midbrain hindbrain involvement in septo optic dysplasia

BACKGROUND AND PURPOSE: Midbrain-hindbrain involvement in septo-optic dysplasia has not been well described, despite reported mutations of genes regulating brain stem patterning. We aimed to describe midbrain-hindbrain involvement in patients with septo-optic dysplasia and to identify possible clinical-neuroimaging correlations. MATERIALS AND METHODS: Using MR imaging, we categorized 38 patients (21 males) based on the presence (group A, 21 patients) or absence (group B, 17 patients) of visible brain stem anomalies. We measured height and anteroposterior diameter of midbrain, pons, and medulla, anteroposterior midbrain/pons diameter (M/P ratio), vermian height, and tegmento-vermian angle, and compared the results with 114 healthy age-matched controls. Furthermore, patients were subdivided based on the type of midline anomalies. The associations between clinical and neuroradiological features were investigated. Post hoc tests were corrected according to Bonferroni adjustment (pB). RESULTS: Patients with brain stem abnormalities had smaller anteroposterior pons diameter than controls (pB CONCLUSION: Midbrain-hindbrain abnormalities are a significant, albeit underrecognized, component of the septo-optic dysplasia spectrum, and are significantly associated with developmental delay in affected patients

Factors affecting the successful implementation of a digital intervention for health financing in a low-resource setting at scale: semistructured interview study with health care workers and management staff

BACKGROUND: Digital interventions for health financing, if implemented at scale, have the potential to improve health system performance by reducing transaction costs and improving data-driven decision-making. However, many interventions never reach sustainability, and evidence on success factors for scale is scarce. The Insurance Management Information System (IMIS) is a digital intervention for health financing, designed to manage an insurance scheme and already implemented on a national scale in Tanzania. A previous study found that the IMIS claim function was poorly adopted by health care workers (HCWs), questioning its potential to enable strategic purchasing and succeed at scale. OBJECTIVE: This study aimed to understand why the adoption of the IMIS claim function by HCWs remained low in Tanzania and to assess implications for use at scale. METHODS: We conducted 21 semistructured interviews with HCWs and management staff in 4 districts where IMIS was first implemented. We sampled respondents by using a maximum variation strategy. We used the framework method for data analysis, applying a combination of inductive and deductive coding to organize codes in a socioecological model. Finally, we related emerging themes to a framework for digital health interventions for scale. RESULTS: Respondents appreciated IMIS's intrinsic software characteristics and technical factors and acknowledged IMIS as a valuable tool to simplify claim management. Human factors, extrinsic ecosystem, and health care ecosystem were considered as barriers to widespread adoption. CONCLUSIONS: Digital interventions for health financing, such as IMIS, may have the potential for scale if careful consideration is given to the environment in which they are placed. Without a sustainable health financing environment, sufficient infrastructure, and human capacity, they cannot unfold their full potential to improve health financing functions and ultimately contribute to universal health coverage

Applying multidimensional computerized adaptive testing to the MSQOL-54: a simulation study

Background: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is one of the most commonly-used MS-specific health-related quality of life (HRQOL) measures. It is a multidimensional, MS-specific HRQOL inventory, which includes the generic SF-36 core items, supplemented with 18 MS-targeted items. Availability of an adaptive short version providing immediate item scoring may improve instrument usability and validity. However, multidimensional computerized adaptive testing (MCAT) has not been previously applied to MSQOL-54 items. We thus aimed to apply MCAT to the MSQOL-54 and assess its performance. Methods: Responses from a large international sample of 3669 MS patients were assessed. We calibrated 52 (of the 54) items using bifactor graded response model (10 group factors and one general HRQOL factor). Then, eight simulations were run with different termination criteria: standard errors (SE) for the general factor and group factors set to different values, and change in factor estimates from one item to the next set at < 0.01 for both the general and the group factors. Performance of the MCAT was assessed by the number of administered items, root mean square difference (RMSD), and correlation. Results: Eight items were removed due to local dependency. The simulation with SE set to 0.32 (general factor), and no SE thresholds (group factors) provided satisfactory performance: the median number of administered items was 24, RMSD was 0.32, and correlation was 0.94. Conclusions: Compared to the full-length MSQOL-54, the simulated MCAT required fewer items without losing precision for the general HRQOL factor. Further work is needed to add/integrate/revise MSQOL-54 items in order to make the calibration and MCAT performance efficient also on group factors, so that the MCAT version may be used in clinical practice and research

