Search

Sarah E Fitzpatrick, Laura Srivorakiat, Logan K Wink, Ernest V Pedapati, Craig A Erickson Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behavior or interest. Research indicates that aggression rates may be higher in individuals with ASD compared to those with other developmental disabilities. Aggression is associated with negative outcomes for children with ASD and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support. Therapeutic strategies including functional behavioral assessment, reinforcement strategies, and functional communication training may have a significant impact in reducing the frequency and intensity of aggressive behavior in individuals with ASD. Pharmacologic treatments, particularly the use of second-generation antipsychotics, may also be of some benefit in reducing aggression in individuals with ASD. With the ever-increasing rate of ASD diagnosis, development of effective therapeutic and pharmacologic methods for preventing and treating aggression are essential to improving outcomes in this disorder. Keywords: autism, autism spectrum disorder, aggression, treatment, antipsychotics, applied behavior analysis

Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons. Convergent effects are dynamic, varying in strength, composition, and biological role between cell types, increasing with functional similarity of the ASD genes examined, and driven by cell-type-specific gene co-expression patterns. Stratification of ASD genes yield targeted drug predictions capable of reversing gene-specific convergent signatures in human cells and ASD-related behaviors in zebrafish. Altogether, convergent networks downstream of ASD risk genes represent novel points of individualized therapeutic intervention., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest.

Background: Post-partum rectus diastasis, or the separation of the abdominal muscles after pregnancy, occurs in conjunction with physical symptoms and impaired quality of life. In Australia, health funding for surgery to treat diastasis was ceased in 2016, but reinstated in mid-2022, providing a unique context from which women's experiences of this condition can be analysed., Objectives: The objective is to examine the experiences of Australian women with post-partum rectus diastasis., Design: This is an interview-style study with qualitative content analysis., Methods: Women diagnosed with rectus diastasis were recruited to complete a baseline questionnaire (n = 45). Twenty-three responded to invitation for one-on-one interview via Zoom® between November 2021 and May 2022. Interviews were recorded, transcribed, and analysed using qualitative content analysis to identify key themes., Results: Eighteen women had undergone caesarean section and eight had twins. Thirteen had private health insurance. Women were most often diagnosed by a physiotherapist (n = 10). Key themes identified included changed physical appearance and function; issues with self-esteem and intimacy; barriers to treatment; lack of recognition as a medical condition; and overall frustration. The impact of rectus diastasis extended beyond physical and psychological symptoms to affect women's social functioning, child rearing, and return to work. There was a complex interaction between healthcare providers' knowledge of rectus the removal of funding for surgical treatment, and limitations of conservative therapy, with women's lived experiences and symptoms. The lack of an established medical definition also influenced the experiences of these women and their engagement with treatment., Conclusion: This study contextualizes women's experience of post-partum rectus diastasis with respect to the unique landscape of Australia's healthcare economy and provides evidence of women's absorption of health policy surrounding this condition. Our qualitative analysis provides critical knowledge for future quantitative studies, the results of which in combination could advance the definition of rectus diastasis and inform healthcare policy surrounding treatment.

