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OBJECTIVE BEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS Participants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA1c at 6 months. RESULTS Baseline characteristics were similar among the three groups (mean HbA1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group. CONCLUSIONS BEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.

Although it represents a valid alternative for patients with type 1 diabetes (T1DM) with insufficient glycemic control and/or with recurrent hypoglycemia, insulin pump therapy (Continuous Subcutaneous Insulin Infusion, CSII) in Italy is nowadays still relatively uncommon. The following review aims to investigate the barriers that limit the transition to CSII and the reasons behind the widespread cases of drop-out, particularly evident in younger patients. Among the interventions that could contribute to the solution of the problem, catheter-less insulin pumps (or patch-pumps) will be described: a tool potentially able to reduce, if not eliminate, some of the main obstacles encountered by patients. In particular, a new opportunity has become available today thanks to the evolution of the generation of catheter-less insulin pumps represented by Accu-Chek® Solo (Roche Diabetes Care GmbH), therefore three clinical cases of patients with T1DM undergoing therapy with the Accu-Chek® Solo insulin pump will be presented and discussed herein.

The purpose of this case study was to assess the degree to which a 12-month power-based resistance-training program improved bone mineral density (BMD) and fall risk for a 70-year-old postmenopausal woman with osteoporosis and increased risk of falling. After an eight-week strength-development phase, we had the patient perform 44 weeks of resistance training with maximal force mobilization by instructing her to complete as many repetitions as possible during each 60-s set. We used dual-energy X-ray absorptiometry (DEXA) to assess BMD and Dynamic Gait Index (DGI) to assess fall risk before and after the intervention. Post compared to pre-training testing indicated an increase in BMD in the lumbar spine (24%) and femoral neck (29%) resulting in changes in T-score of 0.7 and 0.4 SD, respectively. Testing also revealed a seven-point change in DGI which improved her status to "safe ambulator." After a 12-month period of power training, BMD was increased and fall risk was reduced for a postmenopausal woman with osteoporosis and increased risk of falling.

Background: Blood flow restriction (BFR) applied during low intensity resistance training (LIRT) exercise produces hypertrophy and strength gains equivalent to traditional training. The effectivene...

Every year in Italy, there are about 20,000 road accidents involving pedestrians, with a significant number of injuries and deaths. Out of these, about 30% occur at pedestrian crossings, where pedestrians should be protected the most. Here, we propose a new accident prediction model to improve pedestrian safety assessments that allows us to accurately identify the sites with the largest potential safety improvements and define the best treatments to be applied. The accident prediction model was developed using the ISTAT dataset, including information about the fatal and injurious crashes that occurred in Italy in a 5-year period. The model allowed us to estimate the risk level of a road section through a machine-learning approach. Gradient Boosting seems to be an appropriate tool to fit classification models for its flexibility that allows us to capture non-linear relationships that would be difficult to detect via a classical approach. The results show the ability of the model to perform an accurate analysis of the sites included in the dataset. The locations analyzed have been classified based on the potential risk in the following three classes: High, medium, and low. The proposed model represents a solid and reliable tool for practitioners to perform accident analysis with pedestrian involvement.

Background. Diabetes in pregnancy is associated with an increased risk to the woman and to the developing fetus. Currently, there is no consensus on the optimal management strategies for the follow-up and the timing of delivery of pregnancies affected by gestational and pregestational diabetes, with different international guidelines suggesting different management options. Materials and Methods. We conducted a retrospective cohort study from January 2017 to January 2021, to compare maternal and neonatal outcomes of pregnancies complicated by gestational and pregestational diabetes, followed-up and delivered in a third level referral center before and after the introduction of a standardized multidisciplinary management protocol including diagnostic, screening, and management criteria. Results. Of the 131 women included, 55 were managed before the introduction of the multidisciplinary management protocol and included in group 1 (preprotocol), while 76 were managed according to the newly introduced multidisciplinary protocol and included in group 2 (after protocol). We observed an increase in the rates of vaginal delivery, rising from 32.7% to 64.5% ( P < 0.001 ). No differences were found in neonatal outcomes, and the only significant difference was demonstrated for the rates of fetal macrosomia (20% versus 5.3%, P : 0.012). Therefore, the improvements observed in the maternal outcomes did not impact negatively on fetal and neonatal outcomes. Conclusion. The introduction of a standardized multidisciplinary management protocol led to an improvement in the rates of vaginal delivery and in the rate of successful induction of labor in our center. A strong cooperation between obstetricians, diabetologists, and neonatologists is crucial to obtain a successful outcome in women with diabetes in pregnancy.

Purpose This study is aimed at evaluating changes in metrics of glucose control in home-isolated patients with type 1 diabetes and COVID-19 using a continuous glucose monitoring (CGM) system. Methods We included adults aged 18–45 years with type 1 diabetes, using CGM, followed by telemedicine at a Southern Italian University Hospital. Thirty-two home-quarantined subjects with SARS-CoV-2 positive swab constituted the COVID-19 group. Thirty age-matched diabetic individuals without COVID-19 formed the control group. The effects of COVID-19 on glycemic control in patients infected were assessed at different time points [2 weeks before-COVID-19 (Time 1), 2 weeks during-COVID-19 (Time 2) and 2 weeks after COVID-19 (Time 3)] and compared with those without infection. Results A significant reduction of TIR (Time 1 vs Time 2, %, 60.1 ± 16.6 vs 55.4 ± 19.2, P = 0.03), associated with a significant increase of TAR level 2 (10.1 ± 7.3 vs 16.7 ± 12.9, P P P = 0.04), mean glucose values (mg/dL, 160.2 ± 26.5 vs 175.5 ± 32.6, P = 0.001) and standard deviation (59.2 ± 13.1 vs 68.6 ± 17.7, P = 0.001) was observed in patients with COVID-19. No significant change of glycemic metrics was found in the NO COVID-19 group across the time. Conclusion Young home-isolated patients with type 1 diabetes and COVID-19 showed a worsening of glucose control during COVID-19, as compared with age-matched diabetic subjects without the infection.

