Medical Therapy for Peripheral Artery Disease.

PURPOSE OF REVIEW: Patients with lower extremity peripheral artery disease (PAD) are at high risk for major adverse cardiovascular events (MACE) and major adverse limb events (MALE). This manuscript will review the current evidence for medical therapy in patients with PAD according to different clinical features and the overall cardiovascular (CV) risk. RECENT FINDINGS: The management of PAD encompasses non-pharmacologic strategies, including lifestyle modification such as smoking cessation, supervised exercise, Mediterranean diet and weight loss as well as pharmacologic interventions, particularly for high risk patients. Benefits for reduction of CV and limb outcomes have been demonstrated for new therapies, including antithrombotic therapy (i.e., low-dose rivaroxaban plus aspirin), lipid lowering therapy (i.e., proprotein convertase subtilisin/kexin type 9 inhibitors), and glucose lowering therapy (i.e., sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists). However, the adoption of these therapies in PAD remains suboptimal in practice. Implementation science studies have recently shown promising results in PAD patients. Comprehensive medical and non-medical management of PAD patients is crucial to improving patient outcomes, mitigating symptoms, and reducing the risk of MACE and MALE. A personalized approach, considering the patient's overall risk profile and preference, is essential for optimizing medical management of PAD.

Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD.

Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).

Randomized Controlled Trial of a Brief Video Intervention to Reduce Self-Stigma of Mental Illness.

Objective: Self-stigma, a phenomenon wherein individuals internalize self-directed negative stereotypes about mental illness, is associated with negative outcomes related to recovery. This randomized controlled study assessed the efficacy of a brief social contact-based video intervention in reducing self-stigma in a large sample of individuals ages 18-35 endorsing an ongoing mental health condition. We hypothesized that the brief video would reduce self-stigma.Methods: In January and February 2023, we recruited and assigned 1,214 participants to a brief video-based intervention depicting a young individual living with mental illness sharing his personal story or to a non-intervention control. In the 2-minute video, informed by focus groups, a young individual described struggles with mental illness symptoms; this was balanced with descriptions of living a meaningful and productive life. Self-stigma assessments (Stereotype Endorsement, Alienation, Stigma Resistance, Perceived Devaluation Discrimination, Secrecy, and Recovery Assessment Scale) were conducted pre- and post-intervention and at 30-day follow-up.Results: A 2 ✕ 3 group-by-time analysis of variance showed that mean self-stigma scores decreased in the intervention arm relative to control across 5 of 6 self-stigma domains: Stereotype Endorsement (P = .006), Alienation (P < .001), Stigma Resistance (P = .004), Secrecy (P < .001), and Recovery Assessment Scale (P < .001). Cohen d effect sizes ranged from 0.22 to 0.46 for baseline to post-intervention changes. Baseline and 30-day follow-up assessments did not significantly differ.Conclusions: A 2-minute social contact-based video intervention effectively yielded an immediate but not a lasting decrease in self-stigma among young individuals with ongoing mental health conditions. This is the first study to examine the effect of a video intervention on self-stigma. Future trials of self-stigma treatment interventions should explore whether combining existing interventions with brief videos enhances intervention effects.Trial Registration: NCT05878470.

Ethnoracial Risk Variation Across the Psychosis Continuum in the US: A Systematic Review and Meta-Analysis.

Importance: Studies suggest a higher risk of schizophrenia diagnoses in Black vs White Americans, yet a systematic investigation of disparities that include other ethnoracial groups and multiple outcomes on the psychosis continuum is lacking. Objective: To identify ethnoracial risk variation in the US across 3 psychosis continuum outcomes (ie, schizophrenia and other psychotic disorders, clinical high risk for psychosis [CHR-P], and psychotic symptoms [PSs] and psychotic experiences [PEs]). Data Sources: PubMed, PsycINFO and Embase were searched up to December 2022. Study Selection: Observational studies on ethnoracial differences in risk of 3 psychosis outcomes. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Using a random-effects model, estimates for ethnoracial differences in schizophrenia and PSs/PEs were pooled and moderation by sampling and setting was determined, along with the assessment of heterogeneity and risk of bias. Main Outcomes and Measures: Risk of schizophrenia and other psychotic disorder, CHR-P, and conversion to psychosis among CHR-P and PSs/PEs. Results: Of 64 studies in the systematic review, 47 were included in the meta-analysis comprising 54 929 people with schizophrenia and 223 097 with data on PSs/PEs. Compared with White individuals, Black individuals had increased risk of schizophrenia (pooled odds ratio [OR], 2.07; 95% CI, 1.64-2.61) and PSs/PEs (pooled standardized mean difference [SMD], 0.10; 95% CI, 0.03-0.16), Latinx individuals had higher risk of PSs/PEs (pooled SMD, 0.15; 95% CI, 0.08-0.22), and individuals classified as other ethnoracial group were at significantly higher risk of schizophrenia than White individuals (pooled OR, 1.81; 95% CI, 1.31-2.50). The results regarding CHR-P studies were mixed and inconsistent. Sensitivity analyses showed elevated odds of schizophrenia in Asian individuals in inpatient settings (pooled OR, 1.84; 95% CI, 1.19-2.84) and increased risk of PEs among Asian compared with White individuals, specifically in college samples (pooled SMD, 0.16; 95% CI, 0.02-0.29). Heterogeneity across studies was high, and there was substantial risk of bias in most studies. Conclusions and Relevance: Findings of this systematic review and meta-analysis revealed widespread ethnoracial risk variation across multiple psychosis outcomes. In addition to diagnostic, measurement, and hospital bias, systemic influences such as structural racism should be considered as drivers of ethnoracial disparities in outcomes across the psychosis continuum in the US.

