Redox regulation of m6A methyltransferase METTL3 in ß-cells controls the innate immune response in type 1 diabetes.

Type 1 diabetes (T1D) is characterized by the destruction of pancreatic ß-cells. Several observations have renewed the interest in ß-cell RNA sensors and editors. Here, we report that N6-methyladenosine (m6A) is an adaptive ß-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m6A writer methyltransferase 3 (METTL3) levels increase drastically in ß-cells at T1D onset but rapidly decline with disease progression. m6A sequencing revealed the m6A hypermethylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-ßH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in ß-cells delayed diabetes progression in the non-obese diabetic mouse model of T1D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human ß-cells. Collectively, we report that m6A regulates the innate immune response at the ß-cell level during the onset of T1D in humans.

Is the Pentagon-Copying Task More than a Cognitive Feature? Associations with Handgrip Strength, Gait Speed, and Frailty in Older Adults.

BACKGROUND: The pentagon copy is a sensitive item to the prediction of cognitive decline and dementia. Cognitive and physical/motor decline are able to accelerate the evolution of each other by representing a common pathway toward frailty. OBJECTIVES: The objective of the study was to investigate the association of the pentagon-copying task with physical and motor performances and with frailty, in a sample of older adults. METHOD: This observational, cross-sectional, and single-center study was conducted in a Geriatric Outpatients Clinic. Subjects aged ≥65 years were consecutively recruited, on a voluntary basis. Subjects with positive psychiatric history, with a severe neurocognitive disorder, with severe limitations on the upper limbs and/or reporting sensory deficits were excluded. The pentagon-copying task was scored from the Mini-Mental State Examination; the Qualitative Scoring Pentagon Test (QSPT) was also used. Handgrip strength was measured; a 46-item Frailty Index was calculated; in subjects with autonomous walking, a 4-meter gait speed was also measured. RESULTS: The study included 253 subjects (mean age 80.59 ± 6.89 years). Subjects making a wrong pentagon copy showed greater odds of exhibiting a strength deficit (OR = 3.57; p = 0.001) and of being frail (OR = 4.80; p < 0.001), and exhibited a slower gait. The QSTP score was significantly correlated with handgrip strength (r = 0.388) and gait speed (r = 0.188) and inversely correlated with frailty (r = -0.428); the QSTP score was significantly different between the quartiles of handgrip strength and frailty. CONCLUSIONS: The pentagon-copying task might also be confirmed as a quick screening tool of aging trajectories toward frailty by jointly evaluating cognitive and physical performances.

Total Talar Prosthesis, Learning from Experience, Two Reports of Total Talar Prosthesis after Talar Extrusion and Literature Review.

Recently, total talar prosthesis has been proposed to substitute the talus during the management of complex talar lesions such as talar extrusion, comminuted talar fractures, or avascular necrosis. Herein, we report two cases of talar extrusion treated with total talar replacement after a high-intensity trauma. Both cases subsequently required revision surgery due to degenerative changes of the tibial plafond (arthrodesis in the first case, conversion to a total ankle prosthesis in the latter). We report and analyze the literature concerning total talar replacement to discuss strategies that could help improve prosthesis survival and reduce the incidence of osteoarthritis.

The dramatic increase in sudden cardiac deaths and the alarming low survival: A global call to action to improve outcome with the engagement of tertiary education system.

The number of out-of-hospital cardiac arrests, cause of disability and death, has dramatically increased worldwide, but despite the progress, the incidence of survival does not appear to have increased significantly. Bystander cardiopulmonary resuscitation (CPR) remains the principal factor in saving out-of-hospital cardiac arrest victims. Analyzing the immense efforts produced by states and professional organizations to train people in CPR skills for immediate intervention in the occurrence of a cardiac arrest, the primary global strategy is centered on CPR education and training for schoolchildren. But the rate of CPR training remains low, with wide differences among communities. The concept of CPR training for schoolchildren to increase bystander CPR rates needs to be implemented. We suggest a global call to action for the tertiary education system for CPR learning and training, including all undergraduate students regardless of the degree course, as a possible method to improve the traditional CPR training today centered on the secondary education system. Extending CPR training courses to the university educational system could significantly increase the number of people educated in life-saving maneuvers. The final objective is to improve the survival rate of patients with out-of-hospital primary cardiac arrest, which has dramatically increased worldwide.

