Transgenic Overexpression of HDAC9 Promotes Adipocyte Hypertrophy, Insulin Resistance and Hepatic Steatosis in Aging Mice.

Histone deacetylase (HDAC) 9 is a negative regulator of adipogenic differentiation, which is required for maintenance of healthy adipose tissues. We reported that HDAC9 expression is upregulated in adipose tissues during obesity, in conjunction with impaired adipogenic differentiation, adipocyte hypertrophy, insulin resistance, and hepatic steatosis, all of which were alleviated by global genetic deletion of Hdac9. Here, we developed a novel transgenic (TG) mouse model to test whether overexpression of Hdac9 is sufficient to induce adipocyte hypertrophy, insulin resistance, and hepatic steatosis in the absence of obesity. HDAC9 TG mice gained less body weight than wild-type (WT) mice when fed a standard laboratory diet for up to 40 weeks, which was attributed to reduced fat mass (primarily inguinal adipose tissue). There was no difference in insulin sensitivity or glucose tolerance in 18-week-old WT and HDAC9 TG mice; however, at 40 weeks of age, HDAC9 TG mice exhibited impaired insulin sensitivity and glucose intolerance. Tissue histology demonstrated adipocyte hypertrophy, along with reduced numbers of mature adipocytes and stromovascular cells, in the HDAC9 TG mouse adipose tissue. Moreover, increased lipids were detected in the livers of aging HDAC9 TG mice, as evaluated by oil red O staining. In conclusion, the experimental aging HDAC9 TG mice developed adipocyte hypertrophy, insulin resistance, and hepatic steatosis, independent of obesity. This novel mouse model may be useful in the investigation of the impact of Hdac9 overexpression associated with metabolic and aging-related diseases.

Fibrolamellar Hepatocellular Carcinoma (FLHCC) in a Young Patient Presenting With Nausea and Vomiting After a Greasy Meal.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare and distinct subtype of liver cancer, predominantly affecting younger patients without underlying liver diseases. This case report discusses a unique presentation of FLHCC in a 38-year-old male with a past medical history of a well-controlled seizure disorder. The patient presented with nausea, vomiting, and abdominal pain following a fatty meal. Laboratory tests revealed elevated liver enzymes and anemia, and imaging showed a large hepatic lesion. Initial management included a septic workup and broad-spectrum antibiotics. However, a liver biopsy performed subsequently revealed the presence of FLHCC. The patient underwent a successful open right hepatectomy and was managed postoperatively with consideration of his seizure disorder. Follow-up at six months showed a stable postoperative condition without any evidence of recurrence. The diagnosis of FLHCC is challenging due to its rarity and nonspecific presentation. The case emphasizes the importance of considering FLHCC in the differential diagnosis of hepatic lesions, particularly in young patients. Surgical resection remains the primary treatment modality. This case underscores the importance of a thorough evaluation of hepatic lesions, especially in younger patients. It also illustrates the complexities in managing patients with FLHCC, requiring a multidisciplinary approach for optimal outcomes. Further research is necessary to better understand the pathogenesis of FLHCC and to develop more effective treatment strategies.

Systematic review of the use of ultrasound for venous assessment and venous thrombosis screening in spaceflight.

The validity of venous ultrasound (V-US) for the diagnosis of deep vein thrombosis (DVT) during spaceflight is unknown and difficult to establish in diagnostic accuracy and diagnostic management studies in this context. We performed a systematic review of the use of V-US in the upper-body venous system in spaceflight to identify microgravity-related changes and the effect of venous interventions to reverse them, and to assess appropriateness of spaceflight V-US with terrestrial standards. An appropriateness tool was developed following expert panel discussions and review of terrestrial diagnostic studies, including criteria relevant to crew experience, in-flight equipment, assessment sites, ultrasound modalities, and DVT diagnosis. Microgravity-related findings reported as an increase in internal jugular vein (IJV) cross-sectional area and pressure were associated with reduced, stagnant, and retrograde flow. Changes were on average responsive to venous interventions using lower body negative pressure, Bracelets, Valsalva and Mueller manoeuvres, and contralateral IJV compression. In comparison with terrestrial standards, spaceflight V-US did not meet all appropriateness criteria. In DVT studies (n = 3), a single thrombosis was reported and only ultrasound modality criterion met the standards. In the other studies (n = 15), all the criteria were appropriate except crew experience criterion, which was appropriate in only four studies. Future practice and research should account for microgravity-related changes, evaluate individual effect of venous interventions, and adopt Earth-based V-US standards.

