Search

Background: Isotretinoin treatment for acne can reduce adverse psychiatric outcomes in adults, but there has been little investigation of the incidence of psychiatric outcomes in treated adolescents. Methods: This retrospective cohort study using the Rochester Epidemiology Project identified 606 patients aged 12–18 prescribed isotretinoin over a 10‐year period between January 1, 2008 and December 31, 2017. Medical records were reviewed to identify psychiatric diagnoses before and during isotretinoin therapy, as well as psychiatric symptoms not captured by formal diagnoses and changes to isotretinoin dosing because of psychiatric diagnoses or symptoms. Results: One hundred seventy‐seven (29.2%) had a psychiatric diagnosis prior to isotretinoin initiation, but 98 (16.2%) had a new psychiatric diagnosis or psychiatric symptom while taking isotretinoin. Patients with a psychiatric history were no more likely than those without to receive a new psychiatric diagnosis during treatment (4.5% vs. 3.7%; p =.650), but did experience more psychiatric symptoms, primarily low mood and mood swings (23.7% vs. 7.7%; p <.001). Only 25.5% of the 98 with a new psychiatric diagnosis or psychiatric symptom had a subsequent dose change. A dose change was more likely if patients received a new psychiatric diagnosis (41.7% vs. 20.3%; p =.037) or patients did not have a psychosocial explanation for psychiatric symptoms (34.4% vs. 10.8%; p =.009). Conclusions: A substantial proportion of adolescent patients prescribed isotretinoin had a prior psychiatric diagnosis. This predicts more psychiatric symptoms during isotretinoin treatment. Adolescents with a psychiatric history who have worsening symptoms and those with new‐onset psychiatric symptoms would benefit from close monitoring while taking isotretinoin. [ABSTRACT FROM AUTHOR]

Background: Older adults with severe dementia are at increased risk of being physically restrained in nursing homes and acute care settings, but little is known about restraint use among those cared for at home. This study explores caregiver‐reported use of restraints among community‐dwelling older adults with severe dementia. Methods: Using cross‐sectional data from 215 family caregivers, we describe restraint use among older adults with severe dementia living at home. We then use multivariable logistic regression to identify factors associated with restraint use. Results: Nearly half (47%) of caregivers reported on older adults who had been subject to restraints. Most caregivers reporting restraint use suggested safety reasons, such as prevention of falls (68%), wandering (30%), and removal of catheters or feeding tubes (29%); and 44% indicated doctors or other health care providers were involved in the decision to restrain. Feeding tubes (OR = 4.16, 95% CI: 1.27–13.59) and physically aggressive agitation behaviors (OR = 1.93, 95% CI: 1.09–3.40) were associated with higher odds of restraint use among older adults with severe dementia. Caregivers who received strong emotional support from friends (OR = 0.45, 95% CI: 0.21–0.95) were less likely to report restraint use while serving as a caregiver to others (OR = 2.77, 95% CI: 1.36–5.63) increased the odds of restraint use. Conclusions: The pervasiveness of restraint use is concerning and suggests a lack of evidence‐based guidance and support for both caregivers and healthcare providers to prevent restraint use among older adults with severe dementia cared for at home. [ABSTRACT FROM AUTHOR]