Efficacy and Safety of Biological Therapies and JAK Inhibitors in Older Patients with Inflammatory Bowel Disease.

With the introduction of more and more monoclonal antibodies selectively targeting various mediators of the immune system, together with Janus-Kinase (JAK)-inhibitors with variable affinities towards different JAK subtypes, the available therapeutic options for the treatment of inflammatory bowel diseases (IBD) have undergone an acceleration in the last five years. On the other hand, the prevalence of IBD patients over 65-years-old is steadily increasing, and, with this, there is a large population of patients that presents more comorbidities, polypharmacy, and, more frequently, frailty compared to younger patients, exposing them to potentially major risks for adverse events deriving from newer therapies, e.g., infections, cardiovascular risks, and malignancies. Unfortunately, pivotal trials for the commercialization of new therapies rarely include older IBD patients, and those with serious comorbidities are virtually excluded. In the present review, we focus on existing literature from pivotal trials and real-world studies, analyzing data on efficacy/effectiveness and safety of newer therapies in older IBD patients with special emphasis on comorbidities and frailty, two distinct but intercorrelated aspects of the older population since age by itself seems to be of minor importance.

Quality of Life (QoL) in Patients with Chronic Inflammatory Bowel Diseases: How Much Better with Biological Drugs?

BACKGROUND: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic and disabling diseases that affect patient health-related quality of life (HRQoL). IBD patients are frequently exposed to high levels of stress and psychological distress. Biological drugs have been proven to reduce inflammation, hospitalization, and most of the complications that characterize IBDs; their potential contribution to patients' HRQoL remains to be explored. AIM: To evaluate and compare any change in the HRQoL and markers of inflammation in IBD patients undergoing biological drugs (infliximab or vedolizumab). MATERIAL AND METHODS: A prospective observational study was conducted on a cohort of IBD patients, aged >18 years, who were prescribed with infliximab or vedolizumab. Demographic and disease-related data at baseline were collected. Standard hematological and clinical biochemistry parameters, including C-reactive protein (CRP), white blood cells count (WBC), erythrocytes sedimentation rate (ESR), and α1 and α2 globulins were measured after a 12-h fast at baseline (T0), after 6 weeks (T1), and at 14 weeks (T2) of biological treatment. Steroid use, disease activity as measured by the Harvey-Bradshaw index (HBI) and partial Mayo score (pMS) for the CD and UC, respectively, were also recorded at each timepoint. The Short Form 36 Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy (FACIT-F), and Work Productivity and Activity Impairment-General Health Questionnaire (WPAI:GH) were administered to each patient at baseline, T1, and T2 to address the study aims. RESULTS: Fifty eligible consecutive patients (52% with CD and 48% with UC) were included in the study. Twenty-two patients received infliximab and twenty-eight received vedolizumab. We noted a significant reduction in the CRP, WBC, α1, and α2 globulins from T0 to T2 (p = 0.046, p = 0.002, p = 0.008, and p = 0.002, respectively). Participants showed a significant decrease in steroid administration during the observation period. A significant reduction in the HBI of CD patients at all three timepoints and a similarly significant decrease in the pMS of UC patients from baseline to T1 were recorded. Statistically significant changes were observed in all questionnaires during follow-up as well as an overall improvement in the HRQoL. The interdependence analysis carried out between the biomarkers and the scores of the individual subscales showed a significant correlation between the variation (Δ) of the CRP, Hb, MCH, and MCV with physical and emotional dimensions of the SF-36 and FACIT-F tools; work productivity loss expressed by some of the WPAI:GH items negatively correlated with the ΔWBC and positively with the ΔMCV, ΔMCH, and Δ α1 globulins. A sub-analysis according to the type of treatment showed that patients receiving infliximab experienced a more pronounced improvement in their HRQoL (according to both SF-36 and FACIT-F) compared with patients receiving vedolizumab. CONCLUSIONS: Both infliximab and vedolizumab played an important role in contributing to the improvement of the HRQoL in IBD patients by also reducing inflammation and, consequently, steroid use in patients with an active disease. HRQoL, being one of the treatment goals, should also be assessed when taking charge of IBD patients to assess their clinical response and remission. The specific correlation between the biomarkers of inflammation and life's spheres, as well as their possible role as clinical markers of HRQoL, should be further investigated.