Genetics of kidney disorders in Phelan-McDermid syndrome: evidence from 357 registry participants.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by SHANK3 pathogenic variants or chromosomal rearrangements affecting the chromosome 22q13 region. Previous research found that kidney disorders, primarily congenital anomalies of the kidney and urinary tract, are common in people with PMS, yet research into candidate genes has been hampered by small study sizes and lack of attention to these problems. METHODS: We used a cohort of 357 people from the Phelan-McDermid Syndrome Foundation International Registry to investigate the prevalence of kidney disorders in PMS using a cross-sectional design and to identify 22q13 genes contributing to these disorders. RESULTS: Kidney disorders reported included vesicoureteral reflux (n = 37), hydronephrosis (n = 36), dysplastic kidneys (n = 19), increased kidney size (n = 19), polycystic kidneys (15 cases), and kidney stones (n = 4). Out of 315 subjects with a 22q13 deletion, 101 (32%) had at least one kidney disorder, while only one out of 42 (2%) individuals with a SHANK3 pathogenic variant had a kidney disorder (increased kidney size). We identified two genomic regions that were significantly associated with having a kidney disorder with the peak associations observed near positions approximately 5 Mb and 400 Kb from the telomere. CONCLUSIONS: The candidate genes for kidney disorders include FBLN1, WNT7B, UPK3A, CELSR1, and PLXNB2. This study demonstrates the utility of patient registries for uncovering genetic contributions to rare diseases. Future work should focus on functional studies for these genes to assess their potential pathogenic contribution to the different subsets of kidney disorders.

Reconsolidation of traumatic memories protocol compared to trauma-focussed cognitive behaviour therapy for post-traumatic stress disorder in UK military veterans: a randomised controlled feasibility trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) occurs more commonly in military veterans than the general population. Whilst current therapies are effective, up to half of veterans commencing treatment do not complete it. Reconsolidation of Traumatic Memories (RTM) protocol is a novel, easy to train, talking therapy with promising findings. We examine the feasibility of undertaking an efficacy trial of RTM in veterans. METHODS: A parallel group, single-centre randomised controlled feasibility trial with a post-completion qualitative interview study. Sixty military veterans were randomised 2:1 to RTM (n = 35) or Trauma Focussed Cognitive Behaviour Therapy (CBT) (n = 25). We aimed to determine the rate of recruitment and retention, understand reasons for attrition, determine data quality and size of efficacy signal. We explored veterans' perceptions of experiences of joining the trial, the research procedures and therapy, and design improvements for future veteran studies. Military veterans with a diagnosis of PTSD or complex PTSD, and clinically significant symptoms, were recruited between January 2020 and June 2021. Primary outcome was feasibility using pre-determined progression criteria alongside PTSD symptoms, with depression, recovery, and rehabilitation as secondary outcomes. Data were collected at baseline, 6, 12, and 20 weeks. Interviews (n = 15) were conducted after 20 weeks. Both therapies were delivered by trained charity sector provider therapists. RESULTS: Participants' mean age was 53 years, the mean baseline PTSD symptoms score assessed by the Post-traumatic Stress Checklist (PCL-5) was 57 (range 0-80). Fifty had complex PTSD and 39 had experienced ≥ 4 traumas. Data were analysed at 20 weeks for feasibility outcomes (n = 60) and mental health outcomes (n = 45). Seven of eight progression criteria were met. The RTM group experienced a mean 18-point reduction on the PCL-5. TFCBT group participants experienced a mean reduction of eight points. Forty-eight percent of the RTM group no longer met diagnostic criteria for PTSD compared to 16% in the TFCBT group. All veterans reported largely positive experiences of the therapy and research procedures and ways to improve them. CONCLUSION: RTM therapy remains a promising psychological intervention for the treatment of PTSD, including complex PTSD, in military veterans. With specific strengthening, the research protocol is fit for purpose in delivering an efficacy trial. TRIAL REGISTRATION: ISRCTN registration no 10314773 on 01.10.2019. Full trial protocol: available on request or downloadable at ISRCTN reg. no. 10314773.

Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.

An Analysis of Motivating Factors in 1,725 Worldwide Cases of Mass Murder Between 1900-2019.

Mass murder, particularly mass shootings, constitutes a major, growing public health concern. Specific motivations for these acts are not well understood, often overattributed to severe mental illness. Identifying diverse factors motivating mass murders may facilitate prevention. We examined 1,725 global mass murders from 1900-2019, publicly described in English in print or online. We empirically categorized each into one of ten categories reflecting reported primary motivating factors, which were analyzed across mass murderers generally, as well as between U.S- and non-U.S.-based mass-shooters. Psychosis or disorganization related to mental illness were infrequently motivational factors (166; 9.6%), and were significantly more associated with mass murder committed using methods other than firearms. The vast majority (998, 57.86%) of incidents were impulsive and emotionally-driven, following adverse life circumstances. Most mass murderers prompted by emotional upset were found to be driven by despair or extreme sadness over life events (161, 16.13% within the category); romantic rejection or loss, or severe jealousy (204, 20.44% within the category); some specific non-romantic grudge (212, 21.24% within the category); or explosive, overwhelming rage following a dispute (266, 26.65% within the category). Results suggest that policies seeking to prevent mass murder should focus on criminal history, as well as subacute emotional disturbances not associated with severe mental illness in individuals with poor coping skills who have recently experienced negative life events.

Large Chromosome 2p Duplication-Associated Mechanisms and Clinical Presentations.

Chromosome 2p (chr2p) duplication, also known as trisomy 2p, is a rare chromosome abnormality associated with developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most of the reported cases involving trisomy 2p include additional copy number variants (CNVs) in other regions of the genome and are usually small in size. Little is known about the clinical outcomes of large duplications of chr2p as the sole cytogenetic abnormality. In this study, 193 samples at the Greenwood Genetic Center (GGC) with CNVs involving chr2p were evaluated, out of which 86 had chr2p duplications. Among them, 8 patients were identified with large chr2p duplications ranging in size from 9.3 Mb to 89 Mb, and no deletions or duplications involving other chromosomes were identified in those patients. These duplications were associated with inverted duplication, tandem duplication, and duplication as the result of translocation, with no additional CNVs identified by microarray analysis. Confirmation by conventional cytogenetics was performed in 7 of the 8 patients, and the translocations were confirmed by fluorescence in situ hybridization. Interestingly, 1 patient was found to have mosaic complete trisomy 2p as the result of an unbalanced de novo (X;2) chromosomal translocation. X-inactivation was skewed toward the derivative X chromosome, yet it did not appear to extend into the chromosome 2 material. Various shared clinical manifestations were observed in the individuals in this study, including developmental delay, hemifacial hypoplasia, cleft palate, and short stature, and they also have distinct features such as hypotonia, cerebellar hypogenesis, and corpus callosum agenesis, which might result from a gene dosage effect of the duplication. In conclusion, single-event large chr2p duplications can result from different mechanisms, including inverted or tandem duplications within chromosome 2, or translocations involving chromosome 2 and other chromosomes. Partial or complete trisomy 2p is commonly associated with developmental delay, and additional clinical features may be related to gene dosage effects.

Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals.

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.

Self-stigma among people with serious mental illnesses: The use of focus groups to inform the development of a brief video intervention.