Background: Sector resection for Ductal Carcinoma in Situ (DCIS) allows wide excision without compromising breast shape. There are concerns that radiotherapy for some DCIS after sector resection is unnecessary and reduces patient satisfaction and quality of life without affecting survival. This study aimed to investigate whether women with DCIS managed with sector resection without radiotherapy had acceptable rates of recurrence and health-related quality of life outcomes., Methods: Retrospective study of patients who underwent sector resection for DCIS without adjuvant radiotherapy from 1992 to 2021. Tumour size, grade, necrosis, margins, follow up and time to ipsilateral recurrence was recorded. Patients were posted a BREAST-Q to assess health-related quality of life., Results: One hundred and thirty-eight patients were treated for pure DCIS by two surgeons from 1992 to 2018. One hundred and sixteen patients underwent sector resection, 22 had mastectomy. Average age 61 years. Mean follow up 9.14 years. Recurrence rate after sector resection was 18.97%. 55% were DCIS. Annualized recurrence rate was 2.07%. There were no cancer-related deaths. BREAST-Q completion rate was 44%. Satisfaction with breasts, physical, psychosocial, and sexual well-being scores were significantly higher than normative Australian values and a mixed cohort of women who underwent breast conserving surgery with radiotherapy., Conclusion: DCIS can be safely managed with sector resection without radiotherapy and regular long-term follow up. This approach results in low annualized recurrence rates, high levels patient satisfaction and health-related quality of life and should be considered a safe alternative for patients with DCIS to minimize morbidity without affecting cancer survival., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology., Competing Interests: Declaration of interests X.P. is a consultant for the Brain Electrophysiology Laboratory Company., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: An outbreak of leptospirosis occurred in the Top End of the Northern Territory, Australia, during the wet season in early 2021. There were 14 outbreak cases; most were male (12/14; 86%) and non-Indigenous (13/14; 93%) with a median age of 22 years (range 19-52 years). We conducted a descriptive case series to investigate the outbreak. We determined that the outbreak was most likely due to higher than usual rainfall in a workplace with exposure to cattle, heightened by wearing clothing and footwear which offered little protection, with limited use of personal protective equipment (PPE). Increased and ongoing education for cattle industry workers, and promotion of the use of appropriate clothing and PPE, may minimise the risk of future outbreaks. Australia's national surveillance case definition for leptospirosis should be reviewed to incorporate the use of nucleic acid testing in the detection of leptospirosis., (© Commonwealth of Australia CC BY-NC-ND.)

Background: In response to the COVID-19 pandemic, the Yale New Haven Health System began rescheduling nonurgent outpatient appointments as virtual visits in March 2020. While Yale New Haven Health expanded its telemedicine infrastructure to accommodate this shift, many appointments were delayed and patients faced considerable uncertainty., Objective: Medical students created the Medical Student Task Force (MSTF) to help ensure continuity of care by calling patients whose appointments were delayed during this transition to telemedicine., Methods: Eighty-five student volunteers called 3765 internal medicine patients with canceled appointments, completing screening for 2197 patients. Volunteers screened for health care needs, assessed preferences for future appointments, and offered emotional support and information about COVID-19. Urgent or emergent patient concerns were triaged and escalated to providers. In this analysis, we used a mixed-methods approach: call information and provider responses were analyzed quantitatively, and patient feedback was analyzed qualitatively via thematic analysis., Results: Ninety-one percent of patients screened found the MSTF calls helpful. Twenty-one percent of patients reported health concerns, with 1% reporting urgent concerns escalated to and addressed by providers. Themes of patient comments included gratitude for outreach and social contact, utility of calls, and well-wishes for health care workers., Conclusions: By calling patients whose appointments had been canceled during a rapid transition to telemedicine, the MSTF helped bridge a potential gap in care by offering patients communication with their care teams, information, and support. We propose that this model could be used in other care systems urgently transitioning to outpatient telemedicine, whether during ongoing outbreaks of COVID-19 or other public health emergencies., Competing Interests: N.R.D. reports grants and personal fees from Amgen, grants and personal fees from Astra Zeneca, grants from Boehringer Ingelheim, grants and personal fees from Cytokinetics, grants and personal fees from Novartis, grants and personal fees from Relypsa, and personal fees from SC Pharmaceuticals, outside the submitted work. No other authors report conflicts of interest., (© Annika Belzer et al., 2021; Published by Mary Ann Liebert, Inc.)

Background: Occult breast carcinoma is occasionally found in breast reduction specimens. Although its incidence varies widely, there is a trend toward an increased incidence for women with a history of breast cancer. The authors performed a systematic review and meta-analysis of occult carcinoma incidence in breast reduction specimens., Methods: The MEDLINE and Embase databases were searched for peer-reviewed studies with no language restrictions for studies that recorded the incidence of occult carcinoma in breast reduction specimens. Cancer incidence per specimen was pooled for women with and without a history of breast cancer., Results: Forty-two studies were eligible for inclusion, of which 29 were quantitatively analyzed. The pooled incidence of carcinoma was higher within specimens from women with breast cancer (3.4 percent; 95 percent CI, 2.2 to 5.3 percent) than without (0.6 percent; 95 percent CI, 0.4 to 0.8 percent), and this increased likelihood was significant when populations were compared directly (OR, 6.02; 95 percent CI, 3.06 to 11.86; p < 0.0001)., Conclusions: Women with a history of breast cancer have an increased incidence of occult breast carcinoma within their breast reduction specimens compared with women with no breast cancer history. There is a need for preoperative radiology screening, counseling, and histopathology guidelines to ensure adequate diagnosis and management of these women.

