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Börjeson–Forssman–Lehmann syndrome (BFLS) is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in the plant homeodomain finger protein 6 (PHF6) gene. Core features include developmental delay, intellectual disability, dysmorphic craniofacial characteristics, obesity, hypogonadism and digital anomalies. Orofacial clefting has not been recognised as part of the canonical phenotype and is rarely reported in association with BFLS. One cohort study listed cleft lip and/or palate as an uncommon feature without individual case details, and a separate report described a female with a nonsense PHF6 variant and clefting of the hard and soft palate. Here, we describe a BFLS female with a de novo missense PHF6 variant who presented with cleft palate. This case adds to the emerging evidence that clefting, though uncommon, may be a recurrent manifestation. It supports the inclusion of PHF6 in the genetic testing of patients presenting with syndromic orofacial clefting when accompanied by neurodevelopmental delay or dysmorphism.

Political orientation may play a formative role in perceptions of risk associated with COVID-19 vaccination including vaccine myocarditis (CVM). Whether political alignment of news sources plays a role in perception of this risk is unknown. We examined the relationship between political orientation of online media sites and aspects of reporting of CVM. Media sites were classified as \"left\" or \"right\" biased using the Allsides media bias rating report. For each site \"COVID vaccine myocarditis\" was searched in articles posted May 2021 to December 2022. Each search return was reviewed for the following: 1) Did it contain numerical data regarding CVM risk? 2) Did it report benefits of covid vaccination? 3) Did it mention covid infection-related myocarditis? Monthly reports of vaccine-related adverse events were obtained from the Vaccine Adverse Events Reporting System (VAERS). A total of 487 online reports regarding CVM were reviewed. Comparison of monthly report volumes from left vs. right biased media sources demonstrated significant correlation (r = 0.546, p = 0.013). Additionally monthly reporting of CVM was temporally related to monthly volume of VAERS reporting (r = 0.519, p = 0.023). These data suggest that monthly reporting volumes were driven by availability of information regarding CVM rather than media political alignment. Left biased media sources were significantly more likely to include numerical CVM data vs. right biased sources (76.6% vs. 24.3%, p<0.001) and likewise were more likely to include data supporting benefits of covid vaccination (85.1% vs. 21.7%. p<0.001). In contrast, there was no difference regarding mention of COVID-19 infection-related myocarditis (24.5% vs. 24.3%, p = 0.957). Political orientation of online news sites was not associated with frequency of CVM reports but was related to report content, most notably whether reports included numerical data regarding CVM risk. These differential reporting characteristics may contribute to the relationship between political orientation and patient conceptualization of risk of CVM.

Background: Duplications involving Xp22.33, particularly within the pseudoautosomal region 1 (PAR1), are rare. While copy number variants (CNVs) involving SHOX, a dosage-sensitive gene in PAR1, are known to cause growth disorders, large duplications encompassing the entire PAR1 region and beyond show variable associations with skeletal and neurodevelopmental abnormalities. Duplication of the near-complete, isolated PAR1 with a comprehensive clinical description has not been reported. Case Presentation: We report a male patient with a 2.49 Mb duplication encompassing nearly the entire PAR1 region (chrX:200854–2692897, GRCh37). Clinical features included global developmental delay (GDD), autism spectrum disorder (ASD), recurrent seizures, hypotonia with joint hypermobility, dysmorphic features, and proportionate tall stature. The duplicated segment contains 30 genes, including 15 protein-coding genes that escape X-inactivation. Among these, SHOX, DHRSX, ASMT, and CSF2RA are notable candidates contributing to the observed phenotype. Conclusions: This report presents a detailed clinical characterization of a rare, near-complete, isolated PAR1 duplication in a male individual. The co-occurrence of tall stature, GDD, ASD, and seizures raises the possibility of a dosage-related phenotypic effect involving one or more genes within the duplicated interval. While causality cannot be definitively established, these observations contribute to the emerging understanding of the functional consequences of Xp22.33 duplications and suggest that increased copy number within this region may be associated with a clinically significant neurodevelopmental phenotype.