Excess pancreatic elastase alters acinar-ß cell communication by impairing the mechano-signaling and the PAR2 pathways.

Type 1 (T1D) or type 2 diabetes (T2D) are caused by a deficit of functional insulin-producing ß cells. Thus, the identification of ß cell trophic agents could allow the development of therapeutic strategies to counteract diabetes. The discovery of SerpinB1, an elastase inhibitor that promotes human ß cell growth, prompted us to hypothesize that pancreatic elastase (PE) regulates ß cell viability. Here, we report that PE is up-regulated in acinar cells and in islets from T2D patients, and negatively impacts ß cell viability. Using high-throughput screening assays, we identified telaprevir as a potent PE inhibitor that can increase human and rodent ß cell viability in vitro and in vivo and improve glucose tolerance in insulin-resistant mice. Phospho-antibody microarrays and single-cell RNA sequencing analysis identified PAR2 and mechano-signaling pathways as potential mediators of PE. Taken together, our work highlights PE as a potential regulator of acinar-ß cell crosstalk that acts to limit ß cell viability, leading to T2D.

Postprandial Hypotension and Impaired Postprandial Sustained and Selective Attention in Older Inpatients: Is There a Link?

OBJECTIVES: The study aimed to investigate the prevalence of postprandial hypotension (PPH) in older inpatients, to verify the overall postprandial behavior of blood pressure and attentional performances, and to explore the overall associations between blood pressure (including PPH) and attentional performances. Eventually, we aimed to investigate differences on PPH, blood pressure values and attentional performances based on the subjects' frailty status. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A sample of older inpatients at the Geriatric Unit of the University Hospital of Messina (Italy). METHODS: Basal, preprandial, and postprandial blood pressures (75 minutes after the meal) were measured for each patient; PPH was detected according to its empirical definition. Global cognitive functioning, and sustained and selective attention were assessed; a 46-item Frailty Index was calculated. RESULTS: The sample consisted of 112 inpatients (54 females), with a mean age of 80.9 years. The prevalence of PPH was 30.4%; in the postprandial window, a reduction in blood pressure between 10 and 20 mm Hg and a reduction of >20 mm Hg were reported by 27.1% and 29.9% of inpatients, respectively. In the postprandial evaluation, sustained and selective attention markedly decreased. No significant associations were found between PPH occurrence and the postprandial dip of attentional performances, and no significant cognitive differences were found between inpatients with and without PPH. On the other hand, reduced postprandial attentional performances were associated especially with preprandial lower systolic and diastolic blood pressure values. Ultimately, no significant differences in PPH occurrence were found between frail and nonfrail inpatients; frail inpatients significantly exhibited also an overall lower cognitive functioning. CONCLUSIONS AND IMPLICATIONS: In our sample, PPH and impaired postprandial attentional performances were not associated, even though this association deserves further investigation. In hospitalized older adults, the accurate management of blood pressure levels appears relevant, because we evidenced that low blood pressure (especially preprandial) was associated with poor attentional functioning. Although the plausible occurrence of several interfering and confounder factors was observed in an acute care setting, we consider that the screening of attentional functioning among hospitalized older patients could be helpful.

Association between pain, arthropathy and health-related quality of life in patients suffering from acromegaly. A cross-sectional study.

