicant having another graduate degree; and graduation from a top 40 National Institutes of Health-funded program. Data were analyzed using nonoverlapping 95% confidence intervals. Results The survey was completed by 50 (40%) program directors. Sixty-eight percent of respondents stated a student's ranking would be considered more after USMLE Step 1 scores become P/F, and 60% stated medical schools should share clerkship shelf exam scores with residency programs. There were no significant differences in program directors' rankings of applicant metrics following the transition to P/F Step 1. Conclusion Based on our data, program directors will likely not place a greater emphasis on Step 2 scores, despite it being the only remaining objective measure for all applicants following the switch to a P/F Step 1. Nevertheless, program directors expressed an interest in receiving other objective measures, such as shelf exam scores and class ranking, as part of the application process. Notably, we found no significant changes in the rankings of various applicant metrics before and after the transition to P/F Step 1, indicating that the metrics that were important to program directors prior to the change remain just as critical in the new era of admissions.

A Survey of Otolaryngology Residency Programs on Adapting to the United States Medical Licensing Examination (USMLE) Step 1 Transitioning to Pass/Fail.

Objectives In February 2020, the National Board of Medical Examiners (NBME) announced that the United States Medical Licensing Examination (USMLE) Step 1 licensing examination would change from a numerical score to Pass/Fail (P/F). After implementation, many believe that USMLE-Step 2-Clinical Knowledge (CK) will become an important metric for students applying to otolaryngology (ENT). The purpose of this study is to determine factors important to resident selection after these changes. Methods A survey containing 15 questions related to resident selection practices and how changing USMLE Step 1 to P/F would impact future resident selection was designed. It was distributed to all ENT residency programs accredited by the Accreditation Council for Graduate Medical Education (ACGME). Results Forty percent of programs responded; 66% (95% confidence interval (CI): 51.1%-78.4%) felt that changing Step 1 scoring would not lead to students being more prepared for clinical rotations; 55% believe class rank will increase in significance (95% CI: 35.7%-64.3%). There was also an increase in the importance of Step 2 CK, which had a mean ranking of 10.67 prior to changes in Step 1 scoring and increased to 7.80 after P/F. Conclusions The changes in Step 1 scoring will likely lead to increasing importance of other objective measures like class rank or Step 2 CK. This may defeat the intended purpose put forth by the NBME. Therefore, further guidance on measures correlated with student performance as a resident will be integral to the selection process.

Generation of the NeoThy mouse model for human immune system studies.

Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including transplantation immunology, virology and oncology studies. As an alternative to the bone marrow, liver, thymus humanized mouse, which uses fetal tissues for generating a chimeric human immune system, the NeoThy humanized mouse uses nonfetal tissue sources. Specifically, the NeoThy model incorporates hematopoietic stem and progenitor cells from umbilical cord blood (UCB) as well as thymus tissue that is typically discarded as medical waste during neonatal cardiac surgeries. Compared with fetal thymus tissue, the abundant quantity of neonatal thymus tissue offers the opportunity to prepare over 1,000 NeoThy mice from an individual thymus donor. Here we describe a protocol for processing of the neonatal tissues (thymus and UCB) and hematopoietic stem and progenitor cell separation, human leukocyte antigen typing and matching of allogenic thymus and UCB tissues, creation of NeoThy mice, assessment of human immune cell reconstitution and all experimental steps from planning and design to data analysis. This entire protocol takes a total of ~19 h to complete, with steps broken up into multiple sessions of 4 h or less that can be paused and completed over multiple days. The protocol can be completed, after practice, by individuals with intermediate laboratory and animal handling skills, enabling researchers to make effective use of this promising in vivo model of human immune function.

Hepatocyte mARC1 promotes fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1. Results: We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. Impact and implications: We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD.

Evaluating the impact of pass/fail United States Medical Licensing Examination Step 1 scoring on pathology residency selection.