Objectives: Systemic sclerosis (SSc) has the highest mortality rate among the rheumatic diseases, with lung fibrosis leading as the cause of death. A characteristic of severe SSc‐related lung fibrosis is its progressive nature. Although most research has focused on the pathology of the fibrosis, the mechanism mediating the fibrotic spread remains unclear. We hypothesized that extracellular vesicle (EV) communication drives the propagation of SSc lung fibrosis. Methods: EVs were isolated from normal (NL) or SSc‐derived human lungs and primary lung fibroblasts (pLFs). EVs were also isolated from human fibrotic lungs and pLFs induced experimentally with transforming growth factor‐β (TGFβ). Fibrotic potency of EVs was assessed using functional assays in vitro and in vivo. Transmission electron microscopy, nanoparticle tracking analysis, real‐time quantitative polymerase chain reaction (RT‐qPCR), immunoblotting, and immunofluorescence were used to analyze EVs, their cargo, extracellular matrix (ECM) fractions, and conditioned media. Results: SSc lungs and pLFs released significantly more EVs than NL lungs, and their EVs showed increased fibrotic content and activity. TGFβ‐stimulated NL lung cores and pLFs increased packaging of fibrotic proteins, including fibronectin, collagens, and TGFβ, into released EVs. The EVs induced a fibrotic phenotype in recipient pLFs and in vivo in mouse lungs. Furthermore, EVs interacted with and contributed to the ECM. Finally, suppressing EV release in vivo reduced severity of murine lung fibrosis. Conclusions: Our findings highlight EV communication as a novel mechanism for propagation of SSc lung fibrosis. Identifying therapies that reduce EV release, activity, and/or fibrotic cargo in SSc patient lungs may be a viable therapeutic strategy to improve fibrosis. [ABSTRACT FROM AUTHOR]

The Safewards model is used across various mental health settings to reduce incidents of conflict and containment and its efficacy in reducing the use of seclusion and restraint, improving patients' experiences of care, and enhancing safety within clinical settings is well documented (Bowers, Journal of Psychiatric & Mental Health Nursing, 21, 2014, 499). However, there are barriers to successful implementation, including level of staff buy‐in (Baumgardt et al., Frontiers in Psychiatry, 10, 2019, 340; Price et al., Mental Health Practice, 19, 2016, 14). This mixed‐method study assessed the impact of adopting a Safewards model within a clinical supervision framework in an approach, named Group Reflective integrated Practice with Safewards (GRiP‐S), which integrates Safewards theory within the clinical supervision framework. Both quantitative and qualitative data were collected using the questions derived from the Manchester Clinical Supervision Scale −26© (Winstanley & White, The Wiley International Handbook of Clinical Supervision. John Wiley & Sons Ltd, 2014). A total of 67 surveys and eight interviews were completed by nursing staff. Overall, the results showed that the GRiP‐S approach improves the implementation of Safewards and nurses' clinical practice. Nursing staff satisfaction with clinical supervision and Safewards improved post GRiP‐S pre‐GRIP‐S‐ 69.54 (SD 16.059); post‐GRIP‐S 71.47 (SD 13.978). The survey also identified nursing staff's perception of GRiP‐S in the restorative and formative domains of clinical supervision improved. The restorative mean score pre‐GRiP‐S was 28.43 (SD 5.988) and post‐GRiP‐S 29.29 (SD 3.951). The formative mean score pre‐GRiP‐S was 20.10 (SD 5.617) and post‐GRiP‐S 20.63 (SD 13.978). The qualitative results further explained the satisfaction levels and the changes seen in perception domains. The GRiP‐S approach reported (i) improved therapeutic relationships and patient centred care, (ii) improved staff communication and teamwork, (iii) barriers to GRiP‐S engagement, and (iv) assistance with the change process. The results indicate that the GRiP‐S approach had a positive impact on Safewards delivery and supports ongoing change of practice. [ABSTRACT FROM AUTHOR]

Objective: Studies indicate inhaled isopropyl alcohol (IIA) is effective or superior to ondansetron for adult patients. Although quick‐acting and low cost, it cannot be assumed this remedy is suitable for adoption in all settings. We explored how an innovative antiemetic remedy studied in the United States translates to a sub‐Saharan Africa clinic/hospital setting using Rogers' Diffusion of Innovation Framework. Design: Qualitative design with purposive sampling. Sample: Health care staff (n = 11) providing and community members (n = 22) accessing health care services in a sub‐Saharan Africa clinic/hospital. Measurements: Semi‐structured interviews with coding and identification of themes via deductive content analysis using Rogers' Diffusion of Innovation Framework. Results: Nausea and vomiting was a common complaint, with malaria the most common etiology. Participants emphasized treatment of etiology over symptomatic treatment and described previous aromatherapy use. IIA advantages included administration route, quick‐acting, self‐administration, portable, available, and easy trialability. Participants expressed concerns regarding use of term "alcohol" as potentially offensive to others. Conclusion: Use of Rogers' Diffusion of Innovation framework identified barriers and facilitators to translation of a novel antiemetic remedy for sub‐Saharan Africa clinic/hospital settings. Evaluating clinical innovations from perspectives of relative advantage, compatibility, complexity, trialability, and observability enhances adoption of innovations within clinical settings. [ABSTRACT FROM AUTHOR]