INTRODUCTION: Despite successful therapy, acromegalic patients have reduced health-related quality of life (HRQoL) compared to healthy controls. Finding predictors of poor HRQoL can be crucial to improving these patients' global health state.  Aim: The primary objective of the study was to find out predictors of HRQoL. Secondary objectives were: (I) to determine correlations with AcroQoL subscales, and (II) to identify predictors for subscales. MATERIALS AND METHODS: In this cross-sectional study conducted in 2019 at the Messina Policlinic Hospital, 45 acromegalic patients were assessed at the Physical and Rehabilitative Medicine Ambulatory. During routine outpatient clinic attendances, the following questionnaires were administered: Acromegaly Quality of Life Questionnaire (AcroQoL), Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC). We furthermore included the following variables obtained by medical record review: age, BMI, disease duration, previous surgery (Yes/No), previous radiotherapy (Yes/No), use of GH lowering medications (Yes/No), hypertension (Yes/No), diabetes mellitus (Yes/No), and biochemical control of the disease (Yes/No): immunoradiometric assays were employed to serum GH and IGF-1 measurements to identify biochemical control of the disease. Correlation between outcome measures and AcroQoL has been performed. Pearson's r was calculated for continuous data following normal distribution (AcroQoL, PASQ, AcroQoL-B, AcroQoL-R, WOMAC-P), while Spearman's rank order correlation was calculated for non-normally distributed data (WOMAC, WOMAC-F, WOMAC-S, AcroQoL-P) and point-biserial correlation for binary variables (biochemically controlled disease, use of GH lowering medications, radiotherapy, surgery).  The same correlation analysis was performed for the AcroQoL subscales. Multiple linear regression with backwards, stepwise analysis was used to assess the influence on AcroQoL of correlated variables. RESULTS: AcroQoL was strongly negatively correlated with PASQ (r=-0.700, p<0.001) and negatively correlated with WOMAC [rs (43)=-0.530, p<0.001] and among WOMAC subscales with WOMAC-Physical fitness [rs (43)=-0.518, p<0.001] WOMAC-Pain [r (43)=-0.428, p=0.003], WOMAC-Stiffness [rs (43)=-0.393, p=0.007], and radiotherapy [r (43) =-0.314, p=0.035]. After univariate stepwise regression, PASQ was the strongest independent predictor of AcroQoL, with R2 of 0.392 [F (1,43)=27.695, p<0.001]. CONCLUSIONS: This study shows that the severity of painful symptoms is the most important predictor of HRQoL in patients with acromegaly; at the same time, acromegalic arthropathy leads to pain and to a variable amount of functional impairment, exerting great impact on the patient's perception of his health status. Measure of the progression of arthropathy and symptomatic management could lead to a great HRQoL benefit.

Is the relationship between erythropoiesis and renal function one of the secrets of extreme longevity?

BACKGROUND AND AIMS: Renal function and erythropoiesis could be impaired with advancing age. Neutrophil gelatinase-associated lipocalin (NGAL) as well as erythropoietin (EPO) levels are two useful biomarkers of the renal status. In advanced age, the relationships between NGAL, EPO and hemoglobin (Hb) levels remains unknown. The aim of the present study is to evaluate the relationship between renal function and erythropoiesis in a small cohort of centenarians. METHODS AND RESULTS: We observed thirty-one healthy centenarians with normal hemoglobin levels, a mild reduction in eGFR and no need of erythropoiesis support. We found a significant inverse association between NGAL and GFR, hemoglobin levels and EPO, confirming the key role of the renal function on erythropoiesis also in extreme longevity. A gender difference emerged, showing female participants with lower eGFR and Hb values more than males. CONCLUSIONS: Our findings suggested a new link between renal function, erythropoiesis and longevity in centenarians and these could have relevant implications in clinical practice. These findings could explain why very old subjects presenting a slight GFR reduction seemed not to be exposed to a significant risk of mortality.

Redox Regulation of m 6 A Methyltransferase METTL3 in Human ß-cells Controls the Innate Immune Response in Type 1 Diabetes.

Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing ß-cells. Several observations have renewed interest in the innate immune system as an initiator of the disease process against ß-cells. Here, we show that N 6 -Methyladenosine (m 6 A) is an adaptive ß-cell safeguard mechanism that accelerates mRNA decay of the 2'-5'-oligoadenylate synthetase (OAS) genes to control the antiviral innate immune response at T1D onset. m 6 A writer methyltransferase 3 (METTL3) levels increase drastically in human and mouse ß-cells at T1D onset but rapidly decline with disease progression. Treatment of human islets and EndoC-ßH1 cells with pro-inflammatory cytokines interleukin-1 ß and interferon α mimicked the METTL3 upregulation seen at T1D onset. Furthermore, m 6 A-sequencing revealed the m 6 A hypermethylation of several key innate immune mediators including OAS1, OAS2, and OAS3 in human islets and EndoC-ßH1 cells challenged with cytokines. METTL3 silencing in human pseudoislets or EndoC-ßH1 cells enhanced OAS levels by increasing its mRNA stability upon cytokine challenge. Consistently, in vivo gene therapy, to prolong Mettl3 overexpression specifically in ß-cells, delayed diabetes progression in the non-obese diabetic (NOD) mouse model of T1D by limiting the upregulation of Oas pointing to potential therapeutic relevance. Mechanistically, the accumulation of reactive oxygen species blocked METTL3 upregulation in response to cytokines, while physiological levels of nitric oxide promoted its expression in human islets. Furthermore, for the first time to our knowledge, we show that the cysteines in position C276 and C326 in the zinc finger domain of the METTL3 protein are sensitive to S-nitrosylation (SNO) and are significant for the METTL3 mediated regulation of OAS mRNA stability in human ß-cells in response to cytokines. Collectively, we report that m 6 A regulates human and mouse ß-cells to control the innate immune response during the onset of T1D and propose targeting METTL3 to prevent ß-cell death in T1D.

Emotion regulation strategies and difficulties in older adults: A systematic review.

OBJECTIVES: The purpose of this systematic review was to assess the types of emotion regulation (ER) strategies used and difficulties in emotion regulation experienced by older adults, within the theoretical frameworks proposed by Gross, and by Gratz and Roemer, respectively. METHODS: A systematic search was conducted using principal electronic scientific databases (PubMed, Scopus, and Web of Science). The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. RESULTS: The final number of articles included was 44. Older adults reported a higher use of adaptive ER strategies, as well as fewer difficulties in ER, compared with younger adults. Findings from this review also suggest that the use of maladaptive ER strategies can also expose older adults to psychological distress, and may affect their adaptation to negative disease-related outcomes more common in later life. CONCLUSIONS: Older adults generally showed a greater emotional control compared with younger subjects. Adaptive control strategies, rather than maladaptive control strategies, were correlated with more positive outcomes for psychological distress and adaptation to chronic diseases. CLINICAL IMPLICATIONS: Understanding the nature of ER processes in older adults may contribute to implement tailored interventions aimed at reinforcing adaptive ER processes.

E2F1 transcription factor mediates a link between fat and islets to promote ß cell proliferation in response to acute insulin resistance.

Prevention or amelioration of declining ß cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by ß cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced ß cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks ß-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of ß cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables ß cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote ß cell compensation.

Long-Term Influence of Locus of Control and Quality of Life on Metabolic Profile in Elderly Subjects with Type 2 Diabetes.

BACKGROUND: The Locus of Control (LOC) is a mental disposition indicating the individuals' belief that disease-related outcomes are under their own control (Internal), dependent on others (External), or dependent on chance (Chance). Quality of Life (QoL) and LOC may have complex effects on self-care activities and diabetes management in subjects with type 2 diabetes (T2D). The aim of the present study was to evaluate the predictive role of LOC and QoL scores on metabolic control in elderly T2D outpatients, secondly evaluating potential gender differences. METHODS: An extensive set of questionnaires was administered to a group of consecutive elderly T2D outpatients on oral glucose-lowering drugs attending a single diabetes center. Personal and clinical variables were analyzed at baseline (between 1 February and 31 March 2015) and after 6 years of follow-up. RESULTS: At baseline, study participants showed an overall good metabolic control. Diabetes Specific Quality of Life (DSQoL) scores indicated an overall good QoL in both genders, with a higher DSQoL satisfaction score in women. Both genders presented higher scores in the LOC-Internal domain, with men reaching higher scores in the LOC-External domain than women. At the 6-years follow-up, subjects with baseline higher LOC-External score presented better metabolic outcome. In the regression analysis, LOC-External score was an independent predictor of good metabolic control maintenance, but this result was only statistically significant in men. CONCLUSIONS: LOC scores may influence long-term glycemic control in elderly T2D patients on oral glucose-lowering drugs.