Beginning 26 January 2022, the United States Medical Licensing Examination Step 1 changed from a numerical score to Pass/Fail. Historically, residency programs have used Step 1 scores as a valuable metric in assessing the competitiveness of applicants. We assessed how residency program criteria will change when evaluating applicants after Step 1 becomes Pass/Fail. A survey was distributed to the program directors of all 144 pathology residency programs accredited by Accreditation Council for Graduate Medical Education. Survey questions evaluated the importance of using Step 1 and Step 2 Clinical Knowledge (CK) scores when assessing applicants. Participants were asked to rank a list of applicant criteria used before and after Step 1 becomes Pass/Fail. Data were analyzed using chi-squared and paired t-tests with significance at P < 0.05. A total of 34 residency program directors (23.6%) responded to the survey. 76.5% (P< 0.001) of responders believed Step 1 scores were able to predict a resident's ability to pass their board exams, while 41.2% believed Step 2 CK could predict a resident's ability to pass board exams and perform clinically in pathology (P = 0.282). 61.8% of responders agreed that an applicant's medical school ranking would become more important (P = 0.001). There were no significant differences in the relative importance of 16 selection criteria after the change of Step 1 to Pass/Fail. It does not appear that Step 2 CK will become more important. Although results are constrained by a 23.6% response rate, it can be a start to guiding future students through residency applications.

Relevant Dermatoses Among U.S. Military Service Members: An Operational Review of Management Strategies and Telemedicine Utilization.

Despite skin being the largest and most exposed organ of the human body, skin issues can be challenging to diagnose in deployed military service members. Common reasons deployed soldiers seek dermatological evaluation include infections, inflammatory skin conditions, and skin growth. Due to limited access to specialized care in deployed settings, dermatological conditions are undertreated and underdiagnosed. As a result, dermatological conditions are a leading contributor to decreased combat effectiveness among deployed medical forces. To lessen the burden of dermatological diseases, military providers should promptly identify operational skin diseases and alleviate modifiable barriers faced by service members. In a post-pandemic era with novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and monkeypox infections, the duty to effectively treat operational skin lesions is ever important. The need for military dermatologists continues to rise as the global landscape continues to evolve with unprecedented infections and increased bioterrorism threats. Teledermatology offers many solutions to mitigate the high demand for dermatologists during pandemics. Dermatological consultations account for the highest number of telemedicine visits in the US Military Health System (MHS). As such, increased utilization of teledermatology will reduce infection-related dermatological sequelae and prevent the medical evacuation of service members from military operations. This review collates and categorizes relevant dermatological conditions encountered among deployed personnel. This report outlines the standard of care and modified treatments recommended according to potential barriers faced in operational settings.

Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

Perceptions of the Emergency Medicine Resident Selection Process by Program Directors Following the Transition to a Pass/Fail USMLE Step 1.

Background: Beginning January 26th, 2022, the National Board of Medical Examiners transitioned scoring of the United States Medical Licensing Examination (USMLE) Step 1 from a 3-digit score to pass/fail. In the past, the Step 1 score has been weighted heavily by program directors (PDs) as one of the most important metrics when assessing medical student's competitiveness. Objective: The objective of this study was to evaluate the perceptions of emergency medicine (EM) PDs on the transition to a pass/fail USMLE Step 1 exam, and to elicit the opinions of EM PDs on the USMLE examinations' ability to predict resident performance. Methods: A survey consisting of ranking and multiple-choice questions was sent to EM PDs. The multiple-choice questions were asked to determine EM PDs level of confidence in the ability of Step 1 and Step 2 Clinical Knowledge (CK) to predict a student's ability to succeed in residency. The ranking questions focused on assessing each program's current resident selection practices in comparison to expected selection criteria changes following a transition to pass/fail Step 1. R studio and MATLAB were used for statistical analysis, and a P value <0.05 was considered significant. Results: The survey was completed by 57 (20.21%) EM PDs. When asked if Step 1 and Step 2 CK are accurate predictors of a resident's ability to perform clinically within EM, only 10.5% of PDs answered 'yes' to Step 1 being predictive, compared to 31.6% for Step 2 CK. Regarding selection criteria, the top quartile of attributes (standardized letters of evaluation [1st], away rotations [2nd], clerkship grades [3rd] and Step 2 CK score [4th]) remained the same following the transition. Conclusion: Our results indicate that the top quartile of attributes might remain the same, despite most PDs agreeing that Step 2 CK is a better predictor of a resident's performance.

The Impact of COVID-19 Pandemic on Dermatological Conditions: A Novel, Comprehensive Review.