Effects of whole-body vibration or resistive-vibration exercise on blood clotting and related biomarkers: a systematic review.

Whole-body vibration (WBV) and resistive vibration exercise (RVE) are utilized as countermeasures against bone loss, muscle wasting, and physical deconditioning. The safety of the interventions, in terms of the risk of inducing undesired blood clotting and venous thrombosis, is not clear. We therefore performed the present systematic review of the available scientific literature on the issue. The review was conducted following the guidelines by the Space Biomedicine Systematic Review Group, based on Cochrane review guidelines. The relevant context or environment of the studies was "ground-based environment"; space analogs or diseased conditions were not included. The search retrieved 801 studies; 77 articles were selected for further consideration after an initial screening. Thirty-three studies met the inclusion criteria. The main variables related to blood markers involved angiogenic and endothelial factors, fibrinolysis and coagulation markers, cytokine levels, inflammatory and plasma oxidative stress markers. Functional and hemodynamic markers involved blood pressure measurements, systemic vascular resistance, blood flow and microvascular and endothelial functions. The available evidence suggests neutral or potentially positive effects of short- and long-term interventions with WBV and RVE on variables related to blood coagulation, fibrinolysis, inflammatory status, oxidative stress, cardiovascular, microvascular and endothelial functions. No significant warning signs towards an increased risk of undesired clotting and venous thrombosis were identified. If confirmed by further studies, WBV and RVE could be part of the countermeasures aimed at preventing or attenuating the muscular and cardiovascular deconditioning associated with spaceflights, permanence on planetary habitats and ground-based simulations of microgravity.

Genetic and clinical determinants of telomere length.

Many epidemiologic studies have identified important relationships between leukocyte telomere length (LTL) with genetics and health. Most of these studies have been significantly limited in scope by focusing predominantly on individual diseases or restricted to GWAS analysis. Using two large patient populations derived from Vanderbilt University and Marshfield Clinic biobanks linked to genomic and phenomic data from medical records, we investigated the inter-relationship between LTL, genomics, and human health. Our GWAS confirmed 11 genetic loci previously associated with LTL and two novel loci in SCNN1D and PITPNM1. PheWAS of LTL identified 67 distinct clinical phenotypes associated with both short and long LTL. We demonstrated that several diseases associated with LTL were related to one another but were largely independent from LTL genetics. Age of death was correlated with LTL independent of age. Those with very short LTL (<-1.5 standard deviation [SD]) died 10.4 years (p < 0.0001) younger than those with average LTL (±0.5 SD; mean age of death = 74.2 years). Likewise, those with very long LTL (>1.5 SD) died 1.9 years (p = 0.0175) younger than those with average LTL. This is consistent with the PheWAS results showing diseases associating with both short and long LTL. Finally, we estimated that the genome (12.8%) and age (8.5%) explain the largest proportion of LTL variance, whereas the phenome (1.5%) and sex (0.9%) explained a smaller fraction. In total, 23.7% of LTL variance was explained. These observations provide the rationale for expanded research to understand the multifaceted correlations between TL biology and human health over time, leading to effective LTL usage in medical applications.

Pathophysiology, risk, diagnosis, and management of venous thrombosis in space: where are we now?

The recent incidental discovery of an asymptomatic venous thrombosis (VT) in the internal jugular vein of an astronaut on the International Space Station prompted a necessary, immediate response from the space medicine community. The European Space Agency formed a topical team to review the pathophysiology, risk and clinical presentation of venous thrombosis and the evaluation of its prevention, diagnosis, mitigation, and management strategies in spaceflight. In this article, we discuss the findings of the ESA VT Topical Team over its 2-year term, report the key gaps as we see them in the above areas which are hindering understanding VT in space. We provide research recommendations in a stepwise manner that build upon existing resources, and highlight the initial steps required to enable further evaluation of this newly identified pertinent medical risk.

