Biotics as novel therapeutics in targeting signs of skin ageing via the gut-skin axis.

Skin ageing is a phenomenon resulting from the aggregative changes to skin structure and function and is clinically manifested by physical features such as wrinkles, hyperpigmentation, elastosis, telangiectasia, and deterioration of skin barrier integrity. One of the main drivers of skin ageing, UV radiation, negatively influences the homeostasis of cells and tissues comprising the skin by triggering production of immune-mediated reactive oxygen species (ROS) and pro-inflammatory cytokines, as well as a various hormones and neuropeptides. Interestingly, an established link between the gut and the skin coined the 'gut-skin axis' has been demonstrated, with dysbiosis and gut barrier dysfunction frequently observed in certain inflammatory skin conditions and more recently, implicated in skin ageing. Therapeutic use of 'biotics' including prebiotics, probiotics, postbiotics, and synbiotics, which modulate the gut microbiota and production of microbially associated metabolites, influence the activity of the gut mucosal and immune systems and are showing promise as key candidates in addressing signs of skin ageing. In this review we aim to focus on the structure and function of the gut-skin axis and showcase the recent in-vitro and clinical evidence demonstrating the beneficial effects of select biotics in targeting signs of skin ageing and discuss the proposed mechanisms mediated via the gut-skin axis underpinning these effects.

Comparison of Postoperative Bleed Rates and Location of Bleed Between Vessel Sealing Devices after Laparoscopic Sleeve Gastrectomy.

Background: Laparoscopic sleeve gastrectomy (SG) is a commonly performed bariatric procedure. At our institution, two vessel sealing devices, Thunderbeat® (Olympus) and Maryland LigaSure™ (Covidien) are utilized for intraoperative dissection. Methods: A retrospective review of all patients who underwent primary SG from July 2013 through August 2022 was performed to evaluate postoperative bleeding (POB) rates between the two devices. The primary outcome measured was POB as defined by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP), with secondary outcomes including reoperation, source of bleed, and overall safety. Results: A total of 8157 underwent SG. Average BMI and age were 43.2 kg/m2 and 37.1 years, respectively. A total of 6600 (80.9%) were female. Thunderbeat® was utilized in 5143 (63%) cases and Maryland LigaSure™ was used in 3014 (37%) cases. There was no significant difference in overall bleeding between the Thunderbeat® (18/5143, .35%) and the Maryland LigaSure™ (19/3014, .63%; P = .0689). However, there was a difference noted when comparing reoperation for bleeding between Thunderbeat® (9/5143, .17%) and Maryland LigaSure™ (13/3014, .43%; P = .0291). Furthermore, the location of bleeding in the reoperations was more common from the cut edge of the mesentery compared to the staple line with the Maryland LigaSure™ versus the Thunderbeat® (P = .038). Conclusions: The Thunderbeat® device is comparatively more hemostatic than the Maryland LigaSure™ for SG. The location of postoperative bleed may be related to vessel sealing devices used.

Routine extended (30 days) chemoprophylaxis for patients undergoing laparoscopic sleeve gastrectomy may reduce Portomesenteric vein thrombosis rates.

BACKGROUND: Venous thromboembolism (VTE), including Portomesenteric vein thrombosis (PMVT), is a major complication of sleeve gastrectomy (SG). We changed our practice in July 2021 to routinely discharge all SG patients postoperatively with extended chemoprophylaxis for 30 days. OBJECTIVES: Evaluate the efficacy and safety of routine extended chemoprophylaxis compared to 2 prior timeframes using selective extended chemoprophylaxis. SETTING: University Hospital. METHODS: Between 2012-2018, SG patients were discharged on extended chemoprophylaxis for patients deemed "high-risk" for VTE, including patients with body mass index (BMI) >50, and previous VTE. Between 2018-2021, extended chemoprophylaxis was broadened to include patients with positive preoperative thrombophilia panels (including Factor VIII). After 2021, all SG were routinely discharged on extended chemoprophylaxis. The typical regimen was 30 days Lovenox BID (40-mg twice daily for BMI> 40, 60-mg twice daily for BMI >60). Outcomes evaluated were rate of VTE/PMVT and postoperative bleed, including delayed bleed. RESULTS: A total of 8864 patients underwent SG. Average age and BMI were 37.5 years and 43.0 kg/m2, respectively. The overall incidence of PMVT was 33/8864 (.37%). Converting from selective extended chemoprophylaxis (Group 1) to routine extended chemoprophylaxis (Group 3) decreased the rate of PMVT from .55% to .21% (P = .13). There was a significantly higher overall bleeding rate (.85%), including delayed bleeds (.34%) in the routine extended chemoprophylaxis patients (P < .05). These bleeds were mainly managed nonoperatively. CONCLUSIONS: Routine extended (30 day) chemoprophylaxis for all SG may reduce PMVT rate but lead to a higher bleeding rate post-operatively. The vast majority of the increased bleeds are delayed and can be managed non-operatively.

