Association between prescription drugs and all-cause mortality risk in the UK population.

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.

Emerging liver infection of Veillonella parvula associated with acute respiratory distress syndrome: a case report.

Introduction: Veillonella parvula is a bacteria that can be found in normal oral and gastrointestinal flora. Veillonella infection is rare in immunocompetent patients but is known to cause periorbital cellulitis, endocarditis, osteomyelitis and bacteremia; however, its association with acute respiratory distress syndrome (ARDS) has not been previously documented. Case presentation: A 36-year-old female with no known history who presented with right-sided chest, flank and upper abdominal pain after a motor vehicle accident. Computed tomography showed multiple right rib fractures, small right pneumothorax, and a grade 4 liver laceration with active extravasation of the posterior aspect of the right liver lobe. Over the hospital course, the patient developed ARDS and was intubated for hypoxemia. A right posterior liver abscess was percutaneously drained, with a copious amount of air and ~30 ml turbid fluid aspirated. Cultures from the liver abscess grew Veillonella parvula. She was treated with Micafungin, Levofloxacin, and Metronidazole for the hepatic abscess, and was discharged home with outpatient follow-up. Discussion: The authors present one of the first reported cases of a V. parvula infected liver abscess associated with ARDS in an immunocompetent patient. Conclusion: These clinical findings are unique due to the nature of our patient's ARDS onset and the dearth of similar cases in the literature. The favorable outcome of our patient was due to a multidisciplinary and early identification of a V. parvula hepatic abscess. The authors' findings contribute to the future management of V. parvula and a greater understanding of its disseminating effects and presentation in immunocompetent patients.

Re-do Hybrid Deep Venous Arterialization via the Popliteal Venous System: Conversion From a Deep Venous Arterialization to a Superficial Venous Arterialization.

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.

ATAC-clock: An aging clock based on chromatin accessibility.

The establishment of aging clocks highlighted the strong link between changes in DNA methylation and aging. Yet, it is not known if other epigenetic features could be used to predict age accurately. Furthermore, previous studies have observed a lack of effect of age-related changes in DNA methylation on gene expression, putting the interpretability of DNA methylation-based aging clocks into question. In this study, we explore the use of chromatin accessibility to construct aging clocks. We collected blood from 159 human donors and generated chromatin accessibility, transcriptomic, and cell composition data. We investigated how chromatin accessibility changes during aging and constructed a novel aging clock with a median absolute error of 5.27 years. The changes in chromatin accessibility used by the clock were strongly related to transcriptomic alterations, aiding clock interpretation. We additionally show that our chromatin accessibility clock performs significantly better than a transcriptomic clock trained on matched samples. In conclusion, we demonstrate that the clock relies on cell-intrinsic chromatin accessibility alterations rather than changes in cell composition. Further, we present a new approach to construct epigenetic aging clocks based on chromatin accessibility, which bear a direct link to age-related transcriptional alterations, but which allow for more accurate age predictions than transcriptomic clocks.

To Ablate or Not to Ablate: Does Umbilectomy Decrease Donor-Site Complications in DIEP Flap Breast Reconstruction?

BACKGROUND: Improving outcomes for deep inferior epigastric perforator (DIEP) flap breast reconstruction is an evolving area of interest. The aim of this study was to evaluate the effect of umbilectomy in abdominally based breast reconstruction. METHODS: This retrospective study evaluated postoperative outcomes of patients who underwent autologous DIEP flap breast reconstruction at an academic center between January of 2015 and December of 2021 performed by one of two reconstructive surgeons. The primary outcome variable was abdominal donor-site complications. A secondary outcome variable was treatment outcomes for complications. Covariates included demographic information, comorbidities, cancer treatment, and smoking. RESULTS: A total of 408 patients underwent DIEP flap breast reconstruction, with 194 (47.5%) undergoing umbilectomy. Umbilectomy resulted in decreased number of total wounds per patient (0.35 ± 0.795) compared with umbilical preservation (0.75 ± 1.322; P < 0.001), as well as decreased associated risk of any reported wounds (OR, 0.530; P = 0.009). Associations that trended toward significance occurred between umbilectomy and minor wound separation and partial necrosis, with both showing decreased risk. A significant association was noted between umbilectomy and donor-site seroma [χ 2 (1) = 6.348; P = 0.016], showing an increased risk (OR, 5.761). CONCLUSIONS: Umbilectomy should be discussed with patients and considered as a part of DIEP flap breast reconstruction given the reduction in the risk of abdominal donor-site wounds. Although umbilectomy decreases the rate of wounds, it can increase the risk of seroma; therefore, other interventions, such as progressive tension sutures, may be explored to aid in reducing seroma and improving wound healing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

DNA repair-deficient premature aging models display accelerated epigenetic age.