Laparoscopic removal of a dermoid cyst in one ovary and an endometrioma in the other: A case report and literature review.

The coexistence of an endometrioma and a dermoid cyst is very uncommon, and there are few case reports of both conditions in the ovaries. A 41-year-old patient presented with left pelvic pain. She was referred with a bilateral pelvic mass. Magnetic resonance imaging (MRI) confirmed a dermoid cyst on the left ovary and an endometrioma on the right side. The patient was taking ibuprofen to relieve pain until the day of surgery. She was advised to proceed with bilateral laparoscopic cystectomy. During the laparoscopic procedure, the inspection showed that ovaries were bilaterally enlarged with cystic appearances. Bilateral ovarian cystectomy was performed in which a left dermoid cyst was removed intact within the ovary followed by a rupture of the endometrioma on the right. The patient tolerated the procedure without any complications. This case of coexistence of endometrioma and dermoid cyst in each ovary, confirmed by MRI due to atypical findings on ultrasound, highlights how efficient removal of both cyst is crucial.

Hypnotic and Melatonin/Melatonin-Receptor Agonist Treatment in Bipolar Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Bipolar disorder (BD) is a chronic relapsing-remitting psychiatric disorder. Sleep and circadian rhythm disturbances persist during acute mood episodes of the disorder and during euthymia. However, the treatment potential of hypnotic agents that might be used to manage sleep disturbance in BD is not well understood. Similarly, melatonin and medications with a melatonin-receptor agonist mechanism of action may have chronotherapeutic potential for treating people with the disorder, but the impact of these substances on sleep and circadian rhythms and core symptoms in BD is unclear. OBJECTIVE: Our aim was to conduct a systematic review and meta-analysis evaluating the current evidence for hypnotic and melatonin/melatonin-receptor agonist pharmacotherapy for symptoms of sleep disturbance, mania, and depression in patients with BD. METHODS: AMED, Embase, MEDLINE and PsychINFO databases were searched for studies published in English from the date of inception to 31 October 2021. Studies included in this review were randomised controlled trials (RCTs) and non-controlled/non-randomised studies for BD that examined hypnotic medications selected based on a common pattern of usage for treating insomnia (i.e. chloral, clomethiazole, diphenhydramine, doxepin, doxylamine, promethazine, suvorexant, zaleplon, zolpidem, zopiclone, and eszopiclone) and melatonin and the melatonin-receptor agonist drugs ramelteon and agomelatine. Risk of bias was assessed using the RoB2 and AXIS tools. Pooled effect sizes for RCT outcomes were estimated using random-effects models. RESULTS: A total of eleven studies (six RCTs and five experimental feasibility studies) involving 1279 participants were included. Each study examined melatonin or melatonin-receptor agonists. No studies of hypnotics were found that fulfilled the review inclusion criteria. Pilot feasibility studies suggested beneficial treatment effects for symptoms of sleep disturbance, depression, and mania. However, the pooled effect of the two available RCT studies assessing sleep quality via Pittsburgh Sleep Quality Index scores was not statistically significant (g = - 0.04 [95% CI - 0.81 to 0.73]) and neither was the pooled effect for depressive symptoms (four studies; g = - 0.10 [95% CI - 0.27 to 0.08]). Some RCT evidence suggests ramelteon might prevent relapse into depression in BD. The largest efficacy signal detected was for manic symptoms (four studies; g = - 0.44 [95% CI - 1.03 to 0.14]) but there was substantial heterogeneity between studies and patient characteristics. In the two RCTs assessing manic symptoms during acute mania, adjunctive melatonin demonstrated superior treatment effects versus placebo. CONCLUSIONS: There is a paucity of studies examining pharmacological interventions for sleep and circadian rhythm disturbance in BD. Few studies assessed sleep-related symptoms, and none quantitatively examined endogenous melatonin patterns or other circadian rhythms. Melatonin may be a promising candidate for the adjunctive treatment of bipolar mania. However, dose-finding studies and studies with larger sample sizes are needed to confirm its efficacy. We recommend parallel monitoring of sleep and circadian rhythms in future trials. Chronobiology-informed trial designs are needed to improve the quality of future studies. PROTOCOL REGISTRATION: PROSPERO (CRD42020167528).