To investigate the longitudinal growth trajectories of disease-specific quality of life (QoL) dimensions and their associations over 1 year.A longitudinal design. Data were collected between February 2015-May 2017.Four hundred and fifteen stroke survivors (mean age 70.6 years; 81% ischaemic stroke) were recruited after discharge from rehabilitation hospitals and were followed up every 3 months for 1 year. Changes in Stroke Impact Scale (SIS) dimension scores were evaluated using hierarchical linear models (HLMs) and linear, logarithmic, quadratic, and cubic time slope.We observed a significant linear and quadratic increase in most SIS dimensions from the baseline to 12-month follow-up, especially in physical dimensions. The communication dimension was stable over time, while the memory dimension increased only linearly. Higher physical dimension scores were significantly associated with lower age, hypercholesterolaemia, and better physical functioning at baseline, while higher communication was associated with lower age, better physical functioning, and a diagnosis of peripheral vascular disease. Better memory was associated with lower age, married status, better physical functioning, and left-hemisphere stroke. Better participation was associated with lower age and better physical functioning. No significant associations were observed for emotion.This study provides important information about the trajectories of stroke survivors' specific QoL and their associated variables.Stroke has a great impact on stroke survivors' QoL. Disease-specific QoL significantly increases from the baseline to 12-month follow-up, especially in physical dimensions. Lower age, hypercholesterolaemia, better physical functioning, and diagnosis of peripheral vascular disease seem to be associated with better QoL. Through the analyses of associated variables, we identified stroke survivors who are more at risk and who need more tailored interventions to improve their physical, psychological, emotional, and social dimensions.目的: 研究疾病特异性生活质量 (QoL) 各维度在1年内的纵向增长轨迹及其关联性。 设计: 一项纵向设计。在2015年2月至2017年5月之间收集数据。 方法: 招募了415名从康复医院出院的脑卒中幸存者 (平均年龄70.6岁; 81%为缺血性脑卒中) , 在1年内每隔3个月进行一次随访。使用多层线性模型 (HLMs) 和线性、对数、二次方和三次方时间斜率评估脑卒中影响量表 (SIS) 维度评分的变化。 结果: 据观察, 从基线检查到12个月的随访, 大多数脑卒中影响量表维度都呈显著的线性二次方增加趋势, 尤其是身体维度。沟通维度随着时间的推移保持稳定, 而记忆维度仅呈线性增加趋势。较高的身体维度评分与基线时较低的年龄、高胆固醇血症和较好的身体机能显著相关, 而较高的沟通维度评分与较低的年龄、较好的身体机能和周围血管疾病的诊断相关。较高的记忆维度评分与较低的年龄、已婚状态、较好的身体机能和左侧半脑中风相关。较高的参与维度评分与较低的年龄和较好的身体机能有关。情绪方面没有观察到显著的关联。 结论: 本研究提供了有关脑卒中幸存者的特定生活质量及其相关变量的重要轨迹信息。 影响: 脑卒中对脑卒中幸存者的生活质量影响很大。从基线检查到12个月的随访, 疾病特异性生活质量显著提高, 尤其是身体方面。较低的年龄、高胆固醇血症、较好的身体机能和周围血管疾病的诊断似乎与较高的生活质量相关。通过对相关变量的分析, 我们发现脑卒中幸存者的风险更高, 需要对脑卒中幸存者采取更具针对性的干预措施, 以改善脑卒中幸存者的生理、心理、情感和社会维度。.

Aims: This study aims at evaluating the metrics of glycemic control in people with type 1 diabetes using the hybrid closed loop (HCL) system during the COVID-19 lockdown. Methods: This is a retrospective study of thirty adults with type 1 diabetes using HCL and followed with telemedicine at an Italian University Hospital. Data on metrics of glucose control were collected at different times: two weeks before the lockdown (Time 0), first two weeks of lockdown (Time 1), last two weeks of lockdown (Time 2) and first two weeks after the lockdown (Time 3). The primary endpoint was the change in glucose management indicator (GMI) across the different time points. Results: GMI did not worsen over time (Time 1 vs Time 3, 7% vs 6.9%, P < 0.05), whereas a reduction of mean glucose (P = 0.004) and indices of glucose variability was observed. Time in range (TIR) significantly increased (68.5% vs 73.5%, P = 0.012), and time above range (TAR) level 2 (251–400 mg/dL) significantly decreased (P = 0.002). The improvement of TIR and glucose variability was mainly observed in participants < 35 years. Conclusions: Adults with type 1 diabetes using HCL showed a significant improvement of most of the metrics of glucose control during the COVID-19 lockdown.

This study sought to assess comorbidity profiles unique to early-onset-scoliosis (EOS) patients by employing cluster analytics and to determine the influence of isolated comorbidity clusters on perioperative complications, morbidity and mortality using a high powered administrative database. The KID database was queried for ICD-9 codes pertaining to congenital and idiopathic scoliosis from 2003, 2006, 2009, 2012. Patients10 y/o (EOS group) were included. Demographics, incidence and comorbidity profiles were assessed. Comorbidity profiles were stratified by body systems (neurological, musculoskeletal, pulmonary, cardiovascular, renal). K-means cluster and descriptive analyses elucidated incidence and comorbidity relationships between frequently co-occurring comorbidities. Binary logistic regression models determined predictors of perioperative complication development, mortality, and extended length-of-stay (≥75th percentile). 25,747 patients were included (Age: 4.34, Female: 52.1%, CCI: 0.64). Incidence was 8.9 per 100,000 annual discharges. 55.2% presented with pulmonary comorbidities, 48.7% musculoskeletal, 43.8% neurological, 18.6% cardiovascular, and 11.9% renal; 38% had concurrent neurological and pulmonary. Top inter-bodysystem clusters: Pulmonary disease (17.2%) with epilepsy (17.8%), pulmonary failure (12.2%), restrictive lung disease (10.5%), or microcephaly and quadriplegia (2.1%). Musculoskeletal comorbidities (48.7%) with renal and cardiovascular comorbidities (8.2%, OR: 7.9 [6.6-9.4], p 0.001). Top intra-bodysystem clusters: Epilepsy (11.7%) with quadriplegia (25.8%) or microcephaly (20.5%). Regression analysis determined neurological and pulmonary clusters to have a higher odds of perioperative complication development (OR: 1.28 [1.19-1.37], p 0.001) and mortality (OR: 2.05 [1.65-2.54], p 0.001). Musculoskeletal with cardiovascular and renal anomalies had higher odds of mortality (OR: 1.72 [1.28-2.29], p 0.001) and extLOS (OR: 2.83 [2.48-3.22], p 0.001). EOS patients with musculoskeletal conditions were 7.9x more likely to have concurrent cardiovascular and renal anomalies. Clustered neurologic and pulmonary anomalies increased mortality risk by as much as 105%. These relationships may benefit pre-operative risk assessment for concurrent anomalies and adverse outcomes. Level of Evidence: III - Retrospective Prognostic Study.

