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Abstract Background The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Much research has shown previously that inflammation can promote cellular senescence. Microglia are a central nervous system innate immune cell that undergo senescence with aging and during neurodegeneration. The contribution of senescent microglia to multiple sclerosis, an inflammatory neurodegenerative disease, is not clear, but microglia are strongly implicated in chronic active lesion pathology, tissue injury, and disease progression. Drugs that could specifically eliminate dysregulated microglia in multiple sclerosis are therefore of great interest to the field. Results A single-cell analysis of brain tissue from mice subjected to experimental autoimmune encephalomyelitis (EAE), a mouse model of CNS inflammation that models aspects of multiple sclerosis (MS), identified microglia with a strong transcriptional signature of senescence including the presence of BCL2-family gene transcripts. Microglia expressing Bcl2l1 had higher expression of pro-inflammatory and senescence associated genes than their Bcl2l1 negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune genes suggesting they may be proinflammatory and contribute to disease processes in chronic active lesions. Employing a small molecule BCL2-family inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia and macrophages in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice: decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Conclusion These results support the hypothesis that microglia and macrophages exhibit transcriptional features of cellular senescence in EAE and MS, and that microglia expressing Bcl2l1 demonstrate a proinflammatory signature that may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease. Depleting microglia and macrophages using a senolytic results in robust improvement in EAE disease severity, including across measures of neurodegeneration, inflammation, and demyelination, and may therefore represent a novel strategy to address disease progression in multiple sclerosis.

Introduction: Acute leukemias (ALs) are aggressive diseases that lead to death without medical attention. We evaluated the association between delays in diagnosis and poor outcomes in AL by evaluating the symptom onset to treatment intervals in adults with newly diagnosed AL and their effect on an early death (ED). Methods: We assessed adults diagnosed with AL between 2015 and 2020 and evaluated baseline characteristics, the patient interval (PI), diagnostic interval (DI), treatment interval (TI) and the total time interval (TTI) to determine ED-associated factors. Main results: We assessed 102 patients with acute lymphoblastic leukemia (ALL), 57 with acute myeloblastic leukemia (AML) and 29 with acute promyelocytic leukemia (APL). Median interval days were PI 14, DI 10, TI 4 and TTI 31.5. The TI and TTI intervals were lower in APL than in ALL and AML; TI 1 vs. 4 and 3 (p = 0.001) and TTI 21 vs. 31 and 35 (p = 0.016). The 30-day and 60-day EDs were 13.8% and 20.7%, mainly infections. ECOG > 2 (OR = 15.0) and PI < 7 days (OR = 4.06) were associated with 30-day ED; AML (OR = 2.69), high-risk (OR = 3.34), albumin < 3.5 g/dl (OR = 5) and platelets < 20 × 103/uL (OR = 2.71) with a 60-day ED. Conclusion: None of the interval-delays were associated with an ED. Intervals seemed to be longer in patients without an ED, except for the TI, probably because of “the waiting time paradox.” Aggressive manifestations of disease may lead to shorter diagnostic intervals, but increased mortality.

Abstract ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-β in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function.

Abstract Background In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be “PSMA-617”, and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [18F]AlF2+ complexation. Results The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [18F]AlF2+ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [18F]F-PSMA-1007 and [18F]F-PSMA-617-RESCA, [18F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands. Conclusion PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [18F]AlF2+ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [18F]F-PSMA-617-NODA might be of potential interest for clinical applications.