Gender and Psychosocial Differences in Psychological Resilience among a Community of Older Adults during the COVID-19 Pandemic.

The study aimed at exploring gender and additional sociodemographic differences in psychological resilience, as well as the association between resilience and psychological distress in older adults, during the first lockdown in Italy, due to the COVID-19 pandemic. Participants attended an online survey during the first lockdown in May 2020. Psychological distress was assessed through the Depression Anxiety Stress Scale-21, the Resilience Scale (RS) was administered to evaluate psychological resilience, and sociodemographic variables were also collected. The study involved 108 community older adults (mean age 70.02 ± 3.5 years). Comparisons revealed that women reported significantly lower total scores of RS (p = 0.027), as well as lower levels of resilience-related domains, namely Meaningfulness (p = 0.049), Self-Reliance (p = 0.011), Perseverance (p = 0.035), and Existential Aloneness (p = 0.014), compared to men. Significantly higher RS scores were found in older adults being involved in a relationship, compared to those not involved in relationships (p = 0.026), and in older adults with children (p = 0.015), compared to those without offspring, suggesting the importance for older adults of not dealing alone with such a dramatic and stressful event, such as the pandemic. Negative correlations were found between psychological resilience and stress, depression, and anxiety. Linear regressions revealed that lower RS total scores, as well as lower scores in the majority of the RS scales, were associated with greater levels of stress, greater levels of anxiety, and greater levels of depressive symptoms. This study suggested that older women might appear more vulnerable in facing the pandemic, compared to men; having not lived alone through the lockdown period might also be considered as a factor of resilience for older adults.

Trabecular bone score and phalangeal quantitative ultrasound are associated with muscle strength and fracture risk in hemodialysis patients.

There is growing interest in the relationship between chronic kidney disease (CKD) and fragility fracture risk. Bone mineral density (BMD) is a major determinant of bone strength, although its role as a predictor of fracture in advanced CKD and hemodialysis is still under debate. We aimed to further investigate surrogates of bone quality and their associations with muscle strength and fracture risk in hemodialysis. Multiple clinical risk factors for fracture and an estimated 10-year probability of fracture, BMD at lumbar spine and femur, trabecular bone score (TBS), X-ray vertebral morphometry, phalangeal bone quantitative ultrasonography (QUS), tibial pulse-echo ultrasonography (PEUS), and handgrip strength were evaluated in a setting of hemodialysis patients in treatment with acetate-free biofiltration (AFB) or bicarbonate hemodialysis. The bone ultrasound measurements, both at phalangeal and tibial sites, were significantly associated with lumbar and femoral DXA values. Handgrip strength was significantly associated with the 10-year probability of fracture (r = -0.57, p < 0.001 for major fractures and r = -0.53, p < 0.001 for hip fracture, respectively), with femur neck, total femur, and L1-L4 BMD values (r = 0.47, p = 0.04; r = 0.48, p = 0.02; r = 0.58, p = 0.007, respectively), with TBS at the lumbar spine (r = 0.71, p < 0.001) and with the phalangeal QUS measure of AD-SoS (r = 0.369, p = 0.023). In the hemodialysis group, 10 participants (24.3%) reported at least one morphometric vertebral fracture (Vfx); conversely, only six participants (15%) showed Vfx in the control group. In the hemodialysis group, participants with Vfx compared with participants without Vfx reported significantly different TBS, bone transmission time (BTT), cortical thickness, and handgrip strength (p < 0.05). At multiple regression analysis, by identifying as dependent variable the 10-year fracture risk for major fracture, after correcting for age, BMI, time since dialysis, AD-SoS, cortical bone thickness, and handgrip strength, only BTT (ß = -15.21, SE = 5.91, p = 0.02) and TBS (ß = -54.69, SE = 21.88, p = 0.02) turned out as independently associated with fracture risk. In conclusion, hemodialysis patients showed a higher fracture risk and lower surrogate indices of bone strength as TBS and QUS parameters. In this cohort of patients, handgrip strength measurements appeared to be a useful instrument to identify high-fracture-risk subjects.