Hepatocellular carcinoma (HCC) is considered an immunogenic tumor that arises in chronically inflamed livers due to underlying chronic liver disease caused by viral and non-viral pathogenesis. This inflammation leads to tumor development and is associated to higher tumor immunogenicity. For this reason immunotherapeutic approaches may be suitable therapeutic strategies for HCC. Indeed, several preclinical and clinical data support this hypothesis showing that immunotherapy and even more their combination may be a good alternative candidate for the treatment of HCC patients. However, considering that the liver plays a central role in host defense as well as in the maintenance of self-tolerance, it is characterized by a strong intrinsic immune suppressive microenvironment as well as by a high immune evasion, which may represent a major impediment for an effective immune response against tumor. Furthermore, the low expression of tumor antigens on liver cancer cells leads to a lower T-cell activation and tumor infiltration, resulting in a less efficient control of the tumor growth and, consequently, in a worse clinical outcome. For this reason, strategies should be developed to counteract the different factors in the HCC tumor microenvironment playing a major role in reducing the effects of immunotherapy.

Introduction: Research on the trajectory of survivors’ quality of life over time has generally focused on the first six months post-stroke, and results are inconsistent. Indeed, while some studies found an improvement of the stroke survivors’ quality of life from one to six months post-stroke, other studies showed an improvement during inpatient rehabilitation but a worsening at six months after discharge. Aim: To investigate the longitudinal growth trajectories of disease-specific quality of life dimensions and their predictors over one year. Methods: A multicentric longitudinal design were used for this study. Four hundred and fifteen stroke survivors (mean age 70.6 + 12.2 years; 81% ischemic stroke) were recruited after discharge from rehabilitation hospitals and were followed up every three months for one year. Changes in stroke impact scale dimension scores were evaluated using hierarchical linear models and linear, logarithmic, quadratic, and cubic time slope. Results: We observed a significant linear and quadratic increase in most stroke impact scale dimensions from the baseline to 12-month follow-up. The communication dimension was stable over time, while the memory dimension increased only linearly. Higher physical dimensions scores were predicted by lower age, hypercholesterolemia, and better physical functioning at baseline, while higher communication was predicted by lower age, better physical functioning, and a diagnosis of peripheral vascular disease. Better memory was predicted by lower age, married status, better physical functioning, and left-hemisphere stroke. Better participation was predicted by lower age and better physical functioning. No predictors were observed for emotion. Conclusions: Disease-specific quality of life significant increase from the baseline to 12-month follow-up, especially in physical dimensions. Lower age, hypercholesterolemia, better physical functioning and diagnosis of peripheral vascular disease seem to be predictors or better quality of life. Through the analyses of predictors, we identified stroke survivors who are more at risk and who need more tailored interventions to improve quality of life.

Purpose: To describe gender differences concerning glycemic control, cardiovascular risk factors, diabetic complications, concomitant pathologies, and circulating endothelial progenitor cells (EPCs), in a population of young adults with type 1 diabetes. Methods: We collected data from 300 consecutively patients (168 males and 132 females), aged 18–30 years, among those admitted at Diabetes Unit of University of Campania “Luigi Vanvitelli” (Naples, Italy) from March 2012 to January 2017. Circulating levels of seven EPCs phenotypes were determined by flow cytometry. Results: As compared to men, women with type 1 diabetes had a significantly higher HbA1c levels (%, 8.4 ± 1.3 vs. 8.1 ± 1.3, P = 0.020), body mass index (Kg/m2, 24.8 ± 4.2 vs. 23.9 ± 3.9, P = 0.034), HDL-cholesterol (mg/dL, 61.7 ± 13.7 vs. 54.7 ± 13.9, P < 0.001), and a lower count of both CD133+KDR+ and CD34+KDR+CD133+ EPCs (P = 0.022, P < 0.001, respectively). A higher proportion of women had overweight/obesity, and thyroiditis; smoking and sexual dysfunctions were more prevalent in men than in women. Conclusions: Young adults with type 1 diabetes present gender differences with regard to glycemic control, prevalence of some cardiovascular risk factors, sexual dysfunctions and circulating levels of EPCs, most often to the detriment of women.