IntroductionCaring for physically disabled children, particularly in contexts where resources are often insufficient or absent, exposes primary carers to significant psychological strain. The lack of structured mechanisms to address this psychological burden poses a considerable threat to the wellbeing of both carers and the children with disabilities under their care. However, research on the psychological wellbeing of carers in Tanzania is scarce. This study aimed to evaluate the psychological wellbeing and symptoms of anxiety and depression, along with associated factors, of carers of children, and adolescents with physical disabilities in the Kilimanjaro region.MethodsA cross-sectional survey was conducted from November 2020 to June 2021 in the Kilimanjaro region, involving 212 carers. The Swahili versions of the WHO-5 Wellbeing Index and Hopkins Symptoms Check List-25 were used to assess psychological wellbeing and symptoms of anxiety and depression. Data were analysed using IBM SPSS Statistics V.28. Multivariable linear and binary logistic regression were used to assess the associations.ResultsMore than four fifths (81%) of the carers were parents, and most of these parents were mothers (92%). Of the 212 carers, more than half (51%) exhibited poor psychological wellbeing, 42% had symptoms of anxiety, and 38% symptoms of depression. Notably, poor psychological wellbeing was significantly associated with symptoms of anxiety and depression. Results of a multivariable regression analysis indicated that extended family support was associated with better psychological wellbeing and lower odds of symptoms of anxiety and depression. A higher estimated monthly income was associated with better psychological wellbeing, and lower odds of symptoms of depression. Access to rehabilitation for the child was associated with improved psychological wellbeing and decreased likelihood of symptoms of anxiety.ConclusionMany carers of children, and adolescents with physical disabilities in Tanzania are at high risk of having poor psychological wellbeing, and symptoms of anxiety and depression. Support from extended-family networks is crucial in promoting good psychological wellbeing. The government in Tanzania should improve rehabilitation services, especially in disadvantaged rural areas, and integrate mental-health screening for carers in both rehabilitation programmes and primary healthcare.

Background Family interactions, which are always multi-faceted, are complicated further by family members with disabilities. In resource-poor settings, policies and programmes that address the needs of and challenges faced by families are often inaccessible or unavailable. Approximately 13% of the families in Tanzania have at least one member with a disability, yet family-centred research on caring for disabled children and adolescents is scarce in this context. Objective The aim is to explore the needs and challenges faced by families that care for children and adolescents with physical disabilities in the Kilimanjaro Region of north-eastern Tanzania. Methods This qualitative study had a constructivist grounded-theory design. In-depth interviews, using a semi-structured interview guide based on the social-capital framework, were conducted with 12 female participants aged between 24 and 80. A conceptual model of family needs, inspired by Maslow’s hierarchy of needs, informed the analysis. Results Challenging needs were grouped into five categories, which were linked to Maslow’s hierarchy of needs and related to the central concept of ‘adaptive adjustment’: (1) ‘barely surviving’; (2) ‘safety needs in jeopardy’; (3) ‘sociocultural protection’; (4) ‘self-esteem far beyond reach’, and (5) ‘dreaming of self-actualisation’. Conclusion Families caring for children and adolescents with physical disabilities in north-eastern Tanzania have needs that extend beyond the available and accessible resources. Families can adjust and adapt by avoiding certain situations, accepting the reality of their circumstances and exploring alternative ways of coping. A sustainable support system, including social networks, is essential for meeting basic needs and ensuring safety.

AbstractIndonesian women still live with negative stereotypes, which leads to limited employment opportunities for women. Women who work as laborers generally experience role conflict. Most company leaders do not understand the conditions of female workers. They demand female workers to always focus on work, which makes female workers not have a work-family balance, which means they are not experiencing a balance between family and work. This study examined the influence of dual roles and family commitment on role ambiguity and worker well-being. This research is explanatory. The sample was obtained using convenience sampling when the respondents, in this case, were female workers who attended the International Labor Day commemoration in Semarang City. The data collection technique used was a questionnaire and data analysis using SEM-PLS (Structural Equation Modeling Partial Least Square), the sample taken from 374 respondents from female workers in Semarang City. This study found that family role has a positive and significant effect on role ambiguity (β = 0.341; p

The Moncongloe District is an environment that is rich in potential with many Micro, Small, and Medium Enterprises (MSMEs). Business owners in this sector face challenges in managing business finances effectively. Limited financial knowledge is due to the fact that MSMEs do not have a financial background or formal education in this field. This makes it difficult for MSMEs to understand the terms and concepts used in financial reports. This community empowerment program aims to make a positive contribution to business development in Moncongloe District, particularly in recording business finances. The implementation method is through workshops, discussions, questions and answers, and evaluations to provide an understanding of the importance of financial reports for MSMEs. The results of the community empowerment program show that workshop participants experienced an in-depth increase in knowledge about the importance of financial reports which can improve business performance for MSME entrepreneurs and Village-Owned Enterprises (BUMDES) in Moncongloe District, Maros Regency. In addition, participants succeeded in understanding the tools for starting a business, namely the Business Model Canvas, and making simple financial records that can help community empowerment partners in developing more structured and innovative MSME businesses.