Recurrent repeat expansions in human cancer genomes.

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3-8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.

Acute Appendicitis During The COVID-19 Pandemic: A Multicenter, Retrospective Analysis From The US Epicenter.

BACKGROUND: Acute appendicitis (AA) is the most common surgical emergency, with a relatively stable yearly incidence. During the first wave of the COVID-19 pandemic, as New York City (NYC) emerged as the US epicenter, hospitals saw a marked reduction in patients presenting with non-COVID-related diseases. The objective of this study was to characterize the effects of the pandemic on the incidence, presentation, and management of AA. METHODS: A retrospective analysis of patients with AA who presented to two academic medical centers during the NYC COVID peak (March 22nd-May 31st, 2020) was performed. This group was compared to a control cohort presenting during the same period in 2019. Primary outcomes included the incidence of AA, complicated disease, and management. Secondary outcomes included duration of symptoms, hospital length of stay, and complication rates. Statistical analyses were performed using Mann-Whitney U, Chi-square, and Fisher's exact tests. RESULTS: A 49.1% reduction in the incidence of AA was seen between 2019 (n = 114) and 2020 (n = 58). Median duration of symptoms doubled from 1 day in 2019 to 2 days in 2020 (P < .02). Proportionally, the incidence of complicated appendicitis rose from 19.3% to 41.4% (P < .005). 32.4% of patients with uncomplicated AA underwent non-operative management in 2020, compared to 12% in 2019 (P < .02). Hospital length of stay and complication rates were similar between years. DISCUSSION: Significantly fewer AA patients presented during the initial phase of the pandemic. Patients presented later, which may have contributed to a higher proportion of complicated disease. Surgeons were also more likely to treat uncomplicated AA nonoperatively than they were prior. Further research is needed to understand the long-term consequences of these changes.

Multipathway In Vitro Pharmacological Characterization of Specialized Proresolving G Protein-Coupled Receptors.

Specialized proresolving mediators (SPMs) and their cognate G protein-coupled receptors are implicated in autoimmune disorders, including chronic inflammation, rheumatoid arthritis, systemic scleroderma, and lupus erythematosus. To date, six G protein-coupled receptors (GPCRs) have been paired with numerous endogenous and synthetic ligands. However, the function and downstream signaling of these receptors remains unclear. To address this knowledge gap, we systematically expressed each receptor in a human embryonic kindney 293 (HEK293)-Flp-In-CD8a-FLAG cell system. Each receptor was pharmacologically characterized with both synthetic and putative endogenous ligands across different signaling assays, covering both G protein-dependent (Gs, Gi, and Gq) and independent mechanisms (ß-arrestin2 recruitment). Three orphan GPCRs previously identified as SPM receptors (GPR 18, GPR32 and GPR37) failed to express in HEK 293 cells. Although we were unsuccessful in identifying an endogenous ligand for formyl peptide receptor 2 (FPR2)/lipoxin A4 receptor (ALX), with only a modest response to N-formylmethionine-leucyl-phenylalanine (fMLP), we did reveal clear signaling bias away from extracelluar signal-related kinase (ERK) 1/2 phosphorylation for the clinically tested agonist N-(2-{[4-(1,1-difluoroethyl)-1,3-oxazol-2-yl]methyl}-2H-1,2,3-triazol-4-yl)-2-methyl-5-(3-methylphenyl)-1,3-oxazole-4-carboxamide (ACT-389949), adding further evidence for its poor efficacy in two phase I studies. We also identified neuroprotectin D1 as a new leukotriene B4 receptor 1 (BLT1) agonist, implying an alternative target for the neuroprotective effects of the ligand. We confirmed activity for resolvin E1 (RvE1) at BLT1 but failed to observe any response at the chemerin1 receptor. This study provides some much-needed clarity around published receptor-ligand pairings but indicates that the expression and function of these SPM GPCRs remains very much context-dependent. In addition, the identification of signaling bias at FPR2/ALX may assist in guiding design of new FPR2/ALX agonists for the treatment of autoimmune disorders. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to comprehensibly show how several natural mediators and synthetic ligands signal through three specialized proresolving mediator GPCRs using multiple ligands from different classes across four-six endpoint signaling assays. This study discovers new ligand pairings, refutes others, reveals poly-pharmacology, and identifies biased agonism in formyl peptide receptor 2/lipoxin A4 receptor pharmacology. This study highlights the potential of these receptors in treating specific autoimmune diseases, including rheumatoid arthritis, systemic scleroderma, and systemic lupus erythematosus.