OBJECTIVE: People with mental illnesses may avoid or delay treatment due to a fear of labeling and discrimination, a phenomenon known as self-stigma. Self-stigma is a major barrier to care and creates obstacles to pursuing employment, independent living, and a fulfilling social life. We aimed to gather input from people with lived experience of mental illness to develop a social-contact-based, brief video-based intervention to reduce self-stigma. METHOD: Two (n = 12) focus groups were conducted to inform video content and led to the creation of a script and brief video using a professional actor, who described a story of living with schizophrenia while focusing on symptoms, personal struggles, and recovery. Two (n = 9) additional focus groups were held after video development to gather feedback and suggested edits. Focus group transcripts were analyzed using thematic content analysis. RESULTS: Themes emerging in prevideo development included the negative effects of being diagnosed with severe mental illnesses, being stereotyped, the value of relatable recovery stories and seeing the person as a whole, and the utility of focusing on symptoms and experiences rather than diagnosis-specific language. Feedback in the postvideo focus groups was mainly favorable and resulted in edits related to language about "responsibility" and a disclaimer about using a professional actor. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: While participants' experiences of stigma are consistent with extant literature, this is the first study to elicit the perspectives of people living with mental illnesses in developing a video intervention to reduce self-stigma. Studies are needed to examine the efficacy of these videos in reducing self/public stigma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency.

PURPOSE: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. METHODS: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. RESULTS: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. CONCLUSION: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.

Prevalance and course of tobacco use among individuals receiving coordinated specialty care for first-episode psychosis.

AIM: Tobacco use is decreasing among the general population, but persistent use among individuals in treatment for first-episode psychosis (FEP) remains a problem. This study aimed to measure the prevalence and course of tobacco use and explore the associations between tobacco use and clinical outcomes in a FEP sample located in New York State (NYS). METHODS: Participants (N = 870) were from the OnTrackNY system of coordinated specialty care clinics in NYS. Participant data were collected at admission to the program and at every 3 months of follow-up using standardized forms based on reports from clients, client families and chart review. Course of tobacco use was categorized into four groups: no-use, cessation, persistent and initiation over 1 year of follow-up. RESULTS: The prevalence of tobacco use was 12.8% at baseline and 19.9% at 1-year follow-up. Only 3.8% of tobacco users stopped by 1 year follow-up, and 4.9% initiated use. Urbanicity of clinic location (p < .001); age at admission (p = .044); gender (p = .015); ethnoracial group (p = .007); baseline education/employment status (p = .004); and baseline use of any non-tobacco substances (p < .001), including alcohol (p < .001) and cannabis (p < .001), were associated with tobacco course. Findings suggest an association between tobacco use and reduced improvement in symptoms. CONCLUSION: Despite a lower prevalence of tobacco use among OnTrack participants than in other comparable samples, tobacco cessation was minimal and more individuals initiated tobacco use than ceased over the course of follow-up. Efforts to implement tobacco cessation interventions in coordinated specialty care are warranted, since tobacco use is associated with poor health outcomes.

Social and economic costs of gambling problems and related harm among UK military veterans.

INTRODUCTION: Military veterans are at heightened risk of problem gambling. Little is known about the costs of problem gambling and related harm among United Kingdom (UK) Armed Forces (AF) veterans. We investigated the social and economic costs of gambling among a large sample of veterans through differences in healthcare and social service resource use compared with age-matched and gender-matched non-veterans from the UK AF Veterans' Health and Gambling Study. METHODS: An online survey measured sociodemographic characteristics, gambling experience and problem severity, mental health and healthcare resource utilisation. Healthcare provider, personal social service and societal costs were estimated as total adjusted mean costs and utility, with cost-consequence analysis of a single timepoint. RESULTS: Veterans in our sample had higher healthcare, social service and societal costs and lower utility. Veterans had greater contacts with the criminal justice system, received more social service benefits, had more lost work hours and greater accrued debt. A cost difference of £590 (95% CI -£1016 to -£163) was evident between veterans with scores indicating problem gambling and those reporting no problems. Costs varied by problem gambling status. CONCLUSIONS: Our sample of UK AF veterans has higher healthcare, social service and societal costs than non-veterans. Veterans experiencing problem gambling are more costly but have no reduction in quality of life.

CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.

We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated sCAPRIN1+/- human induced pluripotent stem cells via CRISPR-Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1+/- neurons, compatible with its suggested function as translational inhibitor. CAPRIN1+/- neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1+/- neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models.

Development of the First Episode Digital Monitoring mHealth Intervention for People With Early Psychosis: Qualitative Interview Study With Clinicians.