Background: The earliest cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2019. Since the declaration as a pandemic on 11 March 2020, further dermatological conditions continue to be documented. We herein present a novel literature review of dermatological manifestations associated with the Coronavirus Disease 2019 (COVID-19) pandemic. To date, this literature review is the first broad-spectrum examination that analyzes a range of dermatological manifestations related to the COVID-19 pandemic: infection, vaccinations, personal protective equipment (PPE), and psychosocial factors. Methods: A detailed literature search was conducted using key terms for cutaneous manifestations associated with the scope of this review. The search retrieved 2199 articles. Results: The COVID-19 pandemic has triggered a significant range of dermatologic sequela. Etiologies of lesions continue to be investigated. Proposed mechanisms include inflammatory response to spike protein, vitamin D deficiency, ACE2 receptor activation, androgen levels, and increased psychological stress. One prominent mechanism describes viral spike protein invasion into the dermis by binding to the angiotensin-converting enzyme 2 (ACE-2) receptors in keratinocytes, with a secondary immunological response. Conclusions: Dermatologists play an integral role in the proper diagnosis and treatment of COVID-related lesions. Early treatment regimens and timely prophylaxis have been shown to safely reduce infection-related dermatological sequelae. Additional investigations and data collection can reduce disease burden and improve overall prognosis.

Advocacy for Change: An Osteopathic Review of Traumatic Brain Injury Among Combat Veterans.

As a "signature injury" of the Iraq and Afghanistan wars, traumatic brain injury (TBI) remains a major health concern among military service members. Traumatic brain injury is associated with a wide range of symptoms which may be cognitive, emotional, psychological, biochemical, and social in nature. Mild TBI (mTBI) ranks as the most common traumatic brain injury among veterans. Due to the absence of specific symptoms, mTBI diagnosis may be challenging in acute settings. Repetitive traumatic brain injury during combat deployments can lead to devastating chronic neurodegenerative diseases and other major life disruptions. Many cases of TBI remain undetected in veterans and may lead to long-term adverse comorbidities such as post-traumatic stress disorder (PTSD), suicide, alcohol disorders, psychiatric diagnoses, and service-related somatic dysfunctions. Veterans with TBI are almost twice as likely to die from suicide in comparison to veterans without a history of TBI. Veterans diagnosed with TBI experience significant comorbid conditions and thus advocacy for improved care is justified and necessary. Given the complexity and variation in the symptomatology of TBI, a personalized, multimodal approach is warranted in the evaluation and treatment of veterans with TBI and other associated conditions. As such, this review provides a broad overview of treatment options, with an emphasis on advocacy and osteopathic integration in the standard of care for veterans.

Robust engraftment of fetal nonhuman primate CD34-positive cells in immune-deficient mice.

Nonhuman primates (NHPs) represent one of the most important models for preclinical studies of novel biomedical interventions. In contrast with small animal models, however, widespread utilization of NHPs is restricted by cost, logistics, and availability. Therefore, we sought to develop a translational primatized mouse model, akin to a humanized mouse, to allow for high-throughput in vivo experimentation leveraged to inform large animal immunology-based studies. We found that adult rhesus macaque mobilized blood (AMb) CD34+-enriched hematopoietic stem and progenitor cells (HSPCs) engrafted at low but persistent levels in immune-deficient mice harboring transgenes for human (NHP cross-reactive) GM-CSF and IL3, but did not in mice with wild-type murine cytokines lacking NHP cross-reactivity. To enhance engraftment, fetal liver-derived HSPCs were selected as the infusion product based on an increased CD34hi fraction compared with AMb and bone marrow. Coupled with cotransplantation of rhesus fetal thymic fragments beneath the mouse kidney capsule, fetal liver-derived HSPC infusion in cytokine-transgenic mice yielded robust multilineage lymphohematopoietic engraftment. The emergent immune system recapitulated that of the fetal monkey, with similar relative frequencies of lymphocyte, granulocyte, and monocyte subsets within the thymic, secondary lymphoid, and peripheral compartments. Importantly, while exhibiting a predominantly naïve phenotype, in vitro functional assays demonstrated robust cellular activation in response to nonspecific and allogenic stimuli. This primatized mouse represents a viable and translatable model for the study of hematopoietic stem cell physiology, immune development, and functional immunology in NHPs. Summary Sentence: Engraftment of rhesus macaque hematopoietic tissues in immune-deficient mice yields a robust BLT/NeoThy-type primatized mouse model for studying nonhuman primate hematopoiesis and immune function in vivo.

Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling.

AIMS/HYPOTHESIS: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. METHODS: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. RESULTS: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. CONCLUSIONS/INTERPRETATION: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. DATA AVAILABILITY: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .

Revision Anterior Cruciate Ligament Reconstruction with the All-Soft Tissue Quadriceps Tendon Autograft Has Acceptable Early and Intermediate-Term Outcomes.

PURPOSE: The purposes were to (1) examine early to intermediate-term clinical outcomes and complications of revision anterior cruciate ligament reconstruction (ACLR) using all-soft tissue quadriceps tendon (QT) autografts, and (2) compare quadriceps strength between patients who had hamstring versus patella tendon autografts in their previous reconstruction. METHODS: One hundred patients (52 males/48 females; 22.6 ± 8.0 years) undergoing revision ACLR with all-soft tissue QT autografts were prospectively followed. All revision procedures were performed by a single surgeon, using a minimally invasive graft harvest technique and suspensory fixation. Subjective assessment of knee function was obtained before and after surgery with the International Knee Documentation Committee (IKDC) survey. Postoperative knee laxity and isokinetic quadriceps strength were collected at regular intervals. Strength was reported as limb symmetry index (LSI; surgical side divided by nonsurgical side). Complications including hematomas, postoperative loss of knee extension, and graft failures were recorded. To determine clinical significance (P ≤ .05), outcomes were compared using analysis of variance or paired samples t-tests. RESULTS: The mean IKDC scores significantly improved (54.3 ± 13.0 vs 82.8 ± 13.8), with an average follow-up of 42.2 ± 21.2 months. There were no significant changes in knee laxity side-to-side differences: 6 weeks (1.2 ± 1.5 mm), 3 months (1.2 ± 1.8 mm), 6 months (1.4 ± 1.6 mm). Quadriceps LSIs significantly improved from 71.6% ± 19.3% at 6 months to 81.5% ± 19.3% at 12 months for 60°/s isokinetic testing and 76.6% ± 16.4% at 6 months to 83.9% ± 16.9% at 12 months for 180°/s testing. Graft harvest site hematomas developed in 2 patients, postoperative loss of knee extension in 4 patients, and graft failure in 11 patients. No significant differences in quadriceps or hamstrings LSIs were noted between patients with previous hamstring versus patella tendon autografts (P > .050). CONCLUSION: Revision ACLR with all-soft tissue QT autografts has acceptable early and intermediate-term outcomes with reasonable complication rates (11/80 patients with follow-up). Secondary insult to the extensor mechanism via QT autograft harvest does not adversely affect strength after prior patellar tendon versus hamstring autograft. LEVEL OF EVIDENCE: Level IV, cases series subgroup analysis.

A bio-inductive collagen scaffold that supports human primary tendon-derived cell growth for rotator cuff repair.

BACKGROUND: Rotator Cuff (RC) tendon tearing is a common clinical problem and there is a high incidence of revision surgery due to re-tearing. In an effort to improve patient outcome and reduce surgical revision, scaffolds have been widely used for augmentation of RC repairs. However, little is known about how scaffolds support tendon stem cell growth or facilitate tendon regeneration. The purpose of this study is to evaluate the structural and biological properties of a bioactive collagen scaffold (BCS) with the potential to promote tendon repair. Additionally, we conducted a pilot clinical study to assess the safety and feasibility of using the BCS for repair of RC tears. METHODS: A series of physical, ultrastructural, molecular and in vitro tests determined the biocompatibility and teno-inductive properties of this BCS. In addition, a prospective case study of 18 patients with RC tendon tears (>20 â€‹mm in diameter) was performed in an open-label, single-arm study, involving either mini-open or arthroscopic surgical RC repair with the BCS. Clinical assessment of RC repair status was undertaken by MRI-imaging at baseline, 6 and 12 months and patient evaluated questionnaires were taken at baseline as well as 3, 6 & 12 months. RESULTS: The BCS consists of highly purified type-I collagen, in bundles of varying diameter, arranged in a higher order tri-laminar structure. BCS have minimal immunogenicity, being cell and essentially DNA-free as well as uniformly negative for the porcine α-Gal protein. BCS seeded with human primary tendon-derived cells and exposed to 6% uniaxial loading conditions in vitro, supported increased levels of growth and proliferation as well as up-regulating expression of tenocyte differentiation marker genes including TNMD, Ten-C, Mohawk and Collagen-1α1. To test the safety and feasibility of using the BCS for augmentation of RC repairs, we followed the IDEAL framework and conducted a first, open-label single arm prospective case series study of 18 patients. One patient was withdrawn from the study at 3 months due to wound infection unrelated to the BCS. The remaining 17 cases showed that the BCS is safe to be implanted. The patients reported encouraging improvements in functional outcomes (ASES, OSS and Constant-Murley scores), as well as quality of life assessments (AQoL) and a reduction in VAS pain scores. MRI assessment at 12 months revealed complete healing in 64.8% patients (11/17), 3 partial thickness re-tears (17.6%) and 3 full thickness re-tears (17.6%). CONCLUSION: The BCS is composed of type-I collagen that is free of immunogenic proteins and supports tendon-derived cell growth under mechanical loading in vitro. This pilot study shows that it is safe and feasible to use BCS for RC argumentation and further controlled prospective studies are required to demonstrate its efficacy. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The results of this study indicate that this bioactive collagen scaffold has unique properties for supporting tendon growth and that it is non-immunogenic. The clinical study further confirms that the scaffold is a promising biological device for augment of human rotator cuff repairs.