Disseminated Candida lusitaniae: Nosocomial Acquisition Secondary to an Indwelling Urinary Catheter.

Candida lusitaniae is a rare opportunistic pathogen, and its most common risk factors include immunocompromised patients often with an underlying malignancy. It commonly displays resistance to amphotericin B, and historically, echinocandins have been considered first-line treatment. We present a 77-year-old male with a history of diabetes mellitus. He was treated for cellulitis and discharged to a skilled nursing facility with an indwelling urinary catheter. Despite recommendations from the medicine team to remove the catheter, the patient refused even after discussing the risks and benefits. He returned to the hospital 3 weeks later with symptoms of dysarthria, right-sided facial droop, and right-sided weakness. Ultimately, he was determined to have fungemia and native valve endocarditis due to Candida lusitaniae stemming from his indwelling urinary catheter. He was treated with micafungin, but repeated blood cultures continued to grow C. lusitaniae, and he eventually expired following withdrawal of care. We present this case report to illustrate a rare occurence of Candida lusitaniae in a patient without typical risk factors. C. lusitaniae fungemia is an extremely uncommon disease in patients without underlying malignancy. Despite this lack of apparent, classic risk factors, our patient developed endocarditis of his native valve due to C. lusitaniae fungemia from an indwelling urinary catheter. The ability of this organism to form biofilms, and its rapid mutation rate, makes treating C. lusitaniae very difficult. The treatment of choice for C. lusitaniae endocarditis is surgical intervention due to biofilm formation on the cardiac valves. Medical treatment recommendations are currently fluconazole, which is in contrast to the historical use of echinocandins. Infection due to Candida lusitaniae, though rare, should be remembered by clinicians. This particular fungal agent is especially difficult to treat due to its multiple virulence factors. Additionally, the use of indwelling urinary catheters should only occur when proper indications are present and should be promptly discontinued when their placement is no longer necessary.

Thrombophilia prevalence in patients seeking laparoscopic sleeve gastrectomy: extended chemoprophylaxis may decrease portal vein thrombosis rate.

BACKGROUND: Portomesenteric vein thrombosis (PMVT) may occur after laparoscopic sleeve gastrectomy (LSG). Previous studies have shown that PMVT patients may have undiagnosed thrombophilia. We recently changed our practice to check thrombophilia panel in every LSG patient preoperatively. OBJECTIVES: To estimate the thrombophilia prevalence in patients seeking LSG, and determine if extended chemoprophylaxis post LSG reduces PMVT. SETTINGS: University hospital. METHODS: Thrombophilia panels were drawn on every patient seeking LSG after July 2018 at 2 high-volume accredited bariatric surgery centers. A positive panel included factor VIII >150%; protein C <70%; protein S <55%; antithrombin III <83%; and activated protein C resistance <2.13. Patients with a positive panel were discharged on extended chemoprophylaxis. PMVT rates and bleeding occurrences were recorded for LSG patients from August 2018 to March 2019 and were compared with a historic cohort of LSG performed from January 2014 to July 2018. RESULTS: One thousand seventy-five patients seeking LSG had thrombophilia panel checked preoperatively. The cohort was 83% female; mean age and body mass index were 39.2 years and 43 kg/m2, respectively. Of the cohort, 52.4% (563/1075) had positive thrombophilia panel, including factor VIII elevation (91.5%), antithrombin III deficiency (6.0%), protein S deficiency (1.1%), protein C deficiency (.9%), and activated protein C resistance (.5%). Between January 2014 and July 2018, 13 PMVT were diagnosed among 4228 LSG (.3%) and there were 17 bleeding occurrences (.4%). After August 2018, one PMVT was diagnosed among 745 LSG (.1%) and there were 5 bleeding occurrences (.6%). CONCLUSIONS: The estimated thrombophilia prevalence in patients seeking LSG is 52.4%. The majority (91.5%) of these patients have factor VIII elevation. Extended prophylaxis may decrease PMVT postLSG.

New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery.