Prostate cancer, Gleason pattern 3, Gleason score 3 + 3 = 6, ISUP Grade Group 1, tumour grading, tumour classification Keywords: prostate cancer; Gleason pattern 3; Gleason score 3 + 3 = 6; ISUP Grade Group 1; tumour grading; tumour classification EN prostate cancer Gleason pattern 3 Gleason score 3 + 3 = 6 ISUP Grade Group 1 tumour grading tumour classification 741 743 3 11/14/22 20221201 NES 221201 Abbreviations ASAP atypical small acinar proliferation GS Gleason score ISUP International Society of Urological Pathology PIN prostatic intraepithelial neoplasia In a pair of recent articles [1,2], Eggener et al. revived the decade-old argument, which we refuted previously [3], that Gleason score 3 + 3 = 6 (GS6; International Society of Urological Pathology [ISUP] Grade Group 1) prostatic adenocarcinoma should no longer be labelled cancer. Low-grade prostate cancer should still be labelled cancer. [Extracted from the article]

Background: Genetic‐driven deregulation of the amyloid pathway and overproduction of downstream amyloid‐β are known to cause early‐onset Alzheimer's disease (EOAD)1. ALN‐APP is an investigational intrathecally (IT) administered RNAi therapeutic designed to reduce upstream intracellular and extracellular amyloid precursor protein (APP) levels by lowering APP mRNA. As a result, we hypothesize that ALN‐APP may alter the cascade of events that result in neurodegeneration, potentially slowing, halting, or reversing Alzheimer's disease progression. Method: ALN‐APP‐001 (NCT05231785) Part A is an ongoing randomized, double‐blind, placebo‐controlled, Phase 1 single‐ascending dose study in patients with EOAD. Patients are required to have disease onset at age <65 years, Clinical Dementia Rating® global score of 0.5 or 1.0, and Mini Mental State Examination score >20. Patients are being evaluated over 6 months, with further follow‐up of up to 6 months as needed. The primary endpoint is the safety and tolerability of ALN‐APP. Secondary objectives include the evaluation of pharmacokinetics and pharmacodynamic effects of ALN‐APP. Result: 12 patients were enrolled and randomized 2:1 to receive ALN‐APP or placebo in 25mg and 75mg dose cohorts. Baseline characteristics are shown in Table 1. Mean (SD) duration on study was 6.7 (1.7) months for cohort 1 (25mg) and 2.0 (1.0) months for cohort 2 (75mg). Dose‐dependent reductions of soluble APPα and APPβ (sAPPα and sAPPβ) levels in cerebrospinal fluid (CSF) at day 15 were observed following a single dose of ALN‐APP, with mean reductions from baseline of 55% (sAPPα) and 69% (sAPPβ), and maximum reductions of 71% (sAPPα) and 83% (sAPPβ) in the 75mg cohort (n = 4) (Table 2). All adverse events (AEs) by data cut‐off on 01/17/2023 were mild or moderate (Table 3), with no AEs deemed related to study drug by the investigators. Additional cohort data will be presented at the meeting. Conclusion: This first clinical study of a CNS‐administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ. To date, ALN‐APP remains generally well tolerated with all reported AEs mild or moderate. These interim results support further evaluation of ALN‐APP in patients with EOAD. Reference: 1. Hampel H et al. Molecular Psychiatry (2021). 26:5481‐5503. [ABSTRACT FROM AUTHOR]