The Potential of Physical Exercise to Mitigate Radiation Damage-A Systematic Review.

There is a need to investigate new countermeasures against the detrimental effects of ionizing radiation as deep space exploration missions are on the horizon. Objective: In this systematic review, the effects of physical exercise upon ionizing radiation-induced damage were evaluated. Methods: Systematic searches were performed in Medline, Embase, Cochrane library, and the databases from space agencies. Of 2,798 publications that were screened, 22 studies contained relevant data that were further extracted and analyzed. Risk of bias of included studies was assessed. Due to the high level of heterogeneity, meta-analysis was not performed. Five outcome groups were assessed by calculating Hedges' g effect sizes and visualized using effect size plots. Results: Exercise decreased radiation-induced DNA damage, oxidative stress, and inflammation, while increasing antioxidant activity. Although the results were highly heterogeneous, there was evidence for a beneficial effect of exercise in cellular, clinical, and functional outcomes. Conclusions: Out of 72 outcomes, 68 showed a beneficial effect of physical training when exposed to ionizing radiation. As the first study to investigate a potential protective mechanism of physical exercise against radiation effects in a systematic review, the current findings may help inform medical capabilities of human spaceflight and may also be relevant for terrestrial clinical care such as radiation oncology.

The effect of microgravity on the human venous system and blood coagulation: a systematic review.

NEW FINDINGS: What is the central question of this study? Recently, an internal jugular venous thrombus was identified during spaceflight: does microgravity induce venous and/or coagulation pathophysiology, and thus an increased risk of venous thromboembolism (VTE)? What is the main finding and its importance? Whilst data are limited, this systematic review suggests that microgravity and its analogues may induce an enhanced coagulation state due to venous changes most prominent in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability in microgravity and its analogues. However, whether such changes precipitate an increased VTE risk in spaceflight remains to be determined. ABSTRACT: Recently, an internal jugular venous thrombus was identified during spaceflight, but whether microgravity induces venous and/or coagulation pathophysiology, and thus, an increased risk of venous thromboembolism (VTE) is unclear. Therefore, a systematic (Cochrane compliant) review was performed of venous system or coagulation parameters in actual spaceflight (microgravity) or ground-based analogues in PubMed, MEDLINE, Ovid EMBASE, Cochrane Library, European Space Agency, National Aeronautics and Space Administration, and Deutsches Zentrum für Luft-und Raumfahrt databases. Seven-hundred and eight articles were retrieved, of which 26 were included for evaluation with 21 evaluating venous, and five coagulation parameters. Nine articles contained spaceflight data, whereas the rest reported ground-based analogue data. There is substantial variability in study design, objectives and outcomes. Yet, data suggested cephalad venous system dilatation, increased venous pressures and decreased/reversed flow in microgravity. Increased fibrinogen levels, presence of thrombin generation markers and endothelial damage were also reported. Limited human venous and coagulation system data exist in spaceflight, or its analogues. Nevertheless, data suggest spaceflight may induce an enhanced coagulation state in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability. Whether such changes precipitate an increased VTE risk in spaceflight remains to be determined.

A rare presentation of sexsomnia in a military service member.

NONE: Sexsomnias are unconscious sexual behaviors during sleep (parasomnias) that are garnering more attention as they become increasingly evident in forensic cases. Presentations of sexsomnia in active duty service members are seldom described, and often evaluation is clouded by intoxication with substances such as alcohol, sleep deprivation, untreated sleep disturbances, or criminal behavior masquerading as a medical disorder. We present a case of a 40-year-old male soldier evaluated in our sleep clinic for multiple episodes of sleep masturbation occurring over a period of 2 years. The patient was concerned about his suitability for deployment to a combat zone and participation in field training exercises (both require sleeping in groups in an open environment). Video polysomnography confirmed moderate obstructive sleep apnea, and the patient showed improvement with continuous positive airway pressure therapy. The authors also discuss the relevance of this case compared with previously reported sexsomnia cases and expand on parasomnia topics that are more common in military populations.