Purpose: A relationship between thyroid dysfunction and diabetes mellitus has been described by several authors but the role of glycemic variability is still unclear. We planned the present study to evaluate the influence of glycemic variability on thyroid hormones and TSH concentrations in patients with type 1 diabetes mellitus (T1DM).Methods: Seventy-seven young patients with T1DM were enrolled and evaluated for basal glucose concentrations, HbA1c, thyroid hormones and TSH concentrations. Glucose variability was investigated by considering the standard deviation of blood glucose readings and by calculating the mean amplitude of glycemic excursions and continuous overlapping net glycemic action (CONGA). The low (LBGI) and high (HBGI) blood glucose indices were also calculated. The correlations between TSH, thyroid hormones, glycemia and HbA1c were studied in patients and in controls, whereas those between TSH, thyroid hormones and indices of glucose variability only in patients.Results: No correlations were observed in T1DM patients between free thyroid hormones and glycemic values, HbA1c and indices of glucose variability, while an inverse correlation was observed between TSH levels and glycemic values (r = −0.27; p = 0.01), CONGA index (r = −0.35; p = 0.001) and HBGI (r = −0.28; p = 0.01) but not with HbA1c (r = −0.1; p = 0.47). Conclusions: Our results suggest a direct action of glycemic excursions on TSH secretion, regardless of variations of thyroid hormone concentrations. Thus, the evaluation of thyroid function through the assay of TSH concentrations in these patients should be made, if possible, by multiple samples on patients in euglycemic state to avoid underestimation or overestimation of thyroid dysfunction due to a wrong diagnosis of euthyroidism or dysthyroidism with consequent inappropriate choice of therapeutic options.

Continuous glucose monitoring associated with intensive insulin regimens represents a useful tool to lower HbA1c in selected adults with type 1 diabetes. Recent randomized controlled trials demonstrated greater glycemic benefits in type 1 diabetic patients treated with multiple daily injections of insulin and continuous glucose monitoring over usual care. These positive outcomes, however, are counter-balanced by several limitations that restrict the use of continuous glucose monitoring in the real life, including the apparent lack of benefits in children and pregnant diabetic women, the high cost, the stringent patients’ selection, and the presence of a multi-disciplinary team with specific expertise. Pros and Cons of using continuous glucose monitoring in type 1 diabetic patients with multiple daily injections of insulin are here discussed.

Aims GIOIA is an ongoing prospective multicentre study aiming to assess the vascular and metabolic effects of SGLT-2 inhibitors (gliflozins) and DPP-4 inhibitors (gliptins) in the routine clinical practice of patients with type 2 diabetes (T2D). Herein we describe the preliminary effectiveness data at 6 months. Methods SGLT-2i and DPP-4i-naive adult patients with T2D (N = 301 and 260, respectively), with glycated haemoglobin A1c (A1C) >7%, an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2, on background therapy with metformin, insulin or both, are being followed to evaluate markers of vascular (carotid intima-media thickness), myocardial (myocardial diastolic function) and renal (urinary albumin/creatinine ratio) damage during treatment with SGLT-2i or DPP-4i for a period of 24 months. Result At baseline, patients initiated on SGLT-2i are younger (about 6 years) and more heavy (about 7.5 kg), have higher A1C level (0.5% more), a longer diabetes duration and more CV events (20% more) than patients initiated on DPP‐4i. At 6 months, patients on SGLT-2i (N = 298) and DPP-4i (N = 258) exhibit significant ameliorations in A1C (−1.% and −0.7%, respectively), which were greater (−1.2% and −0.81%) in those on a background metformin treatment only. The composite endpoint (A1C ≤ 7.0% + weight loss ≥ 3 kg) was achieved by 24% and 16% of patients receiving SGLT-2i or DPP-4i, respectively. No unexpected adverse events were reported. Conclusions Both SGLT-2i and DPP-4i provide substantial improvements in metabolic parameters in the usual clinical practice of T2D, especially when used as second-line treatment.

Marine litter is a significant and growing pollutant in the oceans. In recent years, the number of studies and initiatives trying to assess and tackle the global threat of marine litter has grown exponentially. Most of these studies, when considering macro-litter, focus on floating or stranded litter, whereas there is less information available about marine litter on the seabed. The aim of this article is to give an overview of the current state-of-the-art methods to address the issue of seafloor macro-litter pollution. The overview includes the following topics: the monitoring of macro-litter on the seafloor, the identification of possible litter accumulation hot spots on the seafloor through numerical models, and seafloor litter management approaches (from removal protocols to recycling processes). The article briefly analyzes the different approaches to involve stakeholders, since the marine litter topic is strongly related to the societal engagement. Finally, attempting to answer to all the critical aspects highlighted in the overview, the article highlights the need of innovative multi- level solutions to induce a change toward sustainable practices, transforming a problem into a real circular economy opportunity.

The Mars 2020 Perseverance rover is equipped with a next-generation engineering camera imaging system that represents an upgrade over previous Mars rover missions. These upgrades will improve the operational capabilities of the rover with an emphasis on drive planning, robotic arm operation, instrument operations, sample caching activities, and documentation of key events during entry, descent, and landing (EDL). There are a total of 16 cameras in the Perseverance engineering imaging system, including 9 cameras for surface operations and 7 cameras for EDL documentation. There are 3 types of cameras designed for surface operations: Navigation cameras (Navcams, quantity 2), Hazard Avoidance Cameras (Hazcams, quantity 6), and Cachecam (quantity 1). The Navcams will acquire color stereo images of the surface with a $96^{\circ}\times 73^{\circ}$ 96 ∘ × 73 ∘ field of view at 0.33 mrad/pixel. The Hazcams will acquire color stereo images of the surface with a $136^{\circ}\times 102^{\circ}$ 136 ∘ × 102 ∘ at 0.46 mrad/pixel. The Cachecam, a new camera type, will acquire images of Martian material inside the sample tubes during caching operations at a spatial scale of 12.5 microns/pixel. There are 5 types of EDL documentation cameras: The Parachute Uplook Cameras (PUCs, quantity 3), the Descent stage Downlook Camera (DDC, quantity 1), the Rover Uplook Camera (RUC, quantity 1), the Rover Descent Camera (RDC, quantity 1), and the Lander Vision System (LVS) Camera (LCAM, quantity 1). The PUCs are mounted on the parachute support structure and will acquire video of the parachute deployment event as part of a system to characterize parachute performance. The DDC is attached to the descent stage and pointed downward, it will characterize vehicle dynamics by capturing video of the rover as it descends from the skycrane. The rover-mounted RUC, attached to the rover and looking upward, will capture similar video of the skycrane from the vantage point of the rover and will also acquire video of the descent stage flyaway event. The RDC, attached to the rover and looking downward, will document plume dynamics by imaging the Martian surface before, during, and after rover touchdown. The LCAM, mounted to the bottom of the rover chassis and pointed downward, will acquire $90^{\circ}\times 90^{\circ}$ 90 ∘ × 90 ∘ FOV images during the parachute descent phase of EDL as input to an onboard map localization by the Lander Vision System (LVS). The rover also carries a microphone, mounted externally on the rover chassis, to capture acoustic signatures during and after EDL. The Perseverance rover launched from Earth on July 30th, 2020, and touchdown on Mars is scheduled for February 18th, 2021.

