The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified ...(SIRT1–SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2–3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.
The
Saccharomyces cerevisiae chromatin silencing factor Sir2 suppresses genomic instability and extends replicative life span. In contrast, we find that mouse embryonic fibroblasts (MEFs) deficient ...for SIRT1, a mammalian Sir2 homolog, have dramatically increased resistance to replicative senescence. Extended replicative life span of SIRT1-deficient MEFs correlates with enhanced proliferative capacity under conditions of chronic, sublethal oxidative stress. In this context, SIRT1-deficient cells fail to normally upregulate either the p19
ARF senescence regulator or its downstream target p53. However, upon acute DNA damage or oncogene expression, SIRT1-deficient cells show normal p19
ARF induction and cell cycle arrest. Together, our findings demonstrate an unexpected SIRT1 function in promoting replicative senescence in response to chronic cellular stress and implicate p19
ARF as a downstream effector in this pathway.
Aims
Amiodarone reduces the incidence of atrial fibrillation (AF) following coronary artery bypass surgery; however, the benefit of perioperative amiodarone in patients undergoing septal myectomy ...(SM) for obstructive hypertrophic cardiomyopathy (oHCM) has not been studied. We hypothesized that prophylactic amiodarone would reduce the incidence of postoperative AF (POAF) following SM for oHCM.
Methods and Results
A single‐centre, pre‐post intervention open‐label study of oral amiodarone (200 mg twice daily starting 7 days preoperatively and 200 mg once daily continuing for 30 days postoperatively) in patients without prior AF undergoing SM for oHCM from 2014 to 2018. The primary outcome was incident AF within 30 days. Secondary outcomes were unplanned readmission, AF treatment, total and intensive care unit (ICU) length of stay (LOS), and pacemaker implantation for high‐grade atrioventricular (AV) block. 61 patients met inclusion criteria with 34 (55.8%) in the pre‐intervention (control) group and 27 (44.2%) in the post‐intervention (amiodarone) group. The incidence of POAF was 11.0% in the amiodarone group compared with 38.2% in the control group (P = 0.017). After adjusting for age, amiodarone was associated with less POAF adjusted odds ratio (aOR) 0.21; 95% confidence interval (CI) 0.05, 0.76; P = 0.016. ICU (2 days IQR 1, 4 vs. 3 days IQR 2, 4; P = 0.165) and total (6 days IQR 5, 6 vs. 6 days IQR 5, 7; P = 0.165) LOS were similar, as was the rate of pacemaker implantation (7.4% vs. 8.3%, P > 0.999). There were no adverse events associated with amiodarone.
Conclusions
Perioperative oral amiodarone is safe and was associated with lower incidence of POAF following SM for oHCM.
Postbariatric hypoglycemia (PBH) can be a devastating complication for which current therapies are often incompletely effective. More information is needed regarding frequency, incidence, and risk ...factors for PBH.
To examine hypoglycemia symptoms following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) and baseline and in-study risk factors.
Multicenter, at 10 US hospitals in 6 geographically diverse clinical centers.
A prospective, longitudinal cohort study of adults undergoing RYGB or LAGB as part of clinical care between 2006 and 2009 were recruited and followed until January 31, 2015, with baseline and annual postoperative research assessments. We analyzed baseline prevalence and post-operative incidence and frequency of self-reported hypoglycemia symptoms as well as potential preoperative risk factors.
In all groups, postoperative prevalence of hypoglycemia symptoms was 38.5%. Symptom prevalence increased postoperatively from 2.8%-36.4% after RYGB in patients without preoperative diabetes (T2D), with similar patterns in prediabetes (4.9%-29.1%). Individuals with T2D had higher baseline hypoglycemia symptoms (28.9%), increasing after RYGB (57.9%). Hypoglycemia symptoms were lower after LAGB, with 39.1% reported hypoglycemia symptoms at only 1 postoperative visit with few (4.0%) having persistent symptoms at 6 or more annual visits. Timing of symptoms was not restricted to the postprandial state. Symptoms of severe hypoglycemia were reported in 2.6-3.6% after RYGB. The dominant risk factor for postoperative symptoms was preoperative symptoms; additionally, baseline selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor use was also associated with increased risk in multivariable analysis. Weight loss and regain were not related to hypoglycemia symptom reporting.
Hypoglycemia symptoms increase over time after RYGB, particularly in patients without diabetes. In a small percentage, symptoms can be persistent or severe and require hospitalization. Preoperative hypoglycemia symptoms and SSRI/SNRI use in RYGB patients without diabetes is associated with increased risk of symptoms.
The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 ...different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.
This study characterizes the US clinical genetics workforce to inform workforce planning and public policy development.
A 32-question survey was electronically distributed to American Board of ...Medical Genetics and Genomics board-certified/eligible diplomates in 2019. We conducted a descriptive analysis of responses from practicing clinical geneticists.
Of the 491 clinical geneticists responding to the survey, a majority were female (59%) and White (79%), worked in academic medical centers (73%), and many engaged in telemedicine (33%). Clinical geneticists reported an average of 13 new and 10 follow-up patient visits per week. The average work week was 50 hours and the majority (58%) worked over half-time in clinical duties. Providers indicated that 39% of new emergency patients wait 3 days or more, and 39% of nonemergency patients wait over 3 months to be seen. Respondents were geographically concentrated in metropolitan areas and many reported unfilled clinical geneticist job vacancies at their institution of more than 3 years.