Literature regarding college student health has documented inadequate education and treatment of certain conditions such as mental health, preventive care, and sexual and reproductive health services. While some health services are available for students on campus, evidence suggests many at‐risk students do not utilize these services. Pharmacists are well‐suited to provide these services to college students, although there is a paucity of published data on the impact and outcomes of pharmacist intervention(s). This paper establishes the need for health interventions in college students, describes evidence supporting the role of a pharmacist on college campuses, and explores opportunities for pharmacists to address these unmet needs. A PubMed search was conducted for studies on college student health and services involving pharmacists using search terms encompassing college students and health‐related keywords. Studies written in English were considered and references from searched studies were manually reviewed for inclusion. When available, studies regarding pharmacist‐specific interventions on college health issues were included. Pharmacists can play a critical role in the treatment and management of psychiatric illnesses on college campuses. Data supporting psychiatric pharmacist recommendations are available. Further, pharmacists have shown interest and patient acceptance when providing sexual and reproductive services, including pharmacist‐provided prescription contraceptive products and preventive health services. Pharmacists can also influence preventive care practices on college campuses through health education including opioid use disorder, preventing overdose, and providing immunizations. While data demonstrate the positive impact pharmacists have on college students related to mental health, preventive health, and sexual health and reproductive services, available evidence is somewhat limited. However, ample opportunities exist to expand this impact. To more clearly and consistently demonstrate their impact on the college student population, pharmacists providing these services should be strongly encouraged to publish their work. [ABSTRACT FROM AUTHOR]

Molecular ionic composites (MICs), made from ionic liquids and a rigid‐rod polymer poly(2,2′‐disulfonyl‐4,4′‐benzidine terephthalamide) (PBDT), are a new type of rigid gel electrolyte that combine fast ion transport with high thermal stability and mechanical strength. In this work, a MIC electrolyte membrane is prepared that is composed of PBDT, lithium bis(trifluoromethylsulfonyl)imide (LiTFSI), and 1‐butyl‐1‐methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (Pyr14TFSI) in a mass ratio of 10:10:80. The ionic conductivity at 25 °C is 0.56 mS cm−1 with no added flammable/volatile components. Although the polymer content is only 10 wt%, this MIC membrane is rigid with a tensile modulus of 410 MPa at room temperature. The MIC membrane remains stable and rigid at 200 °C with the shear storage modulus (G′) only slightly decreasing by 35%. Li/MIC/LiFePO4 cells demonstrate stable cycling performance over a wide temperature range from 23 to 150 °C. The specific discharge capacity at 100 and 150 °C at 1 C rate exceeds 160 mAh g−1. The discharge capacity retention is 99% after 50 cycles at 150 °C. This stable battery performance shows that this low polymer content MIC membrane qualifies for use as a solid electrolyte in lithium metal batteries operating over a wide temperature range. [ABSTRACT FROM AUTHOR]

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss‐of‐function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4‐related EPF phenotype. This report demonstrates comorbid disorders of Saethre‐Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification. [ABSTRACT FROM AUTHOR]

Abbreviation ISUP International Society of Urological Pathology In November 2014, the International Society of Urological Pathology (ISUP) convened a consensus meeting in Chicago, Illinois, USA to consider grading criteria for prostatic adenocarcinoma [1]. While cribriform cancer used to be included in either Gleason pattern 3 or 4, depending on the size and shape of the glands, the ISUP 2014 revision considers all cribriform cancer to be Gleason pattern 4, or even 5 if comedonecrosis is present [19]. An explanation for this increasing interest may be that the Gleason inflation that was fueled by the ISUP 2005 consensus recommendations has pushed a considerable number of cancers from Gleason score 6 to 7 [21]. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. [Extracted from the article]