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.

In vivo reprogramming leads to premature death linked to hepatic and intestinal failure.

The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week). By generating a transgenic reprogrammable mouse strain, avoiding OSKM expression in both liver and intestine, we reduced the early lethality and adverse effects associated with in vivo reprogramming and induced a decrease in organismal biological age. This reprogramming mouse strain, which allows longer-term continuous induction of OSKM with attenuated toxicity, can help better understand rejuvenation, regeneration and toxicity during in vivo reprogramming.

Urbanization associates with restricted gut microbiome diversity and delayed maturation in infants.

Alterations of the microbiome are linked to increasingly common diseases such as obesity, allergy, and inflammatory bowel disease. Post-industrial lifestyles are thought to contribute to the gut microbiome alterations that cause or aggravate these diseases. Comparing communities across the industrialization spectrum can reveal associations between gut microbiome alterations and lifestyle and health, and help pinpoint which specific aspect of the post-industrial lifestyle is linked to microbiome alterations. Here, we compare the gut microbiomes of 60 mother and infant pairs from rural and urban areas of Senegal over two time points. We find that urban mothers, who were more frequently overweight, had different gut microbiome compositions than rural mothers, showing an expansion of Lachnospiraceae and Enterobacter. Urban infants, on the other hand, showed a delayed gut microbiome maturation and a higher susceptibility to infectious diseases. Thus, we identify new microbiome features associated with industrialization, whose association with disease may be further investigated.

Role of the Senescence-Associated Factor Dipeptidyl Peptidase 4 in the Pathogenesis of SARS-CoV-2 Infection.

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.

Psychological impact of the COVID-19 pandemic on breast cancer patients.

PURPOSE: The COVID-19 pandemic uniquely impacted patients with breast cancer as mastectomies were allowed to proceed, yet breast reconstruction surgeries were halted. The purpose of this study was to examine the effect of the COVID-19 pandemic on the rates of breast reconstruction and patients' well-being. METHODS: A chart review included all patients who underwent mastectomy from December 2019 to September 2021. Patients were contacted by a member of the research team and asked to participate in a COVID-19-specific survey and to complete the Hospital Anxiety and Depression Scale (HADS). Patients were then grouped into "surge" or "nonsurge" groups based on the date of mastectomy. RESULTS: Two hundred and fifty-nine patients were included in this study. During the study period, 42% (n = 111) of the patients underwent breast reconstruction. The "surge" group included 106 patients whereas the "nonsurge" group included 153 patients. Fewer patients began breast reconstruction during the surge period compared with the nonsurge period (34.0% vs. 49.0%, p = 0.017). Eighty-six patients participated in the COVID-19 survey. Forty-one percent (n = 35) of the patients felt that their care was disrupted because of COVID-19. Eighty-three patients completed the HADS survey. Overall, 16.8% and 15.7% of the respondents fell into the moderate to severe ranges for both anxiety and depression scales, respectively. CONCLUSIONS: Patients with breast cancer have faced increased difficulties with access to breast reconstruction throughout the COVID-19 pandemic. Our institution demonstrated decreased rates of breast reconstruction and an increase in anxiety and depression. The positive benefits of breast reconstruction cannot be overlooked when determining resource allocation in the future.

A Propensity Score-Matched Comparison of Perioperative Outcomes in Prepectoral Smooth Versus Textured Tissue Expander Breast Reconstruction.

