Generation of two human iPSC lines (HIMRi002-A and HIMRi003-A) derived from Caveolinopathy patients with rippling muscle disease.

Here we introduce the human induced pluripotent stem cell lines (hiPSCs), HIMRi002-A and HIMRi003-A, generated from cultured dermal fibroblasts of 61-year-old (HIMRi002-A) and 38-year-old (HIMRi003-A) female patients, carrying a known heterozygous pathogenic variant (p.A46T) in the Caveolin 3 (CAV3) gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi002-A and HIMRi003-A display typical embryonic stem cell-like morphology, carry the p.A46T CAV3 gene mutation, express several pluripotent stem cell markers, retain normal karyotype (46, XX) and can differentiate in all three germ layers. We postulate that the HIMRi002-A and HIMRi003-A iPSC lines can be used for the characterization of CAV3-associated pathomechanisms and for developing new therapeutic options.

E-Health intervention for subthreshold depression: Reach and two-year effects of a randomized controlled trial.

BACKGROUND: There is evidence for e-Health interventions for full-blown depression. Little is known regarding commonly untreated subthreshold depression in primary care. This randomized controlled multi-centre trial assessed reach and two-year-effects of a proactive e-Health intervention (ActiLife) for patients with subthreshold depression. METHODS: Primary care and hospital patients were screened for subthreshold depression. Over 6 months, ActiLife participants received three individualized feedback letters and weekly messages promoting self-help strategies against depression, e.g., dealing with unhelpful thoughts or behavioural activation. The primary outcome depressive symptom severity (Patient Health Questionnaire;PHQ-8) and secondary outcomes were assessed 6, 12 and 24 months. RESULTS: Of those invited, n = 618(49.2 %) agreed to participate. Of them, 456 completed the baseline interview and were randomized to ActiLife (n = 227) or assessment only (n = 226). Generalised estimation equation analyses adjusting for site, setting and baseline depression revealed that depressive symptom severity declined over time, with no significant group differences at 6 (mean difference = 0.47 points; d = 0.12) and 24 months (mean difference = -0.05 points; d = -0.01). Potential adverse effects were observed at 12 months, with higher depressive symptom severity for ActiLife than control participants (mean difference = 1.33 points; d = 0.35). No significant differences in rates of reliable deterioration or reliable improvement of depressive symptoms were observed. ActiLife increased applied self-help strategies at 6 (mean difference = 0.32; d = 0.27) and 24 months (mean difference = 0.22; d = 0.19), but not at 12 months (mean difference = 0.18; d = 0.15). LIMITATIONS: Self-report measures and lack of information on patients' mental health treatment. DISCUSSION: ActiLife yielded satisfactory reach and increased the use of self-help strategies. Data were inconclusive in terms of depressive symptom changes.

Exploring Risk Factors in Suicidal Ideation and Attempt Concept Cooccurrence Networks.

Suicide is a significant and rising threat to public health. In the United States, 47,500 people died from suicide in 2019, a 10-year increase of 30%. Many researchers are interested in studying the risk factors associated with suicidal ideation and suicide attempt to help inform clinical screening, intervention, and prevention efforts. Many suicide risk factor analyses draw from clinical subdomains and quantify risk factors independently. While traditional modeling approaches might assume independence between risk factors, current suicide research suggests that the development of suicidal intent is a complex, multifactorial process. Thus, it may be beneficial to how suicide risk-factors interact with one another. In this study, we used network analysis to generate visual suicidality risk relationship diagrams. We extract medical concepts from free-text clinical notes and generate cooccurrence-based risk networks for suicidal ideation and suicide attempt. In addition, we generate a network of risk factors for suicidal ideation which evolves into a suicide attempt. Our networks were able to replicate existing risk factor findings and provide additional insight into the degree to which risk factors behave as independent morbidities or as interacting comorbidities with other risk factors. These results highlight potential avenues for risk factor analyses of complex outcomes using network analysis.

Stiripentol in the treatment of adults with focal epilepsy- a retrospective analysis.