INTRODUCTION: Early Onset and Adolescent Idiopathic Scoliosis, relatively common diagnoses (∼3% general population), have been associated with developmental dysplasia of the hip (DDH); a more rare spectrum of anomalies related to the abnormal development of acetabulum, proximal femur, and hip joint. To the best of our knowledge, no high powered investigations have been performed in an attempt to assess incidence and associated risks of DDH in scoliosis patients. METHODS: The KID database was queried for ICD-9 codes from 2003 to 2012 pertaining to EOS (Congenital and Idiopathic 0.05 between groups) developed hip osteonecrosis, 0% of patients were coded as having a hip labral tear, hip ankylosis, and 0.6% (EOS: 0.2%; AIS: 0.9%, p = 0.025) developed hip osteoarthritis. AIS patients were more likely to have recurrent hip dislocations (35.4% vs 17.0%, p

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and accounts for about 6% of all new cancers diagnosed worldwide. Moreover, it is the third and the fifth leading cause of death from cancer in men and women, respectively. HBV and HCV chronic infection is the main risk factor for HCC.A range of therapies are used in the management of HCC according to the extent and severity of liver disease. In this perspective, evaluation of prognosis represents a crucial step for proper management of HCC patients. However, the clinical outcome can be significantly different in HCC patients within the same stage of disease. Therefore, many efforts have been made to define new parameters with more precise prognostic value, and the search for HCC prognostic markers is gaining momentum. The present review aims at providing an update on cellular prognostic markers for HCC.

Background: Continuous subcutaneous insulin infusion (CSII) is increasing worldwide, mostly because of improved technology. The aim of this study was to evaluate the current status of CSII in Italy. Materials and Methods: Physicians from 272 diabetes centers received a questionnaire investigating clinical features, pump technology, and management of patients on CSII. Results: Two hundred seventeen centers (79.8%) joined the study and, by the end of April 2013, gave information about 10,152 patients treated with CSII: 98.2% with type 1 diabetes mellitus, 81.4% adults, 57% female, and 61% with a conventional pump versus 39% with a sensor-augmented pump. CSII advanced functions were used by 68% of patients, and glucose sensors were used 12 days per month on average. Fifty-eight percent of diabetes centers had more than 20 patients on CSII, but there were differences among centers and among regions. The main indication for CSII was poor glucose control. Dropout was mainly due to pump wearability or nonoptimal glycemic control. Twenty-four hour assistance was guaranteed in 81% of centers. A full diabetes team (physician+ nurse + dietician + psychologist) was available in 23% of adult-care diabetes centers and in 53%of pediatric diabetes units. Conclusions: CSII keeps increasing in Italy. More work is needed to ensure uniform treatment strategies throughout the country and to improve pump use.

To achieve the criterion appearance before competing in a physique competition, athletes undergo preparatory regimens involving high-volume intense resistance and aerobic exercise with hypocaloric energy intake. As the popularity of “drug-free” competition increases, more athletes are facing this challenge without the recuperative advantage provided by performance-enhancing drugs. Consequently, the likelihood of loss of lean body and/or bone mass is increased. The purpose of this investigation was to monitor changes in body composition for a 29-year-old self-proclaimed drug-free female figure competitor during a 32-week preparatory regimen comprising high-volume resistance and aerobic exercise with hypocaloric energy intake. We used dual-energy x-ray absorptiometry (DXA) to evaluate regional fat and bone mineral density. During the initial 22 weeks, the subject reduced energy intake and engaged in resistance (4–5 sessions/week) and aerobic (3 sessions/week) training. During the final 10 weeks, the subject increased exercise frequency to 6 (resistance) and 4 (aerobic) sessions/week while ingesting 1130–1380 kcal/day. During this 10-week period, she consumed a high quantity of protein (~55% of energy intake) and nutritional supplements. During the 32 weeks, body mass and fat mass decreased by 12% and 55%, respectively. Conversely, lean body mass increased by 1.5%, an amount that exceeded the coefficient of variation associated with DXA-derived measurement. Total bone mineral density was unchanged throughout. In summary, in preparation for a figure competition, a self-proclaimed drug-free female achieved the low body-fat percentage required for success in competition without losing lean mass or bone density by following a 32-week preparatory exercise and nutritional regimen.

Introduction Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, with a prevalence of 0.6-6.9 depending on the population studied. In contrast to other primary immunodeficiency diseases (PIDDs), symptoms may not appear until the third decade of life. Lack of recognition of CVID is a persistent problem. Myriad confounding clinical phenotypes and frequent infections, including autoimmunity, malignancy, chronic lung disease, granulomatous disease, and gastrointestinal disease, complicate the diagnosis. Often it is years before a diagnosis is made, leading to irreversible morbidities and mortality. Methods Second-year medical students are introduced to CVID during their session on PIDDs that occurs during the immunology/rheumatology course. To assess students’ recognition of CVID, a 15-minute OSCE encounter was created that included a simulation of lung sounds (rhonchi), physical exam cards (clubbing, otitis media with effusion), and moulage of skin (petechiae). A standardized patient (SP) portrayed a patient requesting antibiotics for a sinus infection. Students were tasked to both interview the patient and perform a hypothesis-driven physical exam. A postencounter exercise queried the students on their differential diagnosis and their rationale. Results Item analysis of the case showed high levels of difficulty and strong discrimination between high- and low-performing students in both communication skills and clinical reasoning in CVID. Discussion This SP encounter can be used in both formative and summative assessments to measure the recognition of CVID.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, there is a single drug approved as first-line systemic therapy in advanced unresectable HCC, providing a very limited survival benefit. In earlier stages, 5-year survival rates after surgical and loco-regional therapies are extremely variable depending on the stage of disease. Nevertheless, HCC is considered an immunogenic tumor arising in chronically inflamed livers. In such a scenario, immunotherapy strategies for HCC, in particular combinations including cancer vaccines, may represent a key therapeutic tool to improve clinical outcome in HCC patients. However, a lot of improvement is needed given the disappointing results obtained so far.