Will SARS-CoV-2 Infection Elicit Long-Lasting Protective or Sterilising Immunity? Implications for Vaccine Strategies (2020).

In December 2019, an outbreak of a novel coronavirus (SARS-CoV-2) in Wuhan, China resulted in the current COVID-19 global pandemic. The human immune system has not previously encountered this virus, raising the important question as to whether or not protective immunity is generated by infection. Growing evidence suggests that protective immunity can indeed be acquired post-infection-although a handful of reinfection cases have been reported. However, it is still unknown whether the immune response to SARS-CoV-2 leads to some degree of long-lasting protection against the disease or the infection. This review draws insights from previous knowledge regarding the nature and longevity of immunity to the related virus, SARS-CoV, to fill the gaps in our understanding of the immune response to SARS-CoV-2. Deciphering the immunological characteristics that give rise to protective immunity against SARS-CoV-2 is critical to guiding vaccine development and also predicting the course of the pandemic. Here we discuss the recent evidence that characterises the adaptive immune response against SARS-CoV-2 and its potential implications for the generation of memory responses and long-term protection.

A Review of Orthopaedic Surgical Set-Up and Introduction of the TULIPS Mnemonic - Six Simple Steps for Optimising Set-Up in Orthopaedic Surgery.

Conducting a thorough check to ensure that all equipment and personnel are positioned correctly at the start of any operation is essential for both the safety of the surgical team and the patient outcome. Orthopaedic surgery in particular carries a high risk of occupational injury and this group could benefit greatly from ergonomic improvements. This review highlights multiple factors that can influence safety of surgeons, surgical efficiency and patient outcomes. "TULIPS" is a mnemonic that lists six key steps in optimising the surgical procedure through effective positioning of equipment and personnel pre-operatively. This was trialled by distribution amongst orthopaedic registrars regionally and it received excellent feedback, with the majority changing their current practice. Here we report that using this simple and memorable checklist can assist orthopaedic surgeons in setting up the operating theatre, facilitating ergonomic improvements that can reduce the risk of musculoskeletal injury and radiation exposure.

Cancer stem cell plasticity in glioblastoma multiforme: a perspective on future directions in oncolytic virotherapy.

The cancer stem cell (CSC) hypothesis suggests that a rare population of stem-like cells underpin tumorigenesis. Oncolytic viruses (OVs) demonstrate novel mechanisms of targeting the elusive CSCs with greater selectivity - promising therapeutic potential against solid tumors such as glioblastoma (GBM) that are resistant to conventional treatment. In general, OVs have failed to translate the efficacy from bench to bedside. The success of OVs rely on the hypothesis that eliminating CSCs is key to preventing recurrence. However, newly emerging evidence of CSC plasticity challenge this hypothesis by proposing that the CSC pool can be regenerated from non-CSCs post-treatment. We review this evidence surrounding the CSC hypothesis to propose an original perspective on why several advanced OVs may be failing to reflect their true potential in clinical trials. We argue that preventing non-CSC to CSC dedifferentiation may be critical to achieving long-term treatment efficacy in future OV clinical trials.

A Quality Improvement Initiative: Supporting the Potential of Foundation Year Doctors with a "Trauma Innovation Forum"

Junior doctors rotating through departments arrive with fresh perspectives and are particularly suited for identifying problems and providing creative solutions to improve patient care. They may, however, be unfamiliar with the process of implementing an idea into practice. We recognize the need to support foundation year doctors to develop successful quality improvement projects (QIPs). We developed a new initiative to host an annual event that gives foundation year doctors a platform to develop QIPs for their department. These ideas were pitched to an audience comprising trauma consultants from the Oxford University Hospitals and multidisciplinary staff from hospitals across the region. It offered a dedicated time away from clinical pressure to propose and receive immediate expert feedback from members of the trauma multidisciplinary team. With this refinement and supervisor project matching, it facilitated multiple areas of targeted change for the department in just one evening. In total, eight QIPs were developed from the event. Here we outline our approach and the structure of our event, which can serve as a tool for similar initiatives to be replicated in other hospitals.