Abstract Background Although prostate cancer is a prevalent malignancy worldwide, its clinical presentation and management in the Middle East are not well-documented. This study aims to provide insights into the initial clinical presentation and management of prostate cancer in this region. Methods A retrospective review was conducted on seven institutional databases from six Middle Eastern countries, including Türkiye, Lebanon, Iraq, Syria, Bahrain, and Jordan, to identify patients diagnosed with prostate cancer in 2021. Descriptive analysis was performed on the collected data to provide an overview of the demographic, clinical, and treatment variables. Results A total of 1,136 patients were identified with a median age of 70 (range, 50–84). Most patients (78%) received their prostate cancer diagnosis after presenting with symptoms, as opposed to routine PSA screening. At the time of diagnosis, 35% of men had clinical T3 or T4 disease, 54% with Stage IV disease and 50% with Gleason score ≥ 8. Regarding treatment, 20% of non-metastatic and 22% of metastatic patients received no treatment. Conclusion Most men in this study sought prostate cancer evaluation due to symptoms and were subsequently diagnosed with advanced-stage disease, providing a foundation for future research aimed at understanding the underlying factors behind the observed trends and enabling informed interventions.

Background: Radical cystectomy is a complex procedure imposing significant post-operation complications. Objective: Explore the impact of peri-operative pRBC transfusion on mortality and overall morbidity in a matched cohort. Methods: The American College of Surgeons—National Surgical Quality Improvement Program’s (ACS-NSQIP) dataset was used to select patients who underwent RC in 2008–2019. Patients who witnessed pre-operative transfusion and emergency cases were excluded. Peri-operative pRBC transfusion was defined as an intra-operative or up to 24-h post-operative pRBC transfusion. We matched patients who underwent peri-operative pRBC transfusion to patients who did not receive transfusion. Length of stay, mortality, and overall morbidity were compared between the two matched cohorts. Results: The match cohort was matched on all pre-operative demographics and medical history variables and yielded 3578 matched patients. Patients who underwent peri-operative pRBC transfusion had a longer length of hospital stay (9.3 days) as compared to patients who did not undergo transfusion (8.13 days) (p < 0.001). Furthermore, patients who underwent transfusion also had higher odds of mortality (OR = 1.934) and overall morbidity (OR = 1.443) (p < 0.03). Specifically, patients who underwent transfusion had higher odds of organ space SSI, pneumonia, unplanned intubation, pulmonary embolism, failure to wean off of ventilator, renal insufficiency, urinary tract infections, stroke, myocardial infarction, cardiac arrest requiring CPR, deep vein thrombosis, and septic shock (p < 0.047). Conclusion: Peri-operative pRBC transfusion in RC was associated with longer hospital stays, significant morbidity, and mortality. For this reason, pre-operative patient optimization and possible alternatives to common pRBC practices should be considered in RC to circumvent complications.

Abstract The outer membrane insertase of Gram-negative bacteria, BAM, is a key target for urgently needed novel antibiotics. Functional reconstitutions of BAM have so far been limited to synthetic membranes and with low throughput capacity for inhibitor screening. Here, we describe a BAM functional assay in native membrane environment capable of high-throughput screening. This is achieved by employing outer membrane vesicles (OMVs) to present BAM directly in native membranes. Refolding of the model substrate OmpT by BAM was possible from the chaperones SurA and Skp, with the required SurA concentration three times higher than Skp. In the OMVs, the antibiotic darobactin had a tenfold higher potency than in synthetic membranes, highlighting the need for native conditions in antibiotics development. The assay is successfully miniaturized for 1536-well plates and upscaled using large scale fermentation, resulting in high-throughput capacities to screen large commercial compound libraries. Our OMV-based assay thus lays the basis for discovery, hit validation and lead expansion of antibiotics targeting BAM.