To date, health related quality of life (QoL) has not been systematically evaluated in youth with fragile X syndrome (FXS), the most common single gene cause of autism and the most common inherited form of developmental disability. We describe QoL data gathered using the Pediatric Quality of Life Inventory (PedsQL) completed online by 364 parents of youth with FXS. Parents consistently reported across all gender and age groups that their children experienced the highest QoL in Physical functioning and the lowest QoL in Cognitive functioning. Overall, older children with FXS had increase QoL ratings in the domains of School and Cognitive function.

Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

Objective: Observational studies and anecdotal reports suggest that sertraline, a selective serotonin reuptake inhibitor, may improve language development in young children with fragile X syndrome (FXS)., Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS aged 2 to 6 years., Results: Eighty-one subjects were screened for eligibility, and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and 3 from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language (EL) age equivalent and Clinical Global Impression Scale-Improvement. However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred., Conclusion: This randomized controlled trial of 6 months of sertraline treatment showed no primary benefit with respect to early EL development and global clinical improvement. However, in secondary exploratory analyses, there were significant improvements seen on motor and visual perceptual subtests, the cognitive T score sum on the MSEL, and on one measure of social participation on the Sensory Processing Measure-Preschool. Furthermore, post hoc analysis found significant improvement in early EL development as measured by the MSEL among children with autism spectrum disorder on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but the authors do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.

To date, no drug is approved for the treatment of Fragile X Syndrome (FXS) although many drugs are used to manage challenging behaviors from a symptomatic perspective in this population. While our understanding of FXS pathophysiology is expanding, efforts to devise targeted FXS-specific treatments have had limited success in placebo-controlled trials. Compounds aimed at rectifying excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission, as well as other signaling pathways known to be affected by Fragile X Mental Retardation Protein (FMRP) are under various phases of development in FXS. With the failure of several metabotropic glutamate receptor subtype 5 (mGlur5) selective antagonists under clinical investigation, no clear single treatment appears to be greatly effective. These recent challenges call into question various aspects of clinical study design in FXS. More objective outcome measures are under development and validation. Future trials will likely be aimed at correcting multiple pathways known to be disrupted by the loss of FMRP. This review offers a brief summary of the prevalence, phenotypic characteristics, genetic causes and molecular functions of FMRP in the brain (as these have been extensively reviewed elsewhere), discusses the most recent finding in FXS drug development, and summarizes FXS trials utilizing symptomatic treatment.

We evaluated a community-based physical activity intervention in Georgia senior centers. Participants were a convenience sample that completed the pre-test only (n = 592), or the pre-test, the intervention, and a post-test (n = 418, 98% aged 60 and older, mean age = 75, 83% female, 56% black). The 4-month physical activity intervention, based on the Health Belief Model, included 16 sessions that focused on educator-led chair exercises, promotion of walking, using a pedometer, and recording daily steps. Pre- and post-tests assessed physical activity and physical function, categorized as poor, moderate, or good (Short Physical Performance Battery). Following the intervention, participants improved their physical function (good physical function at pre-test vs. post-test: 16.5% vs. 25.3%, P < or = 0.001), increased minutes of physical activity by 26% (P < or = 0.001) and step counts by 29% (P < or = 0.0001, sub-sample, n = 95), and decreased reports of "it's not safe" as a barrier to physical activity (P < or = 0.05). Increased physical activity (P < or = 0.01) was associated with improved physical function following the intervention. The results of this evaluation provide an evidence base for the effectiveness of this community intervention for improving physical activity and physical function in older adults.