Chronic inflammation is a component of numerous diseases including autoimmune, metabolic, neurodegenerative, and cancer. The discovery and characterization of specialized pro-resolving mediators (SPMs) critical to the resolution of inflammation, and their cognate G protein-coupled receptors (GPCRs) has led to a significant increase in the understanding of this physiological process. Approximately 20 ligands, including lipoxins, resolvins, maresins, and protectins, and 6 receptors (FPR2/ALX, GPR32, GPR18, chemerin1, BLT1, and GPR37) have been identified highlighting the complex and multilayered nature of resolution. Therapeutic efforts in targeting these receptors have proved challenging, with very few ligands apparently progressing through to preclinical or clinical development. To date, some knowledge gaps remain in the understanding of how the activation of these receptors, and their downstream signaling, results in efficient resolution via apoptosis, phagocytosis, and efferocytosis of polymorphonuclear leukocytes (mainly neutrophils) and macrophages. SPMs bind and activate multiple receptors (ligand poly-pharmacology), while most receptors are activated by multiple ligands (receptor pleiotropy). In addition, allosteric binding sites have been identified signifying the capacity of more than one ligand to bind simultaneously. These fundamental characteristics of SPM receptors enable alternative targeting strategies to be considered, including biased signaling and allosteric modulation. This review describes those ligands and receptors involved in the resolution of inflammation, and highlights the most recent clinical trial results. Furthermore, we describe alternative mechanisms by which these SPM receptors could be targeted, paving the way for the identification of new therapeutics, perhaps with greater efficacy and fidelity.

eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.

The recruitment of new members to existing PBSGL small groups: a qualitative study.

Introduction Practice-Based Small Group Learning (PBSGL) is a learning programme widely adopted by primary healthcare professions (general practitioners, general practice nurses and pharmacists) in Scotland and other countries in the UK. PBSGL groups recruit members and decide on meeting dates and venues. Study aims To determine how groups recruit new members and discern what are the important attributes of the new members. Method A grounded theory approach was used with purposive sampling to recruit PBSGL groups to the study. Focus groups drawn from established PBSGL groups were conducted by two researchers following an iterative process, with interviews audio-recorded and transcribed, and codes and themes constructed. Data saturation was achieved. Results and conclusions Four themes were identified that affected group recruitment: group formation and purpose; group culture and ethos; experience and seniority range of group members; professional socialisation and cross-fertilisation. Groups whose main purpose was learning encouraged diverse membership, while groups that were stricter with recruitment often prioritised friendship, group safety, trust and peer support over learning. The variation in group's openness to recruitment may make it difficult for potential members to find a group and this may affect the development and expansion of the PBSGL programme.

Malignant Catatonia Warrants Early Psychiatric-Critical Care Collaborative Management: Two Cases and Literature Review.

Malignant catatonia (MC) is a life-threatening manifestation which can occur in the setting of an underlying neuropsychiatric syndrome or general medical illness and shares clinical and pathophysiological features and medical comorbidities with the Neuroleptic Malignant Syndrome (NMS). The subsequent diagnosis and definitive therapy of MC are typically delayed, which increases morbidity and mortality. We present two cases of MC and review recent literature of MC and NMS, illustrating factors which delay diagnosis and management. When clinical features suggest MC or NMS, we propose early critical care consultation and stabilization with collaborative psychiatric management.

Recovery of a Missile Embolus From the Right Ventricle.

Missile embolism is a clinical entity in which a projectile object enters a blood vessel and is carried to a distant part of the body. We present a case of the discovery of an iliac vein to right ventricle missile embolus in a young man, with successful extraction through a right atriotomy. We provide a historical overview of the literature concerning missile embolism, and we argue that whereas acute embolized projectiles should be removed in almost all cases, it may be reasonable to simply observe an asymptomatic chronic missile embolus.

Validity evidence for Surgical Improvement of Clinical Knowledge Ops: a novel gaming platform to assess surgical decision making.

BACKGROUND: Current surgical education curricula focus mainly on the acquisition of technical skill rather than clinical and operative judgment. SICKO (Surgical Improvement of Clinical Knowledge Ops) is a novel gaming platform developed to address this critical need. A pilot study was performed to collect validity evidence for SICKO as an assessment for surgical decision making. METHODS: Forty-nine subjects stratified into 4 levels of expertise were recruited to play SICKO. Later, players were surveyed regarding the realism of the gaming platform as well as the clinical competencies required of them while playing SICKO. RESULTS: Each group of increasing expertise outperformed the less experienced groups. Mean total game scores for the novice, junior resident, senior resident, and expert groups were 5,461, 8,519, 11,404, and 13,913, respectively (P = .001). Survey results revealed high scores for realism and content. CONCLUSIONS: SICKO holds the potential to be not only an engaging and immersive educational tool, but also a valid assessment in the armamentarium of surgical educators.

Subglottic stenosis and socio-economic deprivation: a 6-year review of the Scottish National Service for Paediatric Complex Airway Reconstruction.

