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ImportancePostoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.ObjectiveTo evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins.Design, Setting, and ParticipantsThe American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023.Main Outcomes and MeasuresMain outcomes were risk factors for local recurrence.ResultsA total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group.Conclusions and RelevanceIn this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

OBJETIVO: Estimar a prevalência de gestação não planejada (GNP) em oito hospitais públicos universitários, distribuídos nas cinco regiões que compõem o Brasil. MÉTODOS: Análise secundária de um estudo transversal multicêntrico nacional, realizado em oito hospitais universitários públicos, entre 1º de junho e 31 de agosto de 2020, no Brasil. Amostra por conveniência incluindo mulheres que deram à luz em período de sessenta dias consecutivos e atenderam aos seguintes critérios: maiores de 18 anos; idade gestacional acima de 36 semanas no parto; com recém-nascido único e vivo, sem malformações. RESULTADOS: Amostra composta por 1.120 puérperas, das quais 756 (67,5%) declararam que a gravidez não tinha sido programada. A mediana da prevalência de GNP foi de 59,7%. Observou-se diferença significativa na prevalência de GNP entre os hospitais: Campinas (54,8%), Porto Alegre (58,2%), Florianópolis (59%), Teresina (61,2%), Brasília (64,3%), São Paulo (64,6%), Campo Grande (73,9%) e Manaus (95,3%) (p < 0,001). Foram fatores significativamente associados a GNP a idade materna, cor negra, menor renda familiar, maior número de filhos, maior número de pessoas convivendo em casa e não ter parceiro. CONCLUSÃO: na amostra estudada, cerca de dois terços das gestações foram declaradas como não programadas. A prevalência de gestação não planejada teve relação com fatores sociais e demográficos e variou significativamente entre os hospitais universitários avaliados.

Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Abstract The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD + can promote the development of senescence. On the other hand, the low NAD + state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD + metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.

Abstract Background and study aims Significant weight regain affects up to one-third of patients after Roux-en-Y gastric bypass (RYGB) and demands treatment. Transoral outlet reduction (TORe) with argon plasma coagulation (APC) alone or APC plus full-thickness suturing TORe (APC-FTS) is effective in the short term. However, no study has investigated the course of gastrojejunostomy (GJ) or quality of life (QOL) data after the first post-procedure year. Patients and methods Patients eligible for a 36-month follow-up visit after TORe underwent upper gastrointestinal endoscopy with measurement of the GJ and answered QOL questionnaires (RAND-36). The primary aim was to evaluate the long-term outcomes of TORe, including weight loss, QOL, and GJ anastomosis (GJA) size. Comparisons between APC and APC-FTS TORe were a secondary aim. Results Among 39 eligible patients, 29 returned for the 3-year follow-up visit. There were no significant differences in demographics between APC and APC-FTS TORe groups. At 3 years, patients from both groups regained all the weight lost at 12 months, and the GJ diameter was similar to the pre-procedure assessment. As to QOL, most improvements seen at 12 months were lost at 3 years, returning to pre-procedure levels. Only the energy/fatigue domain improvement was kept between the 1- and 3-year visits. Conclusions Obesity is a chronic relapsing disease. Most effects of TORe are lost at 3 years, and redilation of the GJA occurs. Therefore, TORe should be considered iterative rather than a one-off procedure.

72 Background: The integration of biopsychosocial screening programs (BSP) has been promoted as a way by which to identify unmet needs and to provide tailored treatments to patients. Studies have reported mixed outcomes regarding the impact of such services on hospital admissions during cancer treatment. This study sought to evaluate the effect of a BSP on hospital admissions and length of stay among a large, heterogenous sample of patients diagnosed with cancer (March 2020 to December 2021). Methods: We enrolled consecutive patients diagnosed with cancer receiving treatment at a single institution located in the capital of Brazil. We assessed patients’ characteristics via chart review (e.g., age, sex, histology, hospital admission, length of hospitalization). In addition, as per the BSP protocol, patients were assessed via standardized self-report questionnaires (Distress Thermometer, FACT-G, Patient-Generated Subjective Global Assessment), and appropriate interventions are provided. This program was offered at no cost to all patients and engagement was voluntary. We compared the number of hospital admissions and length of stay between groups (patients who participated in the BSP vs. those who did not). Mixed linear models adjusted for selected characteristics (age, type of cancer and disease stage) were assessed. Results: A total of 1014 patients were included in this analysis. From the total sample, 84% participated in the BSP and 20% were hospitalized for an average of 9 days (ranging from 1-80 days). Mostly patients were female (63%), median age was 63 years old. Breast cancer (26%), hematological (18%), and gastrointestinal cancer (14%) were the most common types of cancer, and the majority had advanced disease (stage III-IV; 67%). Compared to those who engaged in the BSP, patient’s characteristics were well balanced, however, the proportion of patients hospitalized during their cancer treatment was higher among patients who did not participate in the BSP (27% vs 8%: P = 0.001), as was the length of hospitalization spent more days in the hospital than patients who has participated in the BSP (M = 9.5 days vs M = 4.2 days; P = 0.001). Conclusions: Our findings suggest the benefit of a BSP in reducing hospitalizations and length of stay among patients with cancer. An integrated model of care may assist in targeting patient’s unmet needs and may positively impact clinical and hospital-based outcomes. This is the first study to evaluate the effects of a BSP among a Brazilian population using real world data.

OBJECTIVE The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I–II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%–93%) and 105/110 low-grade (95%, 95% CI 90%–98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%–18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%–28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%–9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 (ClinicalTrials.gov)

Abstract Nicotinamide adenine dinucleotide (NAD) levels decline during aging, contributing to physical and metabolic dysfunction. The NADase CD38 plays a key role in age‐related NAD decline. Whether the inhibition of CD38 increases lifespan is not known. Here, we show that the CD38 inhibitor 78c increases lifespan and healthspan of naturally aged mice. In addition to a 10% increase in median survival, 78c improved exercise performance, endurance, and metabolic function in mice. The effects of 78c were different between sexes. Our study is the first to investigate the effect of CD38 inhibition in naturally aged animals.

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.