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis with a multifactorial pathogenesis. Historically, it has been classified as type 1 and type 2, according to its clinical and histological features. The diagnosis of AIP is challenging and relies on a combination of clinical, histopathologic, serologic, and imaging characteristics. In the available guidelines, the imaging hallmarks of AIP are based on cross-sectional imaging and cholangiopancreatography retrograde endoscopic findings. Endoscopic ultrasound (EUS) is generally used for pancreatic tissue acquisition to rule out pancreatic cancer and diagnose AIP with limited accuracy. Several papers reported the reliability of EUS for providing informative morphologic features of AIP. Nowadays, the improvement in the resolution of EUS conventional images and the development of new ancillary technologies have further increased the diagnostic yield of EUS: contrast-enhanced EUS and EUS elastography are non-invasive and real-time techniques that strongly support the diagnosis and management of pancreatic diseases. In this review article, we will present the role of conventional EUS and ancillary diagnostic techniques in the diagnosis of AIP to support clinicians and endosonographers in managing this condition.

Supraclavicular brachial plexus nerve block is ideal for surgical procedures of the upper limb. Ultrasound guidance continues to grow in popularity as a method of nerve localization, significantly improves the quality of nerve block with a lesser number of complications, it has the advantage of allowing real?time visualization of the plexus, pleura, and vessels along with the needle and local anesthetic spread, although complications cannot be eliminated completely. Ipsilateral recurrent laryngeal nerve (RLN) palsy is a rare complication associated with supraclavicular approach. The incidence of the RLN block occurring with supraclavicular approach is 1.3% of patients, but incidence of block with ultrasound?guided supraclavicular block is not known. There are two cases reported in the world literature, in Mexico there is no evidence in this regard. We discuss the first case report in Mexico and the third in the world of this rare complication which occurred while performing a left supraclavicular perivascular block performed under ultrasound guidance.

Abstract Background Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis. Method In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope. Results We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states. Conclusion In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.

Abstract Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation are not well understood. Here, we show at the atomic level how inositol pyrophosphates interact with SPX domains of subunits Vtc2 and Vtc3 to control the activity of the VTC complex. Vtc2 inhibits the catalytically active VTC subunit Vtc4 by homotypic SPX–SPX interactions via the conserved helix α1 and the previously undescribed helix α7. Binding of inositol pyrophosphates to Vtc2 abrogates this interaction, thus activating the VTC complex. Accordingly, VTC activation is also achieved by site-specific point mutations that disrupt the SPX–SPX interface. Structural data suggest that ligand binding induces reorientation of helix α1 and exposes the modifiable helix α7, which might facilitate its post-translational modification in vivo. The variable composition of these regions within the SPX domain family might contribute to the diversified SPX functions in eukaryotic phosphate homeostasis.

Chronic obstructive pulmonary disease (COPD) is comprised of histopathological alterations such as pulmonary emphysema and peribronchial fibrosis. Matrix metalloproteinase 9 (MMP-9) is one of the key enzymes involved in both types of tissue remodeling during the development of lung damage. In recent studies, it was demonstrated that deflamin, a protein component extracted from Lupinus albus, markedly inhibits the catalytic activity of MMP-9 in experimental models of colon adenocarcinoma and ulcerative colitis. Therefore, in the present study, we investigated for the first time the biological effect of deflamin in a murine COPD model induced by chronic exposure to ozone. Ozone exposure was carried out in C57BL/6 mice twice a week for six weeks for 3 h each time, and the treated group was orally administered deflamin (20 mg/kg body weight) after each ozone exposure. The histological results showed that deflamin attenuated pulmonary emphysema and peribronchial fibrosis, as evidenced by H&E and Masson’s trichrome staining. Furthermore, deflamin administration significantly decreased MMP-9 activity, as assessed by fluorogenic substrate assay and gelatin zymography. Interestingly, bioinformatic analysis reveals a plausible interaction between deflamin and MMP-9. Collectively, our findings demonstrate the therapeutic potential of deflamin in a COPD murine model, and suggest that the attenuation of the development of lung tissue damage occurs by deflamin-regulated MMP-9 catalytic activity.

En este artículo se aborda la presencia de la menstruación en el espacio público y privado de la Unión Soviética. Por un lado, cómo afectaba y se desarrollaba en la vida cotidiana de las mujeres (en sus tareas diarias o su trabajo, además de con qué productos y espacios higiénicos contaban para lidiar con ella). Por otro lado, veremos qué atención le prestaba el sector público (desde medidas y estudios laborales hasta su presencia en el ámbito médico). En definitiva, valorar el grado de invisibilidad de un fenómeno cotidiano del que no se habla en los manuales de Historia.