Summary Objective With the increase of smartphone use and availability over the last decade, mobile healthcare applications have become more accessible. Many of these applications allow users to track behaviors and goals, and acquire feedback and information while on the go. Recent studies appearing in the literature suggest that smartphones may offer a means of augmenting clinical voice assessment by recording individuals with voice disorders outside the clinic for the purpose of extracting acoustic characteristics. This review examines the effectiveness of smartphones in clinical voice assessment and treatment, as reported in the current literature. Methods The PubMed database was searched using a combination and variation of different term related to smartphones, voice, and recording apps, in order to find articles that address the role of smartphones in clinical voice recording and assessment. Results and Conclusion Six studies published in the last 3 years were reviewed and examined in terms of types of device and operating systems used, types of subjects and disorders studied, voice parameters extracted, and microphones used. Considerations such as impact of environmental noise, and privacy and security issues are also examined. While smartphones and mobile apps have the potential to be valuable tools in voice assessment outside the clinic, further efforts are needed for them to be effectively used in a clinical setting.

One of the most significant revisions to the ICH E6 GCP Guideline in the last 20 years was issued in November 2016, adopted by the EMA in December 2016 and by the FDA as a Guidance Document in March 2018. The new section on Quality Management requires the implementation of a systematic approach for managing risks throughout the course of a clinical study. The addendum also emphasizes appropriate sponsor oversight. Currently available risk management solutions are fairly elaborate, having been developed for and adopted mainly by larger companies. Small to medium size companies find these solutions too complex and not easily adaptable. In this paper, we present a simple but robust toolkit for clinical study risk management for small to medium sized organizations in order to facilitate compliance. The toolkit consists of customizable templates for the following: Clinical Risk Management SOP; Clinical Risk Management Plan; Vendor Oversight SOP; Vendor Oversight Plan; and Clinical Risk Log. The tools were prepared by the DIA GCP-QA Community members and presented at the 2018 DIA Annual Meeting in Boston.

Background: Type 1 diabetic patients have high instability of daily glucose levels. The aim of this study was to evaluate the long-term effects of continuous subcutaneous insulin infusion (CSII) therapy, compared with multiple daily injections of insulin (MDI), on glucose variability, in young type 1 diabetic patients transitioned to the adult diabetes care. Methods: Patients aged 18-30 years and considered eligible for insulin pump therapy were included in the study. Ninety-eight patients who started CSII therapy and 125 who remained in MDI completed a 2-year follow-up. Glucose variability was assessed with continuous glucose monitoring using blood glucose standard deviation (BGSD), mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA-2 h), low blood glucose index, high blood glucose index, and average daily risk range. Results: MAGE and BGSD decreased in both groups, with adjusted differences at 2 years of -0.74 mM (95% confidence interval [CI] -1.22 to -0.26, P = 0.003) and -0.3 (CI -0.52 to -0.1, P = 0.005) favoring the pump-therapy group. No significant differences between groups in the other variability indexes were observed. HbA1c decreased in both groups without significant difference (0.05%, -0.26, 0.35, P = 0.77); fasting glucose, insulin dose, and overall hypoglycemia (daily, nocturnal, and severe) decreased more in patients with CSII, compared with those with MDI. Conclusions: Among young adults with type 1 diabetes transitioning from the pediatric care, the use of CSII is associated with lower glucose variability, fasting glycemia, and overall hypoglycemic events than MDI during a 2-year period of follow-up.

The DIA's Good Clinical Practice and Quality Assurance Community (DIA GCP/QA) created a working group to develop templates for a protocol deviation standard operating procedure (SOP) and protocol deviation handling plan (PDHP).The working group consisted of QA auditors, data managers, statisticians, and clinical monitors from several pharmaceutical companies, academia, and independent auditing firms. Various examples of standard operating procedures, data handling plans, and auditing plans were examined, and the core elements extracted into the initial PD SOP and PDHP templates. The draft templates were presented at a workshop at the DIA 51st Annual Meeting held in June 2015 in Washington, DC, and feedback was incorporated. The workshop came at the heels of a previously published position paper, "The Lifecycle and Management of Protocol Deviations."The PD SOP and the PDHP templates are presented in this article. They are a starting point, and each company will need to modify to suit its individual needs.This article expands on the position paper to include concrete tools for the management of protocol deviations, including best practices for detection, classification, mitigation, and management of protocol deviations with a goal to reduce the impact on subject safety and data integrity.

Hepatocellular carcinoma (HCC) is the most common liver malignancy. The prognosis for HCC patients greatly varies according to the stage at diagnosis. Overall it is poor, with a 5-year survival rate of approximately 5-6%. Immunotherapeutic interventions represent a novel and effective therapeutic tool. However, only few immunotherapy trials for HCC have been conducted so far with contrasting results, suggesting that significant improvements are needed. Indeed, the liver is characterized by a strong intrinsic immune suppressive microenvironment which needs to be counterbalanced with immune stimulatory approaches. Therefore, the implementation of combinatorial protocols combining immune stimulatory strategies with specific immunotherapy approaches could result in a dramatic improvement of efficacy and clinical outcome in HCC patients. The present review aims at describing the state of the art in immunotherapy strategies for HCC and future perspectives.