We conducted a population‐based case–control study to examine newborn polyunsaturated fatty acid (PUFA) levels in association with autism spectrum disorder (ASD) and assess PUFA correlation across two time points. ASD cases (n = 200) were identified through the Department of Developmental Services and matched to live‐birth population controls (n = 200) on birth month, year (2010–2011), and sex. Nonesterified PUFAs were measured by isotope dilution liquid chromatography‐high resolution mass spectrometry from archived newborn dried blood spots and maternal mid‐pregnancy serum samples. Crude and adjusted conditional logistic regression models were used to examine the association between neonatal PUFA levels, categorized in quartiles and according to distributional extremes, and ASD. Cubic splines were utilized to examine nonlinear relationships between continuous neonatal PUFAs and ASD. The correlation between neonatal and maternal levels was examined using Pearson correlation coefficients. In adjusted analyses of neonatal PUFA levels, no clear trends emerged, though there was an elevated odds ratio of ASD for the third quartile of linoleic acid, relative to the first (adjusted odds ratio = 2.49, 95% confidence interval: 1.31, 4.70). Cubic spline analysis suggested a nonlinear association between linoleic acid and ASD, though this was not robust to sensitivity analyses. While individual PUFAs were significantly correlated with one another within a given time point, aside from docohexaseanoic acid, PUFAs were not correlated across maternal and neonatal samples. Overall, our findings do not support an association between neonatal PUFA levels and ASD. Future work should confirm and expand these findings by examining associations with phenotypic subgroups and considering PUFAs in other time points. Lay Summary In this study, we examined whether levels of fats known as polyunsaturated fatty acids, measured in newborns, were related to later child diagnosis of autism spectrum disorder (ASD). Overall, we did not find strong evidence for hypothesized reduction in risk of ASD based on newborn levels of these fats. Future studies in larger samples and considering other time points may be useful to explain whether these fats are important in brain development related to ASD. Autism Res 2020, 13: 1601–1613. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Akathisia continues to present a significant challenge in clinical practice. As a class, so‐called atypical, or second‐generation, antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and are commonly used to treat mood disorders. These medications have traditionally been distinguished from first‐generation antipsychotics by their lowered risk of extrapyramidal side effects (EPS) such as dystonia, dyskinesia, akathisia, and pseudoparkinsonism. However, the occurrence of EPS, particularly akathisia, has been demonstrated to some degree in all commercially available SGAs. This review examines the incidence of akathisia in nine newer SGAs in patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We performed a search of PubMed, ClinicalTrials.gov, Cochrane Central Register, and Google Scholar, as well as manufacturer websites and product labeling for published and unpublished clinical trials, meta‐analyses, and systematic reviews. Studies evaluating adult patients with schizophrenia, bipolar disorder, or MDD were eligible for inclusion. Data on treatment‐emergent akathisia rates were gathered from each study, and potential dose‐response relationships were explored. A total of 177 studies were included in this review, comprising 58,069 patients across 414 treatment arms. Compared with placebo with a composite 3.7% incidence of akathisia, individual SGAs produced akathisia at total composite rates ranging from 2.9–13.0% across the included studies. High doses of an SGA were generally associated with an increased risk of akathisia. Clinicians should consider the risk of akathisia when choosing a treatment option and monitor for akathisia in patients beginning therapy with an SGA or following a dose increase of the SGA. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the second most common cancer, affecting both men and women. Fibrosis is a hallmark of LUAD occurring throughout progression with excess production of extracellular matrix (ECM) components that lead to metastatic cell processes. Understanding the ECM cues that drive LUAD progression has been limited due to a lack of tools that can access and report on ECM components within the complex tumor microenvironment. Here, we test whether low‐grade LUAD can be distinguished from normal lung tissue using a novel ECM imaging mass spectrometry (ECM IMS) approach. ECM IMS analysis of a tissue microarray with 20 low‐grade LUAD tissues and 20 normal lung samples from 10 patients revealed 25 peptides that could discriminate between normal and low‐grade LUAD using area under the receiver‐operating curve (AUC) ≥0.7, P value ≤.001. Principal component analysis demonstrated that 62.4% of the variance could be explained by sample origin from normal or low‐grade tumor tissue. Additional work performed on a wedge resection with moderately differentiated LUAD demonstrated that the ECM IMS analytical approach could distinguish LUAD spectral features from spectral features of normal adjacent lung tissue. Conventional liquid chromatography with tandem mass spectrometry (LC‐MS/MS) proteomics demonstrated that specific sites of hydroxylation of proline (HYP) were a main collagen post translational modification that was readily detected in LUAD. A distinct peptide from collagen 3A1 modified by HYP was increased 3.5 fold in low‐grade LUAD compared with normal lung tissue (AUC 0.914, P value <.001). This suggests that regulation of collagen proline hydroxylation could be an important process during early LUAD fibrotic deposition. ECM IMS is a useful tool that may be used to define fibrotic deposition in low‐grade LUAD. [ABSTRACT FROM AUTHOR]