The impact of family business has been recognized globally. However, according to some facts and previous studies, the performance of family businesses may decline as they age and the generations change. The research tried to explore the differences in firm performances based on company size, company age, and the generation of the leaders of the firms to confirm the results from the previous study. The data were compiled from 213 companies that vary in size. There were micro, small, small-medium, big-medium, and big firms. The possible presence of significant differences in firm performance based on company size, age, and generation of the leaders was analyzed using the Analysis of Variances (ANOVA). ANOVA test shows no significant differences in company age, company size, and the generation of the leaders toward their firm performances. The research clarifies the previous studies stating that there are significant differences in those three independent variables toward firm performance. The research also shows no significant difference in different generation of the leaders toward company size. Hence, it means the firm performance of companies cannot be determined only by knowing its size, age, or the generation of the leaders. There must be other factors that can help to identify the firm performance of a company.

Background: Radical cystectomy (RC) is considered a complex procedure that entails significant morbidity and mortality. Objectives: We aimed to determine pre-operative patient characteristics that help predict a prolonged length of hospital stay (PLOS) following RC. Design and Methods: The American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database was used to select patients who underwent RC between the years 2011 and 2020. Prolonged length of stay was defined as a hospital stay ⩾9 days. We compared patient demographics, pre-operative labs, surgical characteristics, and medical history between patients with or without PLOS. Multivariable logistic regression models controlling for pre-operative characteristics and propensity score matching for post-operative complications were conducted to control for possible confounders. Results: The analysis yielded details of 19,158 RC patients of which 6007 (31%) patients had a PLOS. Patients with PLOS were more likely to have post-operative complications that could serve as predictors for the PLOS rather than their pre-operative characteristics. Hence, we matched our cohort for these complications. After matching, patient pre-operative characteristics that predict PLOS included female gender (Odds Ratio (OR) = 5.91), 10-year increase in age (OR = 1.15), non-White race (OR = 1.98), partially or totally dependent functional health status (OR = 2.86), bleeding disorders (OR = 4.67), congestive heart failure (OR = 1.59), pre-operative transfusion (OR = 3.03), and a 20-min increase in operative time (OR = 1.01) ( p < 0.046). Conclusion: Patient demographics and pre-operative factors can help predict PLOS in RC patients. These predictors could serve as tools for patient counseling and risk stratification.

Background: Although endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) using lumen-apposing metal stents (LAMS) has become one of the treatments of choice for acute cholecystitis (AC) in fragile patients, scant data are available on real-life settings and long-term outcomes. Methods: We performed a multicenter retrospective study including EUS-guided GBD using LAMS for AC in 19 Italian centers from June 2014 to July 2020. The primary outcomes were technical and clinical success, and the secondary outcomes were the rate of adverse events (AE) and long-term follow-up. Results: In total, 116 patients (48.3% female) were included, with a mean age of 82.7 ± 11 years. LAMS were placed, transgastric in 44.8% of cases, transduodenal in 53.3% and transjejunal in 1.7%, in patients with altered anatomy. Technical success was achieved in 94% and clinical success in 87.1% of cases. The mean follow-up was 309 days. AEs occurred in 12/116 pts (10.3%); 8/12 were intraprocedural, while 1 was classified as early (15 days). According to the ASGE lexicon, two (16.7%) were mild, three (25%) were moderate, and seven (58.3%) were severe. No fatal AEs occurred. In subgroup analysis of 40 patients with a follow-up longer than one year, no recurrence of AC was observed. Conclusions: EUS-GBD had high technical and clinical success rates, despite the non-negligible rate of AEs, thus representing an effective treatment option for fragile patients.