Cancer genome instability leads to accumulation of mutations which may result into tumor-specific mutated &ldquo, neoantigens&rdquo, not be affected by central T-cell tolerance. Such neoantigens are considered the optimal target for the patient&rsquo, s anti-tumor T cell immunity as well as for personalized cancer immunotherapy strategies. However, only a minor fraction of predicted neoantigens are relevant to the clinical outcome. In the present study, a prediction algorithm was applied using datasets of RNA sequencing from all 377 Hepatocellular carcinoma (HCC) patients available at The Cancer Genome Atlas (TCGA), to predict neoantigens to be presented by each patient's autologous HLA molecules. Correlation with patients&rsquo, survival was performed on the 115 samples for whom the exact date of death was known. A total of 30 samples were used for the training set, and 85 samples were used for the validation sets. Neither the somatic mutations nor the number nor the quality of the predicted neoantigens correlate as single parameter with survival of HCC patients who do not undergo immunotherapy treatment. Furthermore, the preferential presentation of such neoantigens in the context of one of the major histocompatibility complex MHC class I molecules does not have an impact on the survival. On the contrary, the expression of Granzyme A (GZMA) is significantly correlated with survival and, in the context of high GZMA, a direct correlation between number and quality of neoantigens with survival is observed. This is in striking contrast to results described in cancer patients undergoing immunotherapy, in which a strong correlation between Tumor Mutational Burden (TMB), number of predicted neoantigens and survival has been reported.

A retrospective cohort study at a single institution.The aim of this study was to analyze the perioperative and postoperative outcomes of patients who underwent open transforaminal lumbar interbody fusion (O-TLIF) and bilateral minimally invasive surgery (MIS) Wiltse approach TLIF (Wil-TLIF).Several studies have compared open TLIF to MIS TLIF; however, comparing the techniques using a large cohort of one-level TLIFs has not been fully explored.We reviewed the charts of patients undergoing a single-level primary posterior lumbar interbody fusion between 2012 and 2017. The cases were categorized as Open TLIF (traditional midline exposure including lateral exposure of transverse processes) or bilateral paramedian Wiltse TLIF approach. Differences between groups were assessed by t tests.Two hundred twenty-seven patients underwent one-level primary TLIF (116 O-TLIF, 111 Wil-TLIF). There was no difference in age, gender, American Society of Anesthesiologists (ASA), or body mass index (BMI) between groups. Wil-TLIF had the lowest estimated blood loss (EBL; 197 vs. 499 mL O-TLIF, P ≤ 0.001), length of stay (LOS; 2.7 vs. 3.6 days O-TLIF, P ≤ 0.001), overall complication rate (12% vs. 24% O-TLIF, P = 0.015), minor complication rate (7% vs. 16% O-TLIF, P = 0.049), and 90-day readmission rate (1% vs. 8% O-TLIF, P = 0.012). Wil-TLIF was associated with the higher fluoroscopy time (83 vs. 24 seconds O-TLIF, P ≤ 0.001). There was not a significant difference in operative time, intraoperative or neurological complications, extubation time, reoperation rate, or infection rate.In comparing Wiltse MIS TLIF to Open TLIF, the minimally invasive paramedian Wiltse approach demonstrated the lowest EBL, LOS, readmission rates, and complications, but longer fluoroscopy times when compared with the traditional open approach.3.

Hepatocellular carcinoma (HCC) is the most common liver malignancy with a poor prognosis and an overall 5-year survival rate of approximately 5-6%. This is due because standard of care treatment options are limited and none of them shows a sufficient efficacy. HCC is an "inflammation-induced cancer" and preliminary preclinical and clinical data suggest that immunotherapeutic approaches may be a good alternative candidate for the treatment of HCC patients improving the dismal prognosis associated with this cancer. However, recent findings strongly suggest that an optimal immunotherapy in HCC requires the combination of an immune activator with immune modulators, aiming at compensating the strong liver immune suppressive microenvironment. One of the most promising strategy could be represented by the combination of a cancer vaccine with immunomodulatory drugs, such as chemotherapy and checkpoint inhibitors. Very limited examples of such combinatorial strategies have been evaluated in HCC to date, because HCC easily develops resistance to standard chemotherapy, which is also poorly tolerated by patients with liver cirrhosis. The present review describes the most update knowledge in this field.

Clinical trials are designed to evaluate the efficacy, safety, or other characteristics associated with medical products. Trials are usually complex and require a large group of professionals to follow a clinical trial protocol, standard operating procedures, and study-specific manuals, guidelines, and plans. Clinical trial protocols prospectively describe the background and rationale for conducting the trial, the objectives of the trial, the trial design, the equipment to be used, the procedures to be performed, and the statistical methods on how the trial data are to be analyzed. Deviations from the protocol can result in harm to subjects, biased or inaccurate results, and possible rejection of all or part of the trial data by the sponsor or regulatory authorities. Despite preventive efforts, protocol deviations are likely to occur in most trials. This position paper proposes a common definition of protocol deviations and recommends best practices for their detection, classification, and management as part of their life cycle, with a goal of reducing their impact on subject safety and data integrity. The information contained herein is drawn globally from industry experts within the DIA Good Clinical Practice and Quality Assurance community, an industry-wide survey, and presentations with discussions at various industry meetings.