The article focuses on the investigation of profibrotic factors, including TGFβ, packaged in extracellular vesicles, propagating lung fibrosis in systemic sclerosis.

Background: The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a class of progressive neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's Disease (AD). There is a high unmet medical need for new approaches to target Tau in these numerous tauopathies. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs. Method: Here, using our lipophilic C16‐conjugated siRNA for CNS delivery, we identified potent molecules targeting the MAPT gene in both in vitro and in vivo models. Results: Our RNAi molecules targeting the MAPT gene durably reduce MAPT mRNA and Tau protein levels in both in vitro and in vivo model systems. Furthermore, in a 16‐week non‐human primate study, we observed robust target engagement resulting in sustained reduction of MAPT transcript and Tau protein in brain tissue and cerebrospinal fluid. Conclusion: Together, these results suggest that RNAi lowering of Tau could be a novel strategy to address both intra‐ and extra‐cellular accumulation of Tau aggregates, which could have therapeutic advantages for treating tauopathies. [ABSTRACT FROM AUTHOR]

Background: The hyperphosphorylation and subsequent aggregation of the microtubule‐associated protein Tau (encoded by the MAPT gene) is one of the major histopathological hallmarks of numerous tauopathies, including Alzheimer's disease and progressive supranuclear palsy. The intracellular accumulation of aggregated Tau is associated with neuronal loss and disease progression in tauopathies. There is a high‐unmet need to identify strategies to target the intracellular accumulation of Tau aggregates with the aim of slowing tauopathy progression. Method: To model this, we used mice carrying multiple copies of a transgene with a prion promoter driving human MAPT with human tauopathy‐inducing mutation P301S. P301S‐Tau transgenic mice progressively accumulate neuroglial Tau aggregates associated with axonal damage, gliosis, body weight loss, and ambulatory dysfunction. Result: P301S mice treated with a single intracerebroventricular injection of Tau siRNA at eight months of age, had a sustainable decrease in MAPT mRNA and soluble Tau protein for three months following siRNA treatment (reduced ∼83% and ∼59%, respectively). siRNA treatment also prevented the progressive decrease in body weight and abrogated axonal damage, evidenced by decreased neurofilament light (NFL) chain in plasma and cerebrospinal fluid of eleven‐month‐old mice. Importantly, immunohistochemical analysis of misfolded Tau in vivo and HEK293‐4RD‐CFP/YFP Tau aggregate biosensor assay testing in vitro revealed a ∼97% decrease of Tau aggregates in the eleven‐month‐old mice, suggesting there exists a yet‐to‐be identified mechanism of Tau fibril clearance. Conclusion: Together, these results suggest an RNAi therapeutics approach targeting of MAPT mRNA may be sufficient to improve multiple parameters of tauopathy disease progression and a provide a compelling rationale for further development of Tau‐lowering strategies. [ABSTRACT FROM AUTHOR]

Co‐occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < −3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier‐Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel‐like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral‐Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel‐like phenotype and FFS, the last of which has not been associated with any disease gene to date. [ABSTRACT FROM AUTHOR]

With the wide adoption of next‐generation sequencing (NGS)‐based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture‐based learning around these topics is important, there has been growing need for the inclusion of case‐based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice. [ABSTRACT FROM AUTHOR]