Timing of onset and self-management of multiple chronic conditions: A qualitative examination taking a lifespan perspective.

OBJECTIVES: Over two-thirds of older individuals live with multiple chronic conditions, yet chronic diseases are often studied in silos. Taking a lifespan approach to understanding the development of multiple chronic conditions in the older population helps to further elucidate opportunities for targeted interventions that address the complexities of multiple chronic conditions. METHODS: Semi-structured interviews were conducted with 38 older adults (age 64+) diagnosed with at least two chronic health conditions. Content analysis was used to build understanding of how older adults discuss the timing of diagnoses and subsequent self-management of multiple chronic conditions. RESULTS: Findings highlight the complex process by which illnesses unfold in the context of individuals' lives and the subsequent engagement and/or disengagement in self-management behaviors. Two primary themes were evident regarding timing of illnesses: illnesses were experienced within the context of social life events and/or health events, and illnesses were not predominantly seen as connected to one another by patients. Self-management behaviors were described in response to onset of each illness. DISCUSSION: Findings provide insight into how older adults understand their experience of multiple chronic conditions and change in self-management behaviors over time. In order for practitioners to ignite behavioral changes, a person's history and life experiences must be considered.

Topology optimization and 3D printing of multimaterial magnetic actuators and displays.

Upcoming actuation systems will be required to perform multiple tightly coupled functions analogous to their natural counterparts; e.g., the ability to control displacements and high-resolution appearance simultaneously is necessary for mimicking the camouflage seen in cuttlefish. Creating integrated actuation systems is challenging owing to the combined complexity of generating high-dimensional designs and developing multifunctional materials and their associated fabrication processes. Here, we present a complete toolkit consisting of multiobjective topology optimization (for design synthesis) and multimaterial drop-on-demand three-dimensional printing for fabricating complex actuators (>106 design dimensions). The actuators consist of soft and rigid polymers and a magnetic nanoparticle/polymer composite that responds to a magnetic field. The topology optimizer assigns materials for individual voxels (volume elements) while simultaneously optimizing for physical deflection and high-resolution appearance. Unifying a topology optimization-based design strategy with a multimaterial fabrication process enables the creation of complex actuators and provides a promising route toward automated, goal-driven fabrication.

Impact of an Advanced Practice Pharmacist Type 2 Diabetes Management Program: A Pilot Study.

BACKGROUND: The purpose of this study was to describe the impact of an Advanced Practice Pharmacist (APh) on lowering hemoglobin A1c (HbA1c) in patients with type 2 diabetes within a patient centered medical home (PCMH) and to classify the types of therapeutic decisions made by the APh. METHODS: This was a retrospective study using data from electronic health records. The study evaluated a partnership between Chapman University School of Pharmacy and Providence St. Joseph Heritage Healthcare that provided diabetes management by an Advanced Practice Pharmacist in a PCMH under a collaborative practice agreement. Change in the HbA1c was the primary endpoint assessed in this study. The type of therapeutic decisions made by the APh were also evaluated. Descriptive analysis and Wilcoxon signed ranktest were used to analyze data. RESULTS: The study included 35 patients with diagnosis of type 2 diabetes mellitus managed by an APh from May 2017 to December 2017. Most of the patients were 60-79 years old (68.5%), 45.7% were female, and 45.7% were of Hispanic/Latino ethnicity. The average HbA1cwas 8.8%±1.4% (range=6.0%-12.4%) and 7.5%±1.4% (range=5.5%-12.4%) at the initial and final APh visit, respectively (p<0.0001). Therapeutic decisions made by the APh included drug dose increase (35.5% of visits), drug added (16.4%), drug dose decrease (6.4%), drug switch (5.5%), and drug discontinuation (1.8%). CONCLUSION: The Advanced Practice Pharmacist's interventions had a significant positive impact on lowering HbA1c in patients with type 2 diabetes mellitus in a PCMH. The most common therapeutic decisions made by the APh included drug dose increase and adding a new drug.