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BackgroundThe COVID-19 pandemic continues to ravage and burden hospitals around the world. The epidemic started in Wuhan, China, and was subsequently recognized by the World Health Organization as an international public health emergency and declared a pandemic in March 2020. Since then, the disruptions caused by the COVID-19 pandemic have had an unparalleled effect on all aspects of life. ObjectiveWith increasing total hospitalization and intensive care unit admissions, a better understanding of features related to patients with COVID-19 could help health care workers stratify patients based on the risk of developing a more severe case of COVID-19. Using predictive models, we strive to select the features that are most associated with more severe cases of COVID-19. MethodsOver 3 million participants reported their potential symptoms of COVID-19, along with their comorbidities and demographic information, on a smartphone-based app. Using data from the >10,000 individuals who indicated that they had tested positive for COVID-19 in the United Kingdom, we leveraged the Elastic Net regularized binary classifier to derive the predictors that are most correlated with users having a severe enough case of COVID-19 to seek treatment in a hospital setting. We then analyzed such features in relation to age and other demographics and their longitudinal trend. ResultsThe most predictive features found include fever, use of immunosuppressant medication, use of a mobility aid, shortness of breath, and severe fatigue. Such features are age-related, and some are disproportionally high in minority populations. ConclusionsPredictors selected from the predictive models can be used to stratify patients into groups based on how much medical attention they are expected to require. This could help health care workers devote valuable resources to prevent the escalation of the disease in vulnerable populations.

Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21cip1-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.

Cellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.

Although most drugs currently approved are meant to treat specific diseases or symptoms, it has been hypothesized that some might bear a beneficial effect on lifespan in healthy older individuals, outside of their specific disease indication. Such drugs include, among others, metformin, SGLT2 inhibitors and rapamycin. Since 2006, the UK biobank has recorded prescription medication and mortality data for over 500′000 participants, aged between 40 and 70 years old. In this work, we examined the impact of the top 406 prescribed medications on overall mortality rates within the general population of the UK. As expected, most drugs were linked to a shorter lifespan, likely due to the life‐limiting nature of the diseases they are prescribed to treat. Importantly, a few drugs were associated with increased lifespans, including notably Sildenafil, Atorvastatin, Naproxen and Estradiol. These retrospective results warrant further investigation in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Deep venous arterialization (DVA) is a final option for limb salvage in patients with end stage arterial anatomy. We report a 66-year-old dialysis dependent male with forefoot gangrene, Rutherford class 6 chronic limb ischemia, who required a redo endovascular DVA. On initial presentation an angiogram was demonstrated a desert foot with absent tibial runoff to his bilateral lower extremities. After discussion, patient elected to trial DVA in hope of avoiding a major amputation. A hybrid DVA was performed using a Pioneer Plus and.018″ Viabahn stents from the peroneal artery into the peroneal venous system; following this, the peroneal vein was anastomosed to the lesser saphenous vein via an open posterior approach at the ankle. 3 months later, a second DVA was performed by exposing the above knee popliteal artery and vein and creating an end-to-side anastomosis. Of note, the great saphenous vein was less than 2 mm in diameter and no arm vein was available due to history of prior fistulas in bilateral arms. Via the popliteal vein, the posterior tibial vein was selected and additional.018″ Viabahn stents were deployed from the malleolus to the P2 segment of the popliteal vein. Three months after the second hybrid DVA, the patient's forefoot had healed after split thickness skin grafting. Continued patency is noted of the re-do hybrid DVA with minimal calf edema. Newer creative strategies are required for "No Option Chronic Limb Ischemia" which is becoming more relevant in diabetic and dialysis dependent patients. This case illustrates the potential to convert a deep venous arterialization to a superficial venous arterialization for improved venous outflow and wound healing. [ABSTRACT FROM AUTHOR]

Managing patients with severe fixation of intra-abdominal contents, known as frozen abdomen, often creates a vicious cycle of tissue injury that further prolongs open abdomen resolution. We share the management course of a 28-year-old male status post motor vehicle accident with traumatic pancreatitis and complex liver injury. Following multiple laparotomies for abdominal wash out, he developed a frozen abdomen and an entero-atmospheric fistula (EAF) through granulated bowel. The exposed granulated bowel, bilious leak and fistula limited options for abdominal closure and ostomy appliance placement. NovoSorb Biodegradable Temporizing Matrix (BTM) applied to the granulated bowel eventually allowed an ostomy appliance to be placed around the fistula on top of the non-absorbable layer of the BTM. Eventual fistula closure was achieved and appropriate granulation tissue had formed prior to autografting. This is the first report utilizing BTM to aid in the closure of open abdomen in the setting of frozen abdomen with EAF. [ABSTRACT FROM AUTHOR]

During cellular senescence, persistent growth arrest and changes in protein expression programs are accompanied by a senescence-associated secretory phenotype (SASP). In this study, we detected the upregulation of the SASP-related protein dipeptidyl peptidase 4 (DDP4) in human primary lung cells rendered senescent by exposure to ionizing radiation. DPP4 is an exopeptidase that plays a crucial role in the cleavage of various proteins, resulting in the loss of N-terminal dipeptides and proinflammatory effects. Interestingly, our data revealed an association between severe coronavirus disease 2019 (COVID-19) and DDP4, namely that DPP4 levels increased in the plasma of patients with COVID-19 and were correlated with age and disease progression. Although we could not determine the direct effect of DDP4 on viral replication, mechanistic studies in cell culture revealed a negative impact on the expression of the tight junction protein zonula occludens-1 (ZO-1), which contributes to epithelial barrier function. Mass spectrometry analysis indicated that DPP4 overexpressing cells exhibited a decrease in ZO-1 and increased expression of pro-inflammatory cytokines and chemokines. By investigating the effect of DPP4 on the barrier function of human primary cells, we detected an increase in ZO-1 using DPP4 inhibitors. These results provide an important contribution to our understanding of DPP4 in the context of senescence, suggesting that DPP4 plays a major role as part of the SASP. Our results provide evidence that cellular senescence, a hallmark of aging, has an important impact on respiratory infections. [ABSTRACT FROM AUTHOR]

Several premature aging mouse models have been developed to study aging and identify interventions that can delay age‐related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging. [ABSTRACT FROM AUTHOR]