Therapeutic cancer vaccines do not hold promise yet as an effective anti-cancer treatment. Lack of efficacy or poor clinical outcomes are due to several antigenic and immunological aspects that need to be addressed in order to reverse such trends and significantly improve cancer vaccines' efficacy. The newly developed high throughput technologies and computational tools are instrumental to this aim allowing the identification of more specific antigens and the comprehensive analysis of the innate and adaptive immunities. Here, we review the potentiality of systems biology in providing novel insights in the mechanisms of the action of vaccines to improve their design and effectiveness.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and represents the third and the fifth leading cause of cancer-related death worldwide in men and women, respectively. Hepatitis B virus (HBV) and hepatitis C virus (HCV) chronic infections account for pathogenesis of more than 80 % of primary HCC. HCC prognosis greatly varies according to stage at beginning of treatment, but the overall 5-year survival rate is approximately 5-6 %. Given the limited number of effective therapeutic strategies available, immunotherapies and therapeutic cancer vaccines may help in improving the clinical outcome for HCC patients. However, the few clinical trials conducted to date have shown contrasting results, indicating the need for improvements. In the present study, a novel combinatorial strategy, based on metronomic chemotherapy plus vaccine, is evaluated in a mouse model. The chemotherapy is a multi-drug cocktail including taxanes and alkylating agents, which is administered in a metronomic-like fashion. The vaccine is a multi-peptide cocktail including HCV as well as universal tumor antigen TERT epitopes. The combinatorial strategy designed and evaluated in the present study induces an enhanced specific T cell response, when compared to vaccine alone, which correlates to a reduced Treg frequency. Such results are highly promising and may pave way to relevant improvements in immunotherapeutic strategies for HCC and beyond.

STUDY DESIGN Cohort. OBJECTIVE To compare the perioperative morbidity of patients with cardiac stents after spine surgery who continue to take aspirin before and after the operation with a similar group of patients who preoperatively discontinued aspirin. SUMMARY OF BACKGROUND DATA The preoperative discontinuation of anticoagulant therapy has been the standard of care for orthopedic surgical procedures. However, recent literature has demonstrated significant cardiac risk associated with aspirin withdrawal in patients with cardiac stents. Although it has recently been demonstrated that performing orthopedic surgery while continuing low-dose aspirin therapy seems to be safe, studies focused on spinal surgery have not yet been performed. Because of the risk of intraspinal bleeding and the serious consequences of subsequent epidural hematoma with associated spinal cord compression, spinal surgeons have been reluctant to operate on patients taking aspirin. METHODS This institutional review board-approved study included 200 patients. Preoperative parameters and postoperative outcome measures were analyzed for 100 patients who underwent spinal surgery after the discontinuation of anticoagulation therapy and 100 patients who continued to take daily aspirin through the perioperative period. The primary outcome measure was serious bleeding-related postoperative complications such as spinal epidural hematoma. The operative time, intraoperative estimated blood loss, hospital length of stay, transfusion of blood products, and 30-day hospital readmission rates were also recorded and compared. RESULTS The patients who continued taking aspirin in the perioperative period had a shorter hospital length of stay on average (4.1 ± 2.7 vs. 6.2 ± 5.8; P < 0.005), as well as a reduced operative time (210 ± 136 vs. 266 ± 143; P < 0.01), whereas there was no significant difference in the estimated blood loss (642 ± 905 vs. 697 ± 1187), the amount of blood products transfused, overall intra- and postoperative complication rate (8% vs. 11%), or 30-day hospital readmission rate (5% vs. 5%). No clinically significant spinal epidural hematomas were observed in either of the study groups. CONCLUSION The current study has observed no appreciable increase in bleeding-related complication rates in patients with cardiac stents undergoing spine surgery while continuing to take aspirin compared with patients who discontinued aspirin prior to surgery. Although very large studies will be needed to determine whether aspirin administration results in a small complication rate increase, the current study provides evidence that perioperative aspirin therapy is relatively safe in patients undergoing spinal surgery. LEVEL OF EVIDENCE 2.

Background We assessed the long-term effects of a Mediterranean diet on circulating levels of endothelial progenitor cells (EPCs) and the carotid intima-media thickness (CIMT) in patients with type 2 diabetes. Design This was a parallel, two-arm, single-centre trial. Methods Two hundred and fifteen men and women with newly diagnosed type 2 diabetes were randomized to a Mediterranean diet (n = 108) or a low-fat diet (n = 107). The primary outcome measures were changes in the EPC count and the CIMT of the common carotid artery after the treatment period defined as the end of trial (EOT). Results At the EOT, both the CD34+KDR+ and CD34+KDR+CD133+ counts had increased with the Mediterranean diet compared with the low-fat diet (p < 0.05 for both). At the EOT evaluation, there was a significant (p = 0.024) difference of -0.025 mm in the CIMT favouring the Mediterranean diet. Compared with the low-fat diet, the rate of regression in the CIMT was higher in the Mediterranean diet group (51 vs. 26%), whereas the rate of progression was lower (25 vs. 50%) (p = 0.032 for both). Changes in the CIMT were inversely correlated with the changes in EPC levels (CD34+KDR+, r = -0.24, p = 0.020; CD34+KDR+CD133+, r = -0.28, p = 0.014). At the EOT, changes in levels of HbA1c, HOMA, total cholesterol, high-density lipoprotein cholesterol and systolic blood pressure were significantly greater with the Mediterranean diet than with the low-fat diet. Conclusion Compared with a low-fat diet, a long-term trial with Mediterranean diet was associated with an increase in circulating EPCs levels and prevention of the progression of subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes.

Purpose: The aim of this study was to evaluate the prevalence and risk factors associated with female sexual dysfunction (FSD) in young women with type 1 diabetes treated with different intensive insulin regimens. Methods: Type 1 diabetic women aged 18–35 years were included in this study if they had stable couple relationship and no oral contraceptive use. All women were asked to complete the Female Sexual Function Index (FSFI) and other validated multiple-choice questionnaires assessing sexual-related distress (Female Sexual Distress Scale, FSDS), quality of life (SF-36 Health Survey), physical activity (International Physical Activity Questionnaire), depressive symptoms (Zung Self-Rating Depression Scale, SRDS) and diabetes-related problems (Diabetes Integration Scale ATT-19). FSD was diagnosed according to a FSFI score higher than 26.55 and a FSDS score lower than 15. Results: The overall prevalence of FSD in diabetic and control women was 20 and 15 %, respectively (P = 0.446). Compared with the continuous subcutaneous insulin infusion group and control women, diabetic women on multiple daily injections (MDI) had lower global FSFI score (P = 0.007), FSDS score (P = 0.045) and domains such as arousal (P = 0.006), lubrication and satisfaction scores (P