The insulin‐like growth factor (IGF) system plays an important role in variety cellular biological functions; we previously reported levels of IGF binding proteins (IGFBP)‐3 and ‐5 are increased in dermal and pulmonary fibrosis associated with the prototypic fibrosing disease systemic sclerosis (SSc), induce extracellular matrix (ECM) production, and promote fibrosis. We sought to examine the effects of another member of the family, IGFBP‐4, on ECM production and fibrosis using cell‐based, ex vivo organ culture and in vivo mouse lung fibrosis models. IGFBP‐4 mRNA levels were significantly decreased in pulmonary fibroblasts of patients with SSc. ECM components were significantly reduced by endogenous and exogenous IGFBP‐4. IGFBP‐4 also blocked TGF‐β–induced ECM production, and inhibited ECM production ex vivo in human lung and skin in organ culture. In vivo, IGFBP‐4 reduced bleomycin‐induced collagen production and histologic evidence of fibrosis. Silencing IGFBP‐4 expression to mimic levels observed in SSc lung fibroblasts resulted in increased ECM production. IGFBP‐4 reduced mRNA and protein levels of the chemokine receptor CXCR4 and the profibrotic factor CTGF. Furthermore, CTGF silencing potentiated the antifibrotic effects of IGFBP‐4. Reduced IGFBP‐4 levels in SSc lung fibroblasts may contribute to the fibrotic phenotype via loss of IGFBP‐4 antifibrotic activity. [ABSTRACT FROM AUTHOR]

Schaaf‐Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader‐Willi critical region 15q11‐15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader‐Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype–phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling. [ABSTRACT FROM AUTHOR]

Adolescents today suffer from chronic sleep deprivation due to a combination of biological changes to the circadian clock and early morning school bell times. Many school districts are now considering delaying high school start times to accommodate the sleep schedules of teens. This paper explores whether such policy changes can have an unexpected impact on teen car accident rates. This impact could function both through a direct effect on teen sleep deprivation and indirectly through changes to the driving environment, that is, shifting the time and conditions under which teens commute to school. By focusing on late‐night accidents and employing a difference‐in‐differences strategy using adult drivers as a control group, I find evidence of a persistent sleep deprivation mechanism. A 15‐minute delay in school start time causes a significant decrease in late‐night teen accidents of approximately 23%. However, I also find evidence of an opposing mechanism that is present during the morning commuting hours. A 15‐minute delay in high school start time leads to a 21% increase in morning teen car accidents. (JEL I29, J13, R41) [ABSTRACT FROM AUTHOR]

Aims: Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. Methods and results: The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62–0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two‐thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non‐members are able to access a limited number of cases. Conclusions: It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified. [ABSTRACT FROM AUTHOR]

Aims Despite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens. Methods and results The International Society of Urological Pathology ( ISUP) established a reference image database through the input of experts in the field. Three panels were formed, one each for prostate, urinary bladder and renal pathology, consisting of 24 international experts. Each of the panel members uploaded microphotographs of cases into a non-public database. The remaining 23 experts were asked to vote from a multiple-choice menu. Prior to and while voting, panel members were unable to access the results of voting by the other experts. When a consensus level of at least two-thirds or 16 votes was reached, cases were automatically transferred to the main database. Consensus was reached in a total of 287 cases across five projects on the grading of prostate, bladder and renal cancer and the classification of renal tumours and flat lesions of the bladder. The full database is available to all ISUP members at . Non-members may access a selected number of cases. Conclusions It is anticipated that the database will assist pathologists in calibrating their grading, and will also promote consistency in the diagnosis of difficult cases. [ABSTRACT FROM AUTHOR]

The article reflects on the disease-specific treatment strategies for fibrotic diseases. It mentions identification of potential targets as the initial step in development of antifibrotic therapies that provides understanding of pathogenesis of fibrotic diseases to offer opportunities for development of effective antifibrotic treatment strategies. It highlights polypharmacologic therapy that describes inhibition of pathologically relevant targets by use of a single drug.

The article focuses on the side effects of ketamine, which are used in treating postoperative pain, depressive disorder, bipolar disorder and post traumatic stress disorder. The topics discussed includes cases of patients having manic symptoms following ketamine infusions for depression, importance of screening of patients who may receive ketamine, and medicines that appear to be effective in treating mania associated with ketamine.