Accuracy and limitations of the growth hormone (GH) releasing hormone-arginine retesting in young adults with childhood-onset GH deficiency

Background: Re-testing for GH secretion is needed to confirm the diagnosis of GH deficiency (GHD) after adult height achievement in childhood-onset GHD (COGHD). Aim: To define the cut-off of GH peak after retesting with GH-releasing hormone plus arginine (GHRHarg) in the diagnosis of permanent GHD in COGHD of different etiology. Patients and methods: Eighty-eight COGHD (median age 17.2 y), 29 idiopathic GHD (IGHD), 44 cancer survivors (TGHD) and 15 congenital GHD (CGHD) were enrolled in the study; 54 had isolated GHD (iGHD) and 34 had multiple pituitary hormone deficiencies (MPHD). All were tested with insulin tolerance test (ITT) and GHRHarg. IGHD with a GH response to ITT 656\ub5g/L were considered true negatives and served as the control group, and patients with a GH response <6\ub5g/L as true positives. Baseline IGF-I was also measured. The diagnostic accuracy of GHRHarg testing and of IGF-I SDS in patients with GHD of different etiologies was evaluated by ROC analysis. Results: Forty-six subjects with a GH peak to ITT 656\ub5g/L and 42 with GH peak <6 \ub5g/L showed a GH peak after GHRHarg between 8.8\u2013124\ub5g/L and 0.3\u201326.3\ub5g/L, respectively; 29 IGHD were true negatives, 42 were true positives and 17 with a high likelihood GHD showed a GH peak to ITT 656\ub5g/L. ROC analysis based on the etiology indicated the best diagnostic accuracy for peak GH cutoffs after GHRHarg of 25.3 \ub5g/L in CGHD, 15.7 in TGHD, and 13.8 in MPHD, and for IGF-1 SDS at 122.1 in CGHD, 121.5 in TGHD, and 121.9 in MPHD. Conclusions: Our findings indicate that the best cut-off for GH peak after retesting with GHRHarg changes according to the etiology of GHD during the transition age. Based on these results the diagnostic accuracy of GHRHarg remains questionable

MTOR and STAT3 pathway hyper-activation is associated with elevated interleukin-6 levels in patients with shwachman-diamond syndrome: Further evidence of lymphoid lineage impairment

Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome, resulting in neutropenia and a risk of myeloid neoplasia. A mutation in a ribosome maturation factor accounts for almost all of the cases. Lymphoid involvement in SDS has not been well characterized. We recently reported that lymphocyte subpopulations are reduced in SDS patients. We have also shown that the mTOR-STAT3 pathway is hyper-activated in SDS myeloid cell populations. Here we show that mTOR-STAT3 signaling is markedly upregulated in the lymphoid compartment of SDS patients. Furthermore, our data reveal elevated IL-6 levels in cellular supernatants obtained from lymphoblasts, bone marrow mononuclear and mesenchymal stromal cells, and plasma samples obtained from a cohort of 10 patients. Of note, everolimus-mediated inhibition of mTOR signaling is associated with basal state of phosphorylated STAT3. Finally, inhibition of mTOR-STAT3 pathway activation leads to normalization of IL-6 expression in SDS cells. Altogether, our data strengthen the hypothesis that SDS affects both lymphoid and myeloid blood compartment and suggest everolimus as a potential therapeutic agent to reduce excessive mTOR-STAT3 activation in SDS

Rehabilitative treatment of patients with covid-19 infection: The p.a.r.m.a. evidence based clinical practice protocol