BACKGROUND: Mobile health (mHealth) technologies have been used extensively in psychosis research. In contrast, their integration into real-world clinical care has been limited despite the broad availability of smartphone-based apps targeting mental health care. Most apps developed for treatment of individuals with psychosis have focused primarily on encouraging self-management skills of patients via practicing cognitive behavioral techniques learned during face-to-face clinical sessions (eg, challenging dysfunctional thoughts and relaxation exercises), reminders to engage in health-promoting activities (eg, exercising, sleeping, and socializing), or symptom monitoring. In contrast, few apps have sought to enhance the clinical encounter itself to improve shared decision-making (SDM) and therapeutic relationships with clinicians, which have been linked to positive clinical outcomes. OBJECTIVE: This qualitative study sought clinicians' input to develop First Episode Digital Monitoring (FREEDoM), an app-based mHealth intervention. FREEDoM was designed to improve the quality, quantity, and timeliness of clinical and functional data available to clinicians treating patients experiencing first-episode psychosis (FEP) to enhance their therapeutic relationship and increase SDM. METHODS: Following the app's initial development, semistructured qualitative interviews were conducted with 11 FEP treatment providers at 3 coordinated specialty care clinics to elicit input on the app's design, the data report for clinicians, and planned usage procedures. We then generated a summary template and conducted matrix analysis to systematically categorize suggested adaptations to the evidence-based intervention using dimensions of the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME) and documented the rationale for adopting or rejecting suggestions. RESULTS: The clinicians provided 31 suggestions (18 adopted and 13 rejected). Suggestions to add or refine the content were most common (eg, adding questions in the app). Adaptations to context were most often related to plans for implementing the intervention, how the reported data were displayed to clinicians, and with whom the reports were shared. Reasons for suggestions primarily included factors related to health narratives and priorities of the patients (eg, focus on the functional impact of symptoms vs their severity), providers' clinical judgment (eg, need for clinically relevant information), and organizations' mission and culture. Reasons for rejecting suggestions included requests for data and procedures beyond the intervention's scope, concerns regarding dilution of the intervention's core components, and concerns about increasing patient burden while using the app. CONCLUSIONS: FREEDoM focuses on a novel target for the deployment of mHealth technologies in the treatment of FEP patients-the enhancement of SDM and improvement of therapeutic relationships. This study illustrates the use of the FRAME, along with methods and tools for rapid qualitative analysis, to systematically track adaptations to the app as part of its development process. Such adaptations may contribute to enhanced acceptance of the intervention by clinicians and a higher likelihood of integration into clinical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04248517; https://tinyurl.com/tjuyxvv6.

Antimicrobial Resistance Pattern of Escherichia coli Isolates from Small Scale Dairy Cattle in Dar es Salaam, Tanzania.

In Tanzania, information on antimicrobial resistance in small-scale dairy cattle is scarce. This cross-sectional study was conducted to determine the different levels and pattern of antimicrobial resistance (AMR), in 121 Escherichia coli isolated from rectal swab of 201 apparently healthy small-scale dairy cattle in Dar es Salaam, Tanzania. Isolation and identification of E. coli were carried out using enrichment media, selective media, and biochemical tests. Antimicrobial susceptibility testing was carried out using the Kirby-Bauer disk diffusion method on Mueller-Hinton agar (Merck), according to the recommendations of Clinical and Laboratory Standards Institute (CLSI). Resistance was tested against ampicillin, gentamicin, chloramphenicol, trimethoprim-sulfamethoxazole, tetracycline, nalidixic acid, ciprofloxacin and cefotaxime. Resistance to almost all antimicrobial agents was observed. The agents to which resistance was demonstrated most frequently were ampicillin (96.7%), cefotaxime (95.0%), tetracycline (50.4%), trimethoprim-sulfamethoxazole (42.1%) and nalidixic acid (33.1%). In this case, 20 extended-spectrum beta-lactamases (ESBLs) producing E. coli were identified. 74.4% (90/121) of the isolates were Multidrug resistant (MDR), ranging from a combination of three to 8 different classes. The most frequently observed phenotypes were AMP-SXT-CTX with a prevalence of 12.4%, followed by the combination AMP-CTX with 10.7% and TE-AMP-CTX and NA + TE + AMP + CTX with 8.3% each. The high prevalence and wide range of AMR calls for prudent antimicrobial use.

Call for Formalized Pathways in Vascular Medicine Training: JACC Review Topic of the Week.

The burden of vascular diseases and complexity of their management have been growing. Vascular medicine specialists may help to bridge gaps in care, especially as part of multidisciplinary teams. However, there is a limited number of vascular medicine specialists because of constraints in training. Despite established pathways for training in vascular medicine, there are obstacles that restrict completion of training in dedicated programs. A key factor is lack of funding as a result of inadequate recognition by key national accrediting and credentialing organizations. A concerted effort is required to overcome the obstacles to expand vascular medicine training programs and ultimately the pool of vascular medicine specialists. Well-trained vascular medicine specialists will be well positioned to ease the burden of vascular disease and optimize patient outcomes.

Phelan-McDermid syndrome: a classification system after 30 years of experience.

Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to "lose" their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.