The zinc finger homeobox 3 (ZFHX3) gene encodes a transcription factor involved in neurodevelopment and organogenesis. ZFHX3 haploinsufficiency is linked to intellectual disability, epilepsy and neurodevelopmental defects, but its potential involvement in neural tube defects (NTDs) and related structural anomalies is unknown. We report a female proband with a de novo heterozygous ZFHX3 variant (NM_006885.3: c.5876 A>C, p.(Gln1959Pro), identified via exome sequencing. She presented with spina bifida occulta, segmental spinal dysgenesis, bilateral clubfeet, bicuspid aortic valve and genital anomaly. This report suggests an expanded phenotypic spectrum of ZFHX3-associated disorders. Given the known interactions of ZFHX3 with Wnt/β-catenin, mTOR and Hippo signalling pathways, we hypothesise that disruptions in these networks could contribute to NTDs and skeletal defects. No functional studies were performed, so causality cannot be established. Further research and reports of similar phenotypes in ZFHX3 variants are needed to confirm its role in NTDs and other congenital structural anomalies.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by impaired social communication and repetitive behaviours. The genetic basis of ASD is complex and involves both rare variants with large effect sizes and common variants with small effect sizes. Based on current knowledge, the variant is predicted to result in a truncated protein and is considered a variant of uncertain significance (VUS). The USP51 gene has been implicated in neurodevelopment, and its role in the developing brain suggests its potential relevance to ASD. Further studies are needed to establish the association of USP51 variants with ASD and elucidate the full phenotypic spectrum associated with these variants.

Using deep learning model predictions requires not only understanding the model’s confidence but also its uncertainty, so we know when to trust the prediction or require support from a human. In this study, we used Monte Carlo dropout (MCDO) to characterize the uncertainty of deep learning image classification algorithms, including feature fusion models, on simulated synthetic aperture radar (SAR) images of persistent ship wakes. Comparing to a baseline, we used the distribution of predictions from dropout with simple mean value ensembling and the Kolmogorov—Smirnov (KS) test to classify in-domain and out-of-domain (OOD) test samples, created by rotating images to angles not present in the training data. Our objective was to improve the classification robustness and identify OOD images during the test time. The mean value ensembling did not improve the performance over the baseline, in that there was a –1.05% difference in the Matthews correlation coefficient (MCC) from the baseline model averaged across all SAR bands. The KS test, by contrast, saw an improvement of +12.5% difference in MCC and was able to identify the majority of OOD samples. Leveraging the full distribution of predictions improved the classification robustness and allowed labeling test images as OOD. The feature fusion models, however, did not improve the performance over the single SAR-band models, demonstrating that it is best to rely on the highest quality data source available (in our case, C-band).

Objective To examine how female patients with RA form decisions about having children, pregnancy, and medication use. Methods We employed a constructivist grounded theory design and recruited female participants who are 18 years or older, have a rheumatologist-confirmed RA diagnosis, live in Canada, and are able to communicate in English or French. We collected data through semi-structured individual and focus group interviews using telephone or video conferencing technology. Data collection and analysis were iterative, employed theoretical sampling, reflexive journaling, and peer debriefing, and culminated in a theoretical model. Results We recruited 21 participants with a mean age of 34 years and median 10 years since RA diagnosis. Overall, 33% had never been pregnant, 57% had previously been pregnant, and 10% were pregnant at the time of interview. Of those who had experienced pregnancy, 64% had at least one pregnancy while diagnosed with RA and of those, 56% used DMARD(s) during a pregnancy. We constructed a patient-centred framework depicting the dynamic relationships between 4 decision-making processes—(1) using medications, (2) having children, (3) planning pregnancy, and (4) parenting—and the substantial impact of healthcare providers on patients’ experiences making these decisions. These processes were further influenced by participants’ intersecting identities and contextual factors, particularly attitudes towards health and medications, disease onset and severity, familial support system, and experiences interacting with the healthcare system. Conclusion Our framework provides insight into how patients make reproductive decisions in the context of managing RA and the opportunities for providers to support them at each decision-making process. A patient-centred care approach is suggested to support female patients with RA in making reproductive and medication choices aligning with their individual desires, needs, and values.