INTRODUCTION: Textured tissue expanders (TEs) had previously gained popularity due to minimizing expander migration, rotation, and capsule migration. Recent studies, though, have revealed increased risk of anaplastic large-cell lymphoma associated with certain macrotextured implants, prompting surgeons at our institution to switch to smooth TEs; evaluation is thus required for specific viability and similarity of outcomes of smooth TEs. Our study aims to evaluate perioperative complications in prepectoral placement of smooth versus textured TEs. METHODS: Our retrospective study evaluated perioperative outcomes of patients who underwent bilateral prepectoral TE placement, with either smooth or textured TE, at an academic institution between 2017 and 2021 performed by 2 reconstructive surgeons. The perioperative period was defined as the interval between expander placement until conversion to flap/implant or removal of TE due to complications. Our primary outcomes included hematoma, seroma, wounds, infection, unspecified redness, total number of complications, and returns to operating room secondary to complications. Secondary outcomes included time to drain removal, total number of expansions, hospital length of stay, length of time until the next breast reconstruction procedure, next breast reconstruction procedure, and number of expansions. RESULTS: Two hundred twenty-two patients were evaluated in our study (141 textured, 81 smooth). After propensity matching (71 textured, 71 smooth), our univariate logistic regression showed no significant difference in perioperative complications between smooth and textured expanders (17.1% vs 21.1%; P = 0.396) or complications that required a return to the operating room (10.0% vs 9.2%; P = 0.809). No significant differences were noted for hematoma, seroma, infections, unspecified redness, or wounds between both groups. A significant difference was noted in days to drain out (18.57 ± 8.17 vs 20.13 ± 0.07, P = 0.001) and type of the next breast reconstruction procedure (P < 0.001). Our multivariate regression showed that breast surgeon, hypertension, smoking status, and mastectomy weight were significant for increased risk for complications. CONCLUSION: Our study demonstrates similar rates and effectiveness of smooth versus textured TE when used for prepectoral placement, making smooth TEs a safe and valuable alternative for breast reconstruction because of their decreased risk of anaplastic large-cell lymphoma compared with textured TEs.

Microbacterium Cluster EA Bacteriophages: Phylogenomic Relationships and Host Range Predictions.

Bacteriophages are being widely harnessed as an alternative to antibiotics due to the global emergence of drug-resistant pathogens. To guide the usage of these bactericidal agents, characterization of their host specificity is vital-however, host range information remains limited for many bacteriophages. This is particularly the case for bacteriophages infecting the Microbacterium genus, despite their importance in agriculture, biomedicine, and biotechnology. Here, we elucidate the phylogenomic relationships between 125 Microbacterium cluster EA bacteriophages-including members from 11 sub-clusters (EA1 to EA11)-and infer their putative host ranges using insights from codon usage bias patterns as well as predictions from both exploratory and confirmatory computational methods. Our computational analyses suggest that cluster EA bacteriophages have a shared infection history across the Microbacterium clade. Interestingly, bacteriophages of all sub-clusters exhibit codon usage preference patterns that resemble those of bacterial strains different from ones used for isolation, suggesting that they might be able to infect additional hosts. Furthermore, host range predictions indicate that certain sub-clusters may be better suited in prospective biotechnological and medical applications such as phage therapy.

Complete Genome Sequence of the Microbacterium Bacteriophage Chako.

We characterized the complete genome sequence of Chako, an obligate lytic bacteriophage with siphovirus morphology from subcluster EA1 that infects Microbacterium foliorum NRRL B-24224. Its 41.6-kb genome contains 62 putative protein-coding genes and is highly similar to that of bacteriophage HanSolo (99.26% nucleotide identity).

Volumetric Assessment of the Anterior Digastric Muscles: A Deeper Understanding of the Volumetric Changes With Aging.

BACKGROUND: Targeting the deeper, subplatysmal structures in the neck has recently grown in popularity. In particular, interventions targeting the "bulky" anterior digastric (AD) muscle have been described with excellent results. However, much remains to be understood about the deep anatomy of the neck and the age-associated changes of the AD. OBJECTIVES: The aim of this study was to examine the relationship between AD volume and age. METHODS: This retrospective study calculated the AD volume from MRI segmentation in subjects between the ages of 20 to 92 years, scans of whom had previously been recorded. Those with compromised imaging due to pathology or artifact were excluded. Subjects were divided into 4 age-defined cohorts for clinical applicability. RESULTS: This study included 129 patients (male n = 64) with a mean age of 52.3. The AD volume of the reference group was 3.2 cm3. A linear decrease in muscle volume was observed with age compared with the reference group: 2.95 cm3 in the 45- to 54-year-old cohort (P = 0.3), 2.7 cm3 in the 55- to 64-year-old cohort (P = 0.05), and 2.45 cm3 in the >65-year-old cohort (P < 0.001). Male sex (P = 0.0001) and laterality (P = 0.003) were associated with significantly larger volumes. Overweight and obese BMI classification was not associated with a significantly different volume than normal or underweight subjects (P = 0.067). CONCLUSIONS: The study findings suggest an age-associated reduction in AD volume. Gender and laterality significantly affected volume, whereas BMI did not. Although the results do not support the theory of muscular hypertrophy with aging, they reveal that the perceived bulkiness may be due to changes in the surrounding anatomy affecting the morphology of the AD and subsequent blunting of the cervicomental angle.

Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence.

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.

Age-related brain atrophy is not a homogenous process: Different functional brain networks associate differentially with aging and blood factors.