The physio-metabolic effects of time-restricting liquid sugar intake to six-hour windows during the mouse active phase: The effects of active phase liquid sugar consumption.

Obesity is a major public health concern and overconsumption of unhealthy fats and sugary beverages are contributing factors. Time-restricted feeding can reduce obesity-associated pathophysiological parameters by limiting the time of food consumption; however, the effects of time-restricted sugary water consumption are unknown. To examine whether liquid calorie restriction impacts metabolic health, we measured metabolic parameters in mice provided liquid sugar at various intervals during the active phase. The control (Con) group received tap water, the adlibitum fructose-glucose (ALFG) group received ad libitumsugar water and the early fructose-glucose (EFG) and late fructose-glucose (LFG) groups received liquid sugar during the first and last six hours of the active period, respectively. Each group was given free access to chow. Zeitgeber time (ZT) notation was used to set all experimental time points to lights on as ZT 0. The ALFG group exhibited elevated body and adipose tissue weights compared to the other groups and increased hepatic steatosis compared to the Con group. The ALFG group consumed more calories than the other groups during ZT 6-11, indicating that this window may be critical in the promotion of weight gain from liquid sugar consumption. The EFG group exhibited higher levels of energy expenditure than the Con and LFG groups during the first half of the active period (ZT 12-17); however, there was no difference among the groups during the second half of the active period (ZT18-23). In contrast, the EFG group exhibited lower respiratory exchange ratio than other groups during the inactive period as well as the second half of the active period, indicating that the EFG group had greater metabolic flexibility and utilized lipids when carbohydrates from liquid sugar were not available. Additionally, the EFG group was more insulin tolerant than the ALFG and Con groups. Our results support the hypothesis that time-restricted liquid calorie restriction aids in reducing the detrimental metabolic effects of sugary drink consumption.

Western diet-induced obesity disrupts the diurnal rhythmicity of hippocampal core clock gene expression in a mouse model.

Western diet (WD) feeding disrupts core clock gene expression in peripheral tissues and contributes to WD-induced metabolic disease. The hippocampus, the mammalian center for memory, is also sensitive to WD feeding, but whether the WD disrupts its core clock is unknown. To this end, male mice were maintained on a WD for 16 weeks and diurnal metabolism, gene expression and memory were assessed. WD-induced obesity disrupted the diurnal rhythms of whole-body metabolism, markers of inflammation and hepatic gene expression, but did not disrupt diurnal expression of hypothalamic Bmal1, Npas2 and Per2. However, all measured core clock genes were disrupted in the hippocampus after WD feeding and the expression pattern of genes implicated in Alzheimer's disease and synaptic function were altered. Finally, WD feeding disrupted hippocampal memory in a task- and time-dependent fashion. Our results implicate WD-induced alterations in the rhythmicity of hippocampal gene expression in the etiology of diet-induced memory deficits.

SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle.

BACKGROUND AND PURPOSE: In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. METHODS: The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. RESULTS: We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. CONCLUSIONS: We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.