With the rapid expansion of genomic medicine in the past decade, there is still a gap between genetics services needed and workforce capacity. A concerted effort is required to increase the number of clinical geneticists and enhance interdisciplinary teamwork to meet increasing patient needs.
Objectives
To investigate the prevalence and associated psychosocial factors of occasional and repetitive direct self‐injurious behavior (D‐SIB), such as self‐cutting, ‐burning, ‐biting, ‐hitting, ...and skin damage by other methods, in representative adolescent samples from 11 European countries.
Methods
Cross‐sectional assessment of adolescents was performed within the European Union funded project, Saving and Empowering Young Lives in Europe (SEYLE), which was conducted in 11 European countries. The representative sample comprised 12,068 adolescents (F/M: 6,717/5,351; mean age: 14.9 ± 0.89) recruited from randomly selected schools. Frequency of D‐SIB was assessed by a modified 6‐item questionnaire based on previously used versions of the Deliberate Self‐Harm Inventory (DSHI). In addition, a broad range of demographic, social, and psychological factors was assessed.
Results
Overall lifetime prevalence of D‐SIB was 27.6%; 19.7% reported occasional D‐SIB and 7.8% repetitive D‐SIB. Lifetime prevalence ranged from 17.1% to 38.6% across countries. Estonia, France, Germany, and Israel had the highest lifetime rates of D‐SIB, while students from Hungary, Ireland, and Italy reported low rates. Suicidality as well as anxiety and depressive symptoms had the highest odds ratios for both occasional and repetitive D‐SIB. There was a strong association of D‐SIB with both psychopathology and risk‐behaviors, including family related neglect and peer‐related rejection/victimization. Associations between psychosocial variables and D‐SIB were strongly influenced by both gender and country. Only a minor proportion of the adolescents who reported D‐SIB ever received medical treatment.
Conclusion
These results suggest high lifetime prevalence of D‐SIB in European adolescents. Prevalence as well as psychosocial correlates seems to be significantly influenced by both gender and country. These results support the need for a multidimensional approach to better understand the development of SIB and facilitate culturally adapted prevention/intervention.
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective ...immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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•SARS-CoV-2 infection induces profound alterations of the myeloid compartment•Mild COVID-19 is marked by inflammatory HLA-DRhiCD11chi CD14+ monocytes•Dysfunctional HLA-DRloCD163hi and HLA-DRloS100Ahi CD14+ monocytes in severe COVID-19•Emergency myelopoiesis with immature and dysfunctional neutrophils in severe COVID-19
Analysis of patients with mild and severe COVID-19 reveals the presence of dysfunctional neutrophils in the latter that is linked to emergency myelopoiesis.
Medical Education 2011: 45: 1101–1110
Context The superiority of retesting over restudying in terms of knowledge retention and skills acquisition has been proven in both laboratory and classroom ...settings, as well as in doctors’ practice. However, it is still unclear how important retesting strategies are to the learning of relevant factual knowledge in undergraduate medical education.
Methods Eighty students in Years 3–5 of medical school in Munich participated in a prospective, randomised, double‐blinded, controlled study in which they were exposed to 30 electronic flashcards designed to help them memorise key factual knowledge in the domain of clinical nephrology. The flashcards were presented in four successive learning cycles, each consisting of a study period and a subsequent test period. Half of all participants were randomised to repetitive studying (restudy group) and half were randomised to repetitive testing (retest group) of successfully memorised flashcards. Knowledge retention was assessed after 1 week and 6 months. Additionally, personal data, self‐reflection on the efficacy of the learning strategies and judgements of learning were obtained by questionnaires.
Results Repetitive testing promoted better recall than repetitive studying after 1 week (p < 0.001). However, after 6 months general recall was poor and no difference between the restudy and retest groups was observed. Time on task and number of trials, in addition to sex, age, performance and psycho‐social background, did not vary between the groups. Self‐predictions of student performance did not correlate with actual performance.
Conclusions In the context of using electronic flashcards, repetitive testing is a more potent learning strategy than repetitive studying for short‐term but not long‐term knowledge retention in clinical medical students. Although students use testing as a learning strategy, they seem to be unaware of its superiority in supporting short‐term knowledge retention.
Upconverting nanoparticles (UCNPs) are an emerging platform for mechanical force sensing at the nanometer scale. An outstanding challenge in realizing nanometer-scale mechano-sensitive UCNPs is ...maintaining a high mechanical force responsivity in conjunction with bright optical emission. This Letter reports mechano-sensing UCNPs based on the lanthanide dopants Yb3+ and Er3+, which exhibit a strong ratiometric change in emission spectra and bright emission under applied pressure. We synthesize and analyze the pressure response of five different types of nanoparticles, including cubic NaYF4 host nanoparticles and alkaline-earth host materials CaLuF, SrLuF, SrYbF, and BaLuF, all with lengths of 15 nm or less. By combining optical spectroscopy in a diamond anvil cell with single-particle brightness, we determine the noise equivalent sensitivity (GPa/√Hz) of these particles. The SrYb0.72Er0.28F@SrLuF particles exhibit an optimum noise equivalent sensitivity of 0.26 ± 0.04 GPa/√Hz. These particles present the possibility of robust nanometer-scale mechano-sensing.
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