Aging is characterized by a progressive loss of brain volume at an estimated rate of 5% per decade after age 40. While these morphometric changes, especially those affecting gray matter and atrophy of the temporal lobe, are predictors of cognitive performance, the strong association with aging obscures the potential parallel, but more specific role, of individual subject physiology. Here, we studied a cohort of 554 human subjects who were monitored using structural MRI scans and blood immune protein concentrations. Using machine learning, we derived a cytokine clock (CyClo), which predicted age with good accuracy (Mean Absolute Error = 6 y) based on the expression of a subset of immune proteins. These proteins included, among others, Placenta Growth Factor (PLGF) and Vascular Endothelial Growth Factor (VEGF), both involved in angiogenesis, the chemoattractant vascular cell adhesion molecule 1 (VCAM-1), the canonical inflammatory proteins interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the chemoattractant IP-10 (CXCL10), and eotaxin-1 (CCL11), previously involved in brain disorders. Age, sex, and the CyClo were independently associated with different functionally defined cortical networks in the brain. While age was mostly correlated with changes in the somatomotor system, sex was associated with variability in the frontoparietal, ventral attention, and visual networks. Significant canonical correlation was observed for the CyClo and the default mode, limbic, and dorsal attention networks, indicating that immune circulating proteins preferentially affect brain processes such as focused attention, emotion, memory, response to social stress, internal evaluation, and access to consciousness. Thus, we identified immune biomarkers of brain aging which could be potential therapeutic targets for the prevention of age-related cognitive decline.

Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.

Does Fitzpatrick Score Predict Flap Loss? Microsurgical Breast Reconstruction Outcomes of Varying Skin Color.

The aim of this study was to seek evidence that patients with darker Fitzpatrick score skin tones are more susceptible to flap loss due to unsalvaged vascular compromise in autologous flap breast reconstruction. Methods: This is a retrospective study conducted on patients who underwent any type of autologous flap breast reconstruction performed by the two senior authors at an academic center between January 2010 and December 2021. The sole primary outcome variable was flap loss. Patient skin tone was assessed using the Fitzpatrick scale on clinical photographs of patients. Results: A total of 1115 pateints underwent autologous flap breast reconstruction, of which only 56 met both exclusion and inclusion criteria with 58 individual breasts being included in the final study population. The most common race of subjects was White (n = 33; 56.9%) while the most common Fitzpatrick score skin tone was type II (n = 22; 37.9%). The Cochran-Armitage test of trend showed a statistically significant linear trend, P = 0.006, with darker Fitzpatrick score skin tones associated with a higher proportion of flap loss in patients who had vascular compromise. A logistic regression showed that none of the predictor variables were significant. Conclusions: Patients with darker Fitzpatrick skin tones were associated with flap loss after vascular compromise. To prevent flap loss in patients who have darker Fitzpatrick score skin tones, more aggressive flap monitoring should be taken into consideration in the immediate postoperative setting.

BREAST-Q and Donor Site Comparison in Bilateral Stacked Autologous Breast Reconstruction.

Background: Patients undergoing bilateral autologous breast reconstruction may benefit from increased flap volume using bilateral stacked deep inferior epigastric perforator (DIEP) and profunda artery perforator (PAP) flaps. Our aim was to characterize the donor site morbidity and patient-reported outcomes in four-flap breast reconstruction. Methods: Retrospective review was performed for all patients undergoing four-flap breast reconstruction by two surgeons between January 2010 and September 2021. Outcome measures including the BREAST-Q reconstructive module, the lower extremity functional scale (LEFS), inpatient surgical site pain scores by numeric pain rating scale (NPRS), and a postoperative subjective survey comparing donor sites were obtained. Four-flap BREAST-Q scores were compared with bilateral DIEP and bilateral PAP patients. Results: A total of 79 patients undergoing four-flap breast reconstruction were identified. Four-flap BREAST-Q scores (n = 56) were similar to bilateral DIEP and bilateral PAP reconstruction patients. Long-term survey outcomes from the LEFS demonstrated improved score trend after 6 months. Mean instances of donor site pain location recorded at the abdomen were significantly higher than the thigh during the postoperative admission. Subjective survey data revealed more long-term donor site pain at the PAP site, a patient preference for the DIEP donor site, and easier postoperative care for the DIEP donor site. Conclusions: This is the largest consecutive series of four-flap breast reconstruction outcomes reported to date. BREAST-Q scores in four-flap patients demonstrate overall patient satisfaction that is similar to both bilateral DIEP and bilateral PAP reconstruction patients. The DIEP donor site appears to be preferred by patients over the PAP donor site.