OBJECTIVES: The aim of the present study was to evaluate the safety and efficacy of the add-on treatment of stiripentol (STP) in adult patients with severely pharmacoresistant focal or multifocal epilepsy. METHODS: Data on adult patients treated with STP from March 2007 to July 2020 and with at least one clinical follow-up (FU) were retrospectively reviewed. Data on tolerability, efficacy and concomitant medication were evaluated at baseline, 6 months (5.5 ± 1.6 months (mean ± SD)) and 12 months (13.1 ± 3.9 months (mean ± SD)). RESULTS: Data of 22 patients (54.5% male, mean age 34.4 ± 17.79 years (mean ± SD), including mean duration of epilepsy 17.6 ± 25.5 years (mean ± SD), median seizure frequency 30 ± 20 (median ± MAD) per month, and 63.6% being severely intellectually disabled, with 3 to 18 previous anti-seizure-drugs (ASD), were collected. After 6 months, 72.7% of the patients were still taking STP, and 31% of the patients were responders, including 13% who were seizure-free. The 12-month retention rate was 54.4 %, the response rate was 36.4% and 13.6% of patients were seizure-free at the 12-month FU. Reasons for discontinuation were increased seizure frequency, hyperammonaemia and encephalopathy. CONCLUSION: STP seems to be a useful option in the treatment of patients with severely pharmacoresistant epilepsy. Prospective trials are necessary to examine the efficacy of STP in adult patients with pharmacoresistant focal epilepsy.

A comprehensive mapping of outcomes following psychotherapy for adolescent depression: The perspectives of young people, their parents and therapists.

As mental health systems move towards person-centred care, outcome measurement in clinical research and practice should track changes that matter to young people and their families. This study mapped the types of change described by three key stakeholder groups following psychotherapy for depression, and compared the salience of these outcomes with the frequency of their measurement in recent quantitative treatment effectiveness studies for adolescent depression.Using qualitative content analysis, this study identified and categorized outcomes across 102 semi-structured interviews that were conducted with depressed adolescents, their parents, and therapists, as part of a randomized superiority trial. Adolescents had been allocated to Cognitive-Behavioral Therapy, Short-Term Psychoanalytic Psychotherapy, or a Brief Psychosocial Intervention.The study mapped seven high-level outcome domains and 29 outcome categories. On average, participants discussed change in four domains and six outcome categories. The most frequently discussed outcome was an improvement in mood and affect (i.e., core depressive symptoms), but close to half of the participants also described changes in family functioning, coping and resilience, academic functioning, or social functioning. Coping had specific importance for adolescents, while parents and therapists showed particular interest in academic functioning. There was some variation in the outcomes discussed beyond these core themes, across stakeholder groups and treatment arms.Of the outcomes that were frequently discussed in stakeholder narratives, only symptomatic change has been commonly reported in recent treatment studies for adolescent depression. A shift towards considering multiple outcome domains and perspectives is needed to reflect stakeholder priorities and enable more nuanced insights into change processes.

Low-threshold SARS-CoV-2 testing facility for hospital staff: Prevention of COVID-19 outbreaks?

BACKGROUND: The ongoing global SARS-CoV-2 pandemic has caused over 4.7 million infections greatly challenging healthcare workers (HCW) and medical institutions worldwide. The SARS-CoV-2 pandemic has shown to significantly impact mental and physical health of HCW. Thus, implementation of testing facilities supporting HCW are urgently needed. METHODS: A low-threshold SARS-CoV-2 testing facility was introduced at the University Hospital Bonn, Germany, in March 2020. Irrespective of clinical symptoms employees were offered a voluntary and free SARS-CoV-2 test. Furthermore, employees returning from SARS-CoV-2 risk regions and employees after risk contact with SARS-CoV-2 infected patients or employees were tested for SARS-CoV-2 infection. Pharyngeal swabs were taken and reverse transcription polymerase chain reaction for detection of SARS-CoV-2 was performed, test results being available within 24 h. Profession, symptoms and reason for SARS-CoV-2 testing of employees were recorded. RESULTS: Between 9th March and April 30, 2020, a total of 1510 employees were tested for SARS-CoV-2 infection. 1185 employees took advantage of the low-threshold testing facility. One percent (n = 11) were tested positive for SARS-CoV-2 infection, 18% being asymptomatic, 36% showing mild and 36% moderate/severe symptoms (missing 10%). Furthermore, of 56 employees returning from SARS-CoV-2 risk regions, 18% (10/56) were tested SARS-CoV-2 positive. After risk contact tracking by the hospital hygiene 6 patient-to-employee transmissions were identified in 163 employees with contact to 55 SARS-CoV-2 positive patients. CONCLUSION: In the absence of easily accessible public SARS-CoV-2 testing facilities low-threshold SARS-CoV-2 testing facilities in hospitals with rapid testing resources help to identify SARS-CoV-2 infected employees with absent or mild symptoms, thus stopping the spread of infection in vulnerable hospital environments. High levels of professional infection prevention training and implementation of specialized wards as well as a perfectly working hospital hygiene network identifying and tracking risk contacts are of great importance in a pandemic setting.