This study aims to explore and analyze the experience of PAI teachers in carrying out learning process during the pandemic which is focused on three things; emotional regulation in response to school closure policies, their efforts to identify student learning facilities, and the learning strategies they choose. A qualitative approach with the phenomenological method was chosen to obtain information on the learning experiences of Islamic Religious education teachers of six Junior High Schools in Bandung, West Java, which were explored through semi-structured interviews and documentation. The results of the study found that there was psychological involvement and varied responses of the subject to school closure policies. In such conditions, they display self-efficacy to ensure the continuity of learning by carefully identifying student learning facilities and communicating effectively. The process has an impact on the implementation of their chose, with three strategies of Distance Learning (PJJ) from home, namely online; synchronous-asynchronous and outside the network with the module system. This study concludes that teacher self-efficacy plays a very important role in responding to and choosing appropriate learning strategies and technologies in various circumstances to ensure the continuity of learning, and at the same time recommending the improvement of these essential competencies to the Ministry of Education and Culture of the Republic of Indonesia on a regular and programmed basis.

Unresolved tensions frequently lead to the failure of family businesses. Parents and their children should be able to work together to resolve protracted problems. This study intends to explore the intergenerational conflict resolution strategy in an effort to develop new family business values and ensure the sustainability of family enterprises. The respondents in this study were 152 family business owners in Eastern Indonesia. The analysis used is PLS-SEM. The results of this study indicate that creating new value requires three intergenerational conflict resolution strategies: intergenerational collaboration, accommodation, and forcing. The results of this study also show that a family business that is able to create new value will be able to have an impact on the sustainability of the family business. This study contributes to the Thomas-Kilmann conflict mode approach, wherein the Thomas-Kilmann conflict mode instrument method leads to the creation of new values and sustainability in family enterprises.

Severe behavioral problems (SBPs) are common contributors to morbidity and reduced quality of life for adults with intellectual and developmental disabilities (IDD) and their families. Current medications for SBPs show equivocal effectiveness and are associated with a high risk of side effects. New and safe treatments are urgently needed. While preliminary studies suggest that medical cannabinoids, particularly the synthetic cannabinoid nabilone, are plausible treatment options for SBPs in adults with IDD, data on the tolerability, safety and efficacy of nabilone in this population has never been investigated. Thus, we propose this first-ever Phase I pre-pilot open-label clinical trial to obtain preliminary data on the adherence, tolerability and safety profiles of nabilone in adults with IDD, and explore changes in SBPs pre- to post-treatment. We hypothesize that nabilone has favorable tolerability and safety profile for adults with IDD. The preliminary results will inform the next-stage pilot randomized controlled trials, followed by fully powered clinical trials eventually. This research helps fill the evidence gap in the use of cannabinoids in individuals with IDD to meet the needs of patients, families, and service providers.

PURPOSEThe COVID-19 pandemic is a colossal challenge for global health; nonetheless, specific subgroups face considerably higher risks for infection and mortality. Among patients with malignant diseases, those with hematologic neoplasms are at a higher risk for poor outcomes. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and their short-term consequences in Latin America.METHODSMulticenter, prospective, observational, cohort study including patients older than 14 years from 14 centers in four countries (Mexico, Peru, Guatemala, and Panama) who had a confirmed diagnosis of acute leukemia, and who were undergoing active treatment since the first COVID-19 case in each country until the cutoff on July 15, 2020.RESULTSWe recruited 635 patients. Treatment modifications because of the COVID-19 pandemic were reported in 40.8% of cases. The main reason for such modifications was logistic issues (55.0%) and the most frequent modification was chemotherapy delay (42.0%). A total of 13.1% patients developed COVID-19 disease, with a mortality of 37.7%. Several factors were identified as independently associated with mortality, including a diagnosis of acute myeloid leukemia (odds ratio 2.38 [95% CI, 1.47 to 3.84]; P < .001), while the use of telemedicine was identified as a protective factor (odds ratio 0.36 [95% CI, 0.18 to 0.82]; P = .014).CONCLUSIONThese results highlight the collateral damage of COVID-19 in oncology patients.