Background: The impact of the SARS-CoV-2 on the National Health System (NHS) required a reorganization of the various levels of care, which also involved the rehabilitation reality. Aim of the work: A clinical practice review of the literature was conducted to provide operational-rehabilitation guidelines adapt-ed to the local reality and to the recent corporate reorganization in the context of the COVID-19 emergency. Methods: A practice review of the available scientific evidence was regularly conducted from the start of the COVID-19 pandemic to periodically update the clinical practice guidelines. Articles that met the following inclusion criteria were included: studies conducted on human adult subjects with COVID-19 infection, un-dergoing rehabilitation in any hospitalization setting. Results: The results of this clinical practice update were periodically discussed with colleagues and collaborators in a multi-professional team, in order to guarantee a good clinical practice protocol, named P.A.R.M.A. Conclusions: The P.A.R.M.A. protocol is the result of a periodic review literature update, which has allowed us to take charge of patients affected by COVID-19 ac-cording to the most up-to-date clinical evidences, guaranteeing a shared and uniform treatment within a local reality in an era of health emergency. (www.actabiomedica.it)

1601d Hazard determinants of carbon nanotubes (cnts) driving molecular initiating events (mies) in adverse outcome pathways (aops) of airways diseases

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Beyond disease: Happiness, goals, and meanings among persons with multiple sclerosis and their caregivers

The experience of persons with multiple sclerosis (MS) and their caregivers is usually investigated in terms of emotional distress and health-related quality of life, while well-being indicators remain largely underexplored. In addition, findings are often interpreted from the clinical perspective, neglecting socio-cultural aspects that may crucially contribute to individuals' functioning. At the methodological level, most studies rely on scaled instruments, not allowing participants to freely express their needs and resources. Based on the bio-psycho-social perspective endorsed by the International Classification of Functioning, well-being indicators were investigated among 62 persons with MS (PwMS), their 62 caregivers and two control groups, matched by age and gender. Participants completed the Positive Affect Negative Affect Schedule (PANAS), the Satisfaction with Life Scale (SWLS), and the Eudaimonic and Hedonic Happiness Investigation instrument (EHHI). EHHI provides information on participants' happiness, goals and meanings through scaled and open-ended questions, contextualized within major life domains. No relevant differences emerged among PwMS and caregivers, compared with the respective control groups, as concerns life domains associated with happiness, goals and meaning. Participants across groups prominently mentioned family, highlighting its intrinsic value and its relevance as a sharing context; health did not represent a major theme for PwMS; community, society and religion/spirituality issues were substantially neglected by all participants. PwMS and caregivers reported lower levels of positive affect than their control groups, while no substantial differences emerged for negative affect, happiness and meaningfulness levels in life and across most domains. Results suggest that the experience of MS is associated with well-being in relevant life domains, such as family and close relationships. Although PwMS and caregivers identified a lower number of goals and meaning-related opportunities compared to control groups, they showed a positive adjustment to disease through the development of personal and family resources. These assets are often undervalued by health professionals and social institutions, while they could be fruitfully exploited through the active involvement of PwMS and their families as expert and exemplary informants in initiatives aimed at promoting the well-being of individuals and communities

Longitudinal dynamics of circulating tumor cells and circulating tumor DNA for treatment monitoring in metastatic breast cancer

PURPOSE: Liquid biopsy-based biomarkers, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), are increasingly important for the characterization of metastatic breast cancer (MBC). The aim of the study was to explore CTCs and ctDNA dynamics to better understand their potentially complementary role in describing MBC. METHODS: The study retrospectively analyzed 107 patients with MBC characterized with paired CTCs and ctDNA assessments and a second prospective cohort, which enrolled 48 patients with MBC. CTCs were immunomagnetically isolated and ctDNA was quantified and then characterized through next-generation sequencing in the retrospective cohort and droplet digital polymerase chain reaction in the prospective cohort. Matched pairs variations at baseline, at evaluation one (EV1), and at progression were tested through the Wilcoxon test. The prognostic role of ctDNA parameters was also investigated. RESULTS: Mutant allele frequency (MAF) had a significant decrease between baseline and EV1 and a significant increase between EV1 and progression. Number of detected alterations steadily increased across timepoints, CTCs enumeration (nCTCs) significantly increased only between EV1 and progression. MAF dynamics across the main altered genes was then investigated. Plasma DNA yield did not vary across timepoints both in the retrospective cohort and in the prospective cohort, while the short fragments fraction showed a potential role as a prognostic biomarker. CONCLUSION: nCTCs and ctDNA provide complementary information about prognosis and treatment benefit. Although nCTCs appeared to assess tumor biology rather than tumor burden, MAF may be a promising biomarker for the dynamic assessment of treatment response and resistance