[Clinical symptoms of autoinflammatory diseases]. / Klinische Symptomatik autoinflammatorischer Erkrankungen.

Systemic autoinflammatory diseases are characterized by a spontaneous chronic inflammatory reaction mediated by the innate immunity. The inflammatory processes involve many organs including the skin. Diagnosis remains a challenge despite new molecular genetic methods, but early diagnosis is crucial for the prevention of long-term complications such as amyloidosis. Skin manifestations are often observed early in the course of the disease and can be decisive in the diagnosis.

Transplantation of gene-modified haematopoietic stem cells: Application and clinical considerations.

Autologous and allogeneic haematopoietic stem cell (HSC) transplantation has been performed in patients with various malignant and non-malignant haematological disorders for more than 50 years. Ex vivo gene modification of HSCs for autologous transplantation opens up new therapeutic avenues for genetic and infectious diseases. Major advances have been made over the last three decades with respect to gene modification of HSCs and transplantation strategies, ultimately culminating in the approval of two such therapies in Europe (Strimvelis for a rare primary immune deficiency, and LentiGlobin for beta-thalassaemia). Newer gene-modifying technologies and treatment regimens have also recently come to the fore, which hold great promise for the development of safer and more effective treatments. We provide an overview of the current state of gene-modified HSC therapies, highlighting success stories, limitations and important considerations for achieving successful translation of these therapies to the clinic.

Association of CCL2 with systemic inflammation in Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)-1 system, but the exact pathophysiological pathways remain largely unknown. OBJECTIVES: To identify and characterize the pathogenetic players in SchS. METHODS: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme-linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse-transcriptase polymerase chain reaction and ELISA. RESULTS: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL-1ß (immune cells, fibroblasts) and tumour necrosis factor (TNF)-α (fibroblasts) were important CCL2 inducers. TNF-α, but not IL-17, strengthened the CCL2-inducing effect of IL-1ß in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF-α and IL-1ß serum levels in patients with SchS. Therapeutic IL-1ß blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. CONCLUSIONS: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS.

Defining the Normal Dorsal Contour of the Corpus Callosum with Time.

BACKGROUND AND PURPOSE: Morphological changes of the corpus callosum have been associated with a large number of congenital neurocognitive and psychiatric disorders. Focal defects or notches of the dorsal surface of the corpus callosum have not been well characterized. Our purpose was the following; 1) to characterize the dorsal contour of the corpus callosum during the life span, 2) to characterize the relationship of contour deviations to neighboring vessels, and 3) to determine whether contour deviations are congenital or acquired. MATERIALS AND METHODS: We retrospectively reviewed normal sagittal T1-weighted brain MR images. A "notch" was defined as a concavity in the dorsal surface at least 1 mm in depth. The corpus callosum was considered to be "undulating" if there were >2 notches, including an anterior and posterior notch. The presence of a pericallosal artery and its relationship to a notch were assessed. RESULTS: We reviewed 1639 MR imaging studies, spanning 0-89 years of age. A total of 1102 notches were identified in 823 studies; 344 (31%) were anterior, 660 (60%) were posterior, and 98 (9%), undulating. There was a positive correlation between the prevalence (P < .001) and depth (P = .028) of an anterior notch and age and a negative correlation between the prevalence of a posterior notch and age (P < .001). There was no difference between patient sex and corpus callosum notching (P = .884). Of the 823 studies with notches, 490 (60%) were associated with a pericallosal artery (P < .001). CONCLUSIONS: The prevalence and depth of notches in the anterior corpus callosum increase significantly with age; this finding suggests that most notches are acquired. There is a significant positive association between the presence of a corpus callosum notch and adjacent pericallosal arteries, suggesting that this may play a role in notch formation.