Background: Myelodysplastic syndrome (MDS) is associated with persistent immune activation. High mobility group box-1 (HMGB1) is a ubiquitous, functionally diverse, non-histone intranuclear protein. During acute and chronic inflammatory states, HMGB1 is actively released by inflammatory cells, further amplifying the inflammatory response. A role in MDS and other hypoplastic bone marrow (BM) disorders is incompletely understood. Objectives: The objective of the study is to evaluate whether circulating HMGB1 is elevated in patients with MDS and other BM failure syndromes [namely, aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH)]. Design: This is a observational, cross-sectional, single-center, exploratory study. Methods: We evaluated circulating concentrations of HMGB1, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in patients with MDS and age-matched hematologically healthy controls as well as patients with AA and PNH. Results: We included 66 patients with MDS and 65 age-matched controls as well as 44 patients with other BM failures (AA = 27, PNH = 17). Circulating levels of HMGB1 were higher in patients with MDS [median, 4.9 ng/ml; interquartile range (IQR): 2.3–8.1] than in AA (median, 2.6 ng/ml; IQR: 1.7–3.7), PNH (median, 1.7 ng/ml; IQR: 0.9–2.5), and age-matched healthy individuals (median, 1.9 ng/ml; IQR: 0.9–2.5) ( p = 0.0001). We observed higher concentrations of HMGB1 in the very low/low-risk MDS patients than in the intermediate/high/very high-risk ones ( p = 0.046). Finally, in comparison with patients with AA, those with hypocellular MDS (h-MDS) had significantly higher levels of circulating HMGB1 ( n = 14; median concentration, 5.6 ng/ml, IQR: 2.8–7.3; p = 0.006). We determined a circulating HMGB1 value of 4.095 ng/ml as a diagnostic cutoff differentiator between h-MDS and AA. Conclusion: These observations indicate that circulating HMGB1 is increased in patients with MDS. HMGB1 (but not IL-1β or TNF-α) differentiated between MDS and other BM failures, suggesting that HMGB1 may be mechanistically involved in MDS and a druggable target to decrease inflammation in MDS.

Abstract The COVID-19 pandemic is still raging in most countries. Although the recent mass vaccination campaign has opened a new chapter in the battle against SARS-CoV-2, the world is still far from herd immunity. There is an urgent need to identify healthy people at high risk of contracting COVID-19, as well as supplements and nutraceuticals that can reduce the risk of infection or mitigate symptoms. In the present study, a metabolic phenotype that could protect individuals from SARS-CoV-2 infection or predispose them to developing COVID-19 was investigated. Untargeted metabolomics was performed on serum samples collected from 51 healthcare workers who were in good health at the beginning of the COVID-19 outbreak in Italy, and who were later exposed to the same risk of developing COVID-19. Half of them developed COVID-19 within three weeks of the blood collection. Our results demonstrate the presence of a specific signature associated with protection from SARS-CoV-2. Circulating monolaurin, which has well-known antiviral and antibacterial properties, was higher in protected subjects, suggesting a potential defensive role against SARS-CoV-2 infection; thus, dietary supplements could boost the immune system against this infection. In addition, our data demonstrate that people with higher levels of cholesterol are at higher risk of developing COVID-19. The present study demonstrates that metabolomics can be of great help for developing personalized medicine and for supporting public healthcare strategies. Studies with larger cohorts of subjects are necessary to confirm our findings.

Nowadays, we face a profound fragmentation of knowledge, which is addressed in distinctive ways, conforming to the specifics of each field of knowledge and having a specific lexicon and ways to interpret reality. To better understand and communicate the complexity of the reality of motor and sports sciences in Italy, it is necessary to study its ontology based on a holistic and comprehensive approach such as System Thinking (ST). So, this preliminary review aimed to verify the coherence of terminology used by Italian academics (who study methodologies related to teaching) and practical communities (who live the reality of daily teaching) in motor and sports sciences, specifically regarding the didactic of physical and sports education. For this purpose, according to Design Based Research (DBR), a first investigation of the interpretative semantics of the discipline's specific terms was accomplished with the support of multiple sources of information such as documents, databases, and brainstorming performed by experts (representing the guiding team and stakeholders from all considered communities). Moreover, the frequency of some terms and keywords considered in European (ERC) and Italian (CUN) legislation was assessed to contextualize better the impact of common practice community keywords on the scientific and regulatory community. Successively, the studies that analyzed the terms from 2000 to 2020 in the leading scientific search engines (SCOPUS and Web of Science) were also investigated. Results indicate that in the CUN and ERC areas, there is a total absence of the most relevant lemma to the community of practice. Furthermore, significant terms such as play, sports education, psychomotricity, and gymnastics are less considered or unconsidered in the specific scientific and didactic fields. Possible solutions for a specific semantic model to reduce the gap are finally hypothesized and presented.