Single-nucleus RNA-Seq reveals singular gene signatures of human ductal cells during adaptation to insulin resistance.

Adaptation to increased insulin demand is mediated by ß cell proliferation and neogenesis, among other mechanisms. Although it is known that pancreatic ß cells can arise from ductal progenitors, these observations have been limited mostly to the neonatal period. We have recently reported that the duct is a source of insulin-secreting cells in adult insulin-resistant states. To further explore the signaling pathways underlying the dynamic ß cell reserve during insulin resistance, we undertook human islet and duct transplantations under the kidney capsule of immunodeficient NOD/SCID-γ (NSG) mouse models that were pregnant, were insulin-resistant, or had insulin resistance superimposed upon pregnancy (insulin resistance + pregnancy), followed by single-nucleus RNA-Seq (snRNA-Seq) on snap-frozen graft samples. We observed an upregulation of proliferation markers (e.g., NEAT1) and expression of islet endocrine cell markers (e.g., GCG and PPY), as well as mature ß cell markers (e.g., INS), in transplanted human duct grafts in response to high insulin demand. We also noted downregulation of ductal cell identity genes (e.g., KRT19 and ONECUT2) coupled with upregulation of ß cell development and insulin signaling pathways. These results indicate that subsets of ductal cells are able to gain ß cell identity and reflect a form of compensation during the adaptation to insulin resistance in both physiological and pathological states.

Changes in Cognitive and Functional Status and in Quality of Life of Older Outpatients during the COVID-19 Pandemic.

BACKGROUND: Older adults denoted one of the populations that mostly suffered from the consequences of the COVID-19 pandemic. The cost of confinement was paid in terms of social isolation, distance from relatives and friends, lack of social support, and limited access to the healthcare system, which had a negative impact on health of older adults with comorbidities and frailty. OBJECTIVES: The purpose of the present study was to report the consequences of the COVID-19 pandemic on cognitive performances, functional status, and health-related quality of life among frail outpatients, compared to pre-pandemic status. METHOD: The current sample was part of a larger sample of frail and pre-frail outpatients, who were first evaluated at the clinic between April and May 2019 and who underwent a first follow-up evaluation between April and May 2020. Those outpatients who have undergone the first follow-up evaluation were contacted between April and May 2021 and were asked to voluntarily participate in a second telephone-based evaluation. Cognitive performances (through Mini Mental State Examination - MMSE), functional independency in basic and instrumental daily activities, physical and mental components of health-related quality of life (SF-12 PCS and SF-12 MCS, respectively) were evaluated and compared to previous evaluations. RESULTS: Seventy one outpatients (mean age of 80.69 years) completed the present follow-up evaluation. Patients reported significantly lower cognitive performances (mean MMSE 19.37; p < 0.001), lower physical quality of life (mean score 31.69; p < 0.001), and lower mental quality of life (mean score 38.79; p < 0.001) compared to both pre-pandemic baseline and the first follow-up. Moreover, patients showed a significantly reduced independency in basic daily activities (mean score 3.8; p = 0.004), and a significantly reduced independency in managing telephone (p = 0.012) and medications (p = 0.035), compared to baseline. CONCLUSIONS: The COVID-19 pandemic has been a prolonged stressor over time, which has markedly affected health-related quality of life of outpatients, and it can be considered a stressor that might have contributed to the patients' greater cognitive and functional vulnerability.