Transplantation of gene-modified haematopoietic stem cells: Application and clinical considerations

Autologous and allogeneic haematopoietic stem cell (HSC) transplantation has been performed in patients with various malignant and non-malignant haematological disorders for more than 50 years. Ex vivo gene modification of HSCs for autologous transplantation opens up new therapeutic avenues for genetic and infectious diseases. Major advances have been made over the last three decades with respect to gene modification of HSCs and transplantation strategies, ultimately culminating in the approval of two such therapies in Europe (Strimvelis for a rare primary immune deficiency, and LentiGlobin for beta-thalassaemia). Newer gene-modifying technologies and treatment regimens have also recently come to the fore, which hold great promise for the development of safer and more effective treatments. We provide an overview of the current state of gene-modified HSC therapies, highlighting success stories, limitations and important considerations for achieving successful translation of these therapies to the clinic

Ventral hernia recurrence in women of childbearing age: a systematic review and meta-analysis.

BACKGROUND: There is no consensus agreement on the optimal management strategy for ventral hernia in women of childbearing age. The theoretical increased risk of ventral hernia recurrence can impact management strategies. We conducted a systematic review of the literature to report the ventral hernia recurrence rate in women of childbearing age who underwent hernia repair prior to their pregnancy and propose a management algorithm. METHODS: We systematically searched multiple databases including MEDLNE, PubMed, and the Cochrane Library sources from inception to August, 2017. Two reviewers independently identified 314 primary studies, assessed methodological quality, and extracted data. Quality of included studies was assessed by employing the Newcastle Ottawa quality assessment tool for cohort studies. A separate tool was utilized for assessing the methodological quality of case series. A meta-analysis of proportions was conducted of studies reporting incidence of recurrence using STATA, employing a random effects model, to calculate a pooled weighted incidence rate (with 95% confidence interval). Descriptive statistics were employed to report the findings of studies which did not report any ventral hernia recurrence. RESULTS: Five retrospective studies were included in our review, enrolling a total of 14,638 female participants. Upon stratifying patients according to pregnancy status after primary hernia repair, 13,494 were found to be in the non-pregnant cohort whereas 1,144 were included in the pregnant cohort. Overall, 9% (95% CI 8-9%) of the non-pregnant patients experienced a recurrence whereas 12% (95% CI 10-15%) of patients that became pregnant subsequent to a ventral hernia repair experienced a recurrence. No major adverse events were recorded throughout the course of pregnancy. CONCLUSIONS: Ventral hernias in women of childbearing age have a pooled recurrence rate of 12%. Pregnancy may be considered a risk factor for ventral hernia recurrence. Female patients of childbearing age with asymptomatic or minimally symptomatic ventral hernias that do not pose a significant strain on the patients' quality of life could be provided with the option of watchful waiting, with appropriate education of risks while discussing management.

Activity of plazomicin in combination with other antibiotics against multidrug-resistant Enterobacteriaceae.

Plazomicin is a next-generation aminoglycoside that was approved by the US FDA in June 2018 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis due to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. Plazomicin is active against multi-drug resistant (MDR) Enterobacteriaceae, where combination therapy is often used to treat infections caused by these pathogens. To determine synergy with other antibiotics, plazomicin was combined with antibiotics in checkerboard assays against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides and ß-lactams; 10 Escherichia coli isolates, 8 Klebsiella spp. isolates, 10 Enterobacter spp. isolates, and 2 Citrobacter freundii isolates were evaluated. Plazomicin had potent activity against MDR Enterobacteriaceae, including aminoglycoside-resistant strains, with MIC ranges of 0.5 - 2 µg/mL against E. coli isolates, 0.12 - 8 µg/mL against Klebsiella spp. isolates, 0.25 - 2 µg/mL against Enterobacter spp. isolates, and 0.06 - 0.25 µg/mL against C. freundii isolates. Synergy between plazomicin and piperacillin/tazobactam or ceftazidime was observed by checkerboard studies and confirmed by time-kill assays. No combination showed antagonism. These studies indicate that plazomicin has potential as a monotherapy and as combination therapy for treating serious Gram-negative infections caused by MDR Enterobacteriaceae.