OBJECTIVE: Subglottic stenosis is the third most common cause of stridor in children, and severe cases may need surgical reconstruction. Babies born to parents in high-deprivation areas are at increased risk of prematurity and low birth weight. This may require intensive care admission with prolonged intubation, hence, putting them at increased risk of subglottic stenosis. We aimed to review cases of subglottic stenosis requiring surgical intervention in the Scottish population and its association with socio-economic deprivation. METHODS: We collected retrospective data on all children who underwent open reconstructive surgery for subglottic stenosis between January 2005 and January 2011 at the Royal Hospital for Sick Children, Yorkhill, which provides the national complex airway reconstruction service for Scotland. The Scottish Index of Multiple Deprivation (SIMD) was used to categorise deprivation based on the child's home postal code. Incidence figures were calculated based on the total number of births in each deprivation category over the time period. RESULTS: There were a total of 53 cases of subglottic stenosis undergoing surgery in Scotland over the last 6 years, of which 31 were acquired and 22 were congenital. The most common procedure performed was laryngotracheal reconstruction with cartilage grafts (46 cases). No association was found between deprivation and the incidence of acquired or congenital subglottic stenosis. CONCLUSION: Our data is the first attempt to review the incidence of subglottic stenosis in the Scottish population and its association with deprivation. Perhaps surprisingly, we found no association.

Sentinel lymph node biopsy is successful and accurate in male breast carcinoma.

BACKGROUND: Men and women with breast cancer have similar risks of morbidity related to axillary lymph node dissection (ALND). Sentinel lymph node (SLN) biopsy minimizes this risk. We report results from the largest series of SLN biopsies for male breast cancer and compare this experience with that of female counterparts treated concurrently. STUDY DESIGN: The Memorial Sloan-Kettering Cancer Center SLN biopsy database showed that 7,315 SLN biopsy procedures were performed for primary breast cancer from September 1996 to July 2005. Of these, 78 (1.0%) procedures were performed in men. Followup data were obtained from medical record review. RESULTS: SLN biopsy was successful in 76 of 78 (97%) patients. Negative SLNs were found in 39 of 76 (51%) patients. In 3 (8%) patients with negative SLNs, a positive non-SLN was found, identified by intraoperative palpation. Positive SLNs were found in 37 of 76 (49%) patients. In 22 of 37 (59%), node positivity was determined intraoperatively, prompting immediate ALND. In 15 of 37 (41%) patients with positive SLNs, node positivity was determined postoperatively. Of these 15, 9 (60%) underwent completion ALND. In the 2 of 78 (3%) patients with failed SLN biopsy procedures, ALND was performed and yielded positive nodes. At a median followup of 28 months (range 5 to 96 months), there were no axillary recurrences. Compared with their female counterparts, men with breast cancer had larger tumors and were more likely to have positive nodes. CONCLUSIONS: SLN biopsy is successful and accurate in male breast cancer patients. Although a larger proportion of men have positive nodes, for men with negative nodes, SLN biopsy may reduce morbidity related to ALND.

A declining rate of completion axillary dissection in sentinel lymph node-positive breast cancer patients is associated with the use of a multivariate nomogram.

OBJECTIVE: To compare sentinel lymph node (SLN)-positive breast cancer patients who had completion axillary dissection (ALND) with those who did not, with particular attention to clinicopathologic features, nomogram scores, rates of axillary local recurrence (LR), and changes in treatment pattern over time. BACKGROUND: While conventional treatment of SLN-positive patients is to perform ALND, there may be a low-risk subgroup of SLN-positive patients in whom ALND is not required. A multivariate nomogram that predicts the likelihood of residual axillary disease may assist in identifying this group. METHODS: Among 1960 consecutive SLN-positive patients (1997-2004), 1673 (85%) had ALND ("SLN+/ALND") and 287 (15%) did not ("SLN+/no ALND"). We compare in detail the clinicopathologic features, nomogram scores, and rates of axillary LR between groups. RESULTS: Compared with the SLN+/ALND group, patients with SLN+/no ALND were older, had more favorable tumors, were more likely to have breast conservation, had a lower median predicted risk of residual axillary node metastases (9% vs. 37%, P < 0.001), and had a marginally higher rate of axillary LR (2% vs. 0.4%, P = 0.004) at 23 to 30 months' follow-up; half of all axillary LR in SLN+/no ALND patients were coincident with other local or distant sites. For patients in whom intraoperative frozen section was either negative or not done, the rate of completion ALND declined from 79% in 1997 to 62% in 2003 to 2004 but varied widely by surgeon, ranging from 37% to 100%. For 10 of 10 evaluable surgeons, the median nomogram scores in the SLN+/no ALND group were