Background Given the rising incidence of young-onset colorectal cancer (yCRC) among individuals younger than 50 years old, understanding the economic burden of yCRC is required to inform the delivery of healthcare services. Therefore, we conducted a systematic review of studies assessing the direct medical costs of yCRC, and where relevant average-age onset CRC (aCRC). Methods We searched MEDLINE, EMBASE, and Web of Science from inception to May 2022 for original, peer-reviewed studies, that reported direct medical costs (e.g., chemotherapy, radiotherapy, outpatient visits, inpatient care, prescription medications) for yCRC and aCRC. We used a modified version of the Consolidated Health Economic Evaluation Reporting Standards checklist to appraise the studies. Costs were inflation-adjusted to 2020 US dollars. Results We included 14 studies from 10 countries, including the USA, England, France, Korea, Vietnam, China, Italy, Australia, Canada and Japan. Five studies focused on prevalent disease and reported annualized per-capita cost of prevalent yCRC, ranging from $2,263 to $16,801 and $1,412 to $14,997 among yCRC and aCRC cases, respectively. Nine studies estimated the cost of incident disease. Synthesis of per-capita costs incurred 12 months following colorectal cancer diagnosis ranged from $23,368 to $89,945 for yCRC and $19,929 to $67,195 for aCRC. Five studies used multivariable approaches to compare costs associated with yCRC and aCRC, four showed no differences and one suggested greater costs with yCRC. Conclusion Our synthesis of direct medical costs of yCRC across multiple jurisdictions provide relevant information for healthcare decisions, including on-going considerations for expanding CRC screening strategies to younger adults.

Background To conduct a systematic review and thematic synthesis of qualitative studies on the pregnancy and early parenting experiences of patients with inflammatory arthritis (IA). Methods We searched online databases for English-language, qualitative studies capturing the experiences of females with IA or their healthcare providers with pregnancy and/or early parenthood. We extracted findings from included studies and used thematic synthesis to develop descriptive and higher-order analytical themes. Results Of 20 included studies, our analysis identified 5 analytical themes among patients and 3 among providers. Patients’ reproductive desires, the impact of IA on their ability to experience pregnancy, and the availability of information to guide preparedness informed their pregnancy decisions. Patients’ IA management, pregnancy expectations, and access to support influenced their reproductive experiences. Patients’ experiences seeking information and care revealed substantial gaps in reproductive care provision to patients with IA. Reproductive uncertainty related to IA placed a heavy burden on patients’ emotional and psychological wellbeing. Reproductive care provision was influenced by providers’ perceived professional responsibility to address patients’ reproductive goals, fears of negative outcomes, and capacity to harness patient trust, incorporate reproductive care into rheumatology practice and facilitate multi-disciplinary care coordination. Conclusions Our review illuminated several barriers to experiencing pregnancy among patients with IA, particularly related to pregnancy planning support, availability of information, and care coordination among the patient’s healthcare team. To improve care, these barriers may be mitigated through the provision of relevant, practical, and consistent information as well as patient-centred multi-disciplinary approaches for managing pregnancy among patients with IA.

Background Due to the growing use of cannabis for the purposes of pain relief, evidence is needed on the impact of cannabis use on concurrent analgesic use. Therefore, our objective was to evaluate the association between the use of cannabis and codeine. Methods We conducted a cross-sectional study using data from the nationally representative Canadian Tobacco, Alcohol and Drugs Survey (2017). The primary explanatory variable was self-reported use of cannabis within the past year. The outcome was the use of codeine-containing product(s) within the past year. We used multivariable binomial logistic regression models. Results Our study sample comprised 15,459 respondents including 3338 individuals who reported cannabis use within the past year of whom 955 (36.2%) used it for medical purposes. Among individuals who reported cannabis use, the majority were male ( N = 1833, 62.2%). Self-reported use of cannabis was associated with codeine use (adjusted odds ratio [aOR] 1.89, 95% CI 1.36 to 2.62). Additionally, when limited to cannabis users only, we found people who used cannabis for medical purposes to be three times more likely to also report codeine use (adjusted odds ratio [aOR] 2.96, 95% CI 1.72 to 5.09). Discussion The use of cannabis was associated with increased odds of codeine use, especially among individuals who used it for medical purposes. Our findings suggest a potential role for healthcare providers to be aware of or monitor patients’ use of cannabis, as the long-term adverse events associated with concurrent cannabis and opioid use remain unknown.