Aims To assess the interobserver reproducibility of individual Gleason grade 4 growth patterns. Methods and results Twenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. 'Consensus' was defined as at least 80% agreement, and 'favoured' as 60-80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern ('complex fused'). Conclusions Consensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached. [ABSTRACT FROM AUTHOR]

I propose a model of postsecondary education in which major field of study can be used by individuals to signal productivity to employers. Under this signaling model, I show that geographic areas with high access to elite universities result in fewer science, technology, engineering, and mathematics ( STEM) majors among lower ability students at nonelite colleges. This is distinct from the prediction of a full information model in which access to elite schools should only affect high ability individuals directly. Using data from the National Center for Education Statistics' Baccalaureate & Beyond survey, I find evidence that is consistent with the signaling model prediction, specifically a 2.3-3.7 percentage point or 16%-25% decrease in the probability of choosing a STEM major among lower ability students in areas with greater access to elite colleges. ( JEL I21, J24) [ABSTRACT FROM AUTHOR]

Objective Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. Methods We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1+/− mice. Results Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14low cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1+/− mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD. [ABSTRACT FROM AUTHOR]

Objective To examine whether lung endothelial cells (ECs) from patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) express mesenchymal cell-specific proteins and gene transcripts, indicative of the occurrence of endothelial-to-mesenchymal phenotypic transition (EndoMT). Methods Lung tissue from 6 patients with SSc-associated pulmonary fibrosis was examined by histopathology and immunohistochemistry. Confocal laser microscopy was utilized to assess the simultaneous expression of EC and myofibroblast molecular markers. CD31+CD102+ ECs were isolated from the lung tissue of 2 patients with SSc-associated ILD and 2 normal control subjects, and the expression of EC and mesenchymal cell markers and other relevant genes was analyzed by quantitative polymerase chain reaction, immunofluorescence microscopy, and Western blotting. Results Immunohistochemical staining revealed cells expressing the EC-specific marker CD31 in the subendothelial, perivascular, and parenchymal regions of the lungs from all SSc patients. Confocal microscopy identified cells displaying simultaneous expression of von Willebrand factor and α-smooth muscle actin in small and medium-sized arterioles in the SSc lung tissue but not in normal control lungs. CD31+CD102+ ECs isolated from SSc lungs expressed high levels of mesenchymal cell-specific genes (type I collagen, type III collagen, and fibronectin), EC-specific genes (type IV collagen and VE-cadherin), profibrotic genes (transforming growth factor β1 and connective tissue growth factor), and genes encoding EndoMT-related transcription factors (TWIST1 and SNAI2). Conclusion Cells coexpressing EC- and mesenchymal cell-specific molecules are present in the lungs of patients with SSc-associated ILD. CD31+CD102+ ECs isolated from SSc lungs simultaneously expressed mesenchymal cell- and EC-specific transcripts and proteins. Collectively, these observations demonstrate the occurrence of EndoMT in the lungs of patients with SSc-associated ILD. [ABSTRACT FROM AUTHOR]

Pathogenic variants in CHD2 (chromodomain helicase DNA‐binding protein 2) have been reported in neurodevelopmental disorders with a broad spectrum of phenotypic variability, ranging from mild intellectual disability to atonic‐myoclonic epilepsy. However, given the paucity of reported cases the extent of this phenotypic spectrum is currently unknown. Furthermore, all confirmed pathogenic CHD2 variants reported to date have been de novo, preventing the study of intrafamilial phenotypic heterogeneity and creating ambiguity regarding recurrence risk, penetrance, and expressivity. Here, we report the first known case of an inherited pathogenic CHD2 variant in affected mother and daughter. This case demonstrates intrafamilial phenotypic heterogeneity and confirms potential heritability of CHD2‐related neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the criteria for our search. In addition, we performed a retrospective case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants. [ABSTRACT FROM AUTHOR]