GROW: a model for mentorship to advance women's leadership in global health.

In this essay, we discuss the under-representation of women in leadership positions in global health (GH) and the importance of mentorship to advance women's standing in the field. We then describe the mentorship model of GROW, Global Research for Women. We describe the theoretical origins of the model and an adapted theory of change explaining how the GROW model for mentorship advances women's careers in GH. We present testimonials from a range of mentees who participated in a pilot of the GROW model since 2015. These mentees describe the capability-enhancing benefits of their mentorship experience with GROW. Thus, preliminary findings suggest that the GROW mentorship model is a promising strategy to build women's leadership in GH. We discuss supplemental strategies under consideration and next steps to assess the impact of GROW, providing the evidence to inform best practices for curricula elsewhere to build women's leadership in GH.

Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-Resistant Enterobacteriaceae.

The next-generation aminoglycoside plazomicin, in development for infections due to multidrug-resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and ß-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC50/90 of 0.5/4 µg/ml and sustained 3-log10 kill against MDR Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp.

Delineation between different components of chronic pain using dimension reduction - an ASL fMRI study in hand osteoarthritis.

BACKGROUND: Traditional psychometric measures aimed at characterizing the pain experience often show considerable overlap, due to interlinked affective and modulatory processes under central nervous system control. Neuroimaging studies have been employed to investigate this complexity of pain processing, in an attempt to provide a quantifiable, adjunctive description of pain perception. In this exploratory study, we examine psychometric and neuroimaging data from 38 patients with painful osteoarthritis of the carpometacarpal joint. We had two aims: first, to utilize principal component analysis (PCA) as a dimension reduction strategy across multiple self-reported endpoints of pain, cognitive and affective functioning; second, to investigate the relationship between identified dimensions and regional cerebral blood flow (rCBF) as an indirect measure of brain activity underpinning their ongoing pain experiences. METHODS: Psychometric data were collected using validated questionnaires. Quantitative estimates of rCBF were acquired using pseudo-continuous arterial spin-labelled functional magnetic resonance imaging. RESULTS: Two principal components were identified that accounted for 73% of data variance; one related to pain scores and a second to psychological traits. Voxel-wise multiple regression analysis revealed a significant negative association between the 'pain score' component and rCBF to a right temporal lobe cluster, including the amygdala and the parahippocampal cortex. CONCLUSION: We suggest this association may represent a coping mechanism that aims to reduce fear-related pain-anxiety. Further investigation of central brain processing mechanisms in osteoarthritis-related pain may offer insights into more effective therapeutic strategies. SIGNIFICANCE: This study demonstrates that dimension reduction using PCA allows insight into pain perception and its affective components in relation to brain activation patterns in patients with painful hand osteoarthritis.

In chronic spontaneous urticaria, high numbers of dermal endothelial cells, but not mast cells, are linked to recurrent angio-oedema.

BACKGROUND: Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder characterized by recurrent weals, angio-oedema or both. Recent studies have shown that the number of endothelial cells is increased in the skin of patients with CSU, but the underlying mechanisms and clinical implications of this are unclear. AIM: To evaluate whether mast cell (MC) or endothelial cell (EC) numbers correlate with CSU and whether they are relevant for disease duration, disease activity or the presence of clinical features. METHODS: We determined the numbers of CD31+ ECs and MCs in nonlesional skin of 30 patients with CSU using quantitative histomorphometry, and assessed their correlation with each other and with clinical features such as disease duration, disease activity and occurrence of angio-oedema. RESULTS: The numbers of MCs and ECs were high in the nonlesional skin of patients with CSU, but did not correlate with each other. Neither MC number nor EC number correlated with disease duration or disease activity. Interestingly, patients with high numbers of cutaneous CD31+ ECs had higher rates of recurrent angio-oedema and vice versa. CONCLUSIONS: Based on these findings, we speculate that vascular remodelling and MC hyperplasia in patients with CSU occurs independently and via different mechanisms. Targeting of the mechanisms that drive neoangiogenesis in CSU may result in novel therapeutic strategies for the management of patients with angio-oedema.