Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism.

In this study, we evaluated the implementation of a second-tier genetic screening test using an amplicon-based next-generation sequencing (NGS) panel in our laboratory during the period of 1 September 2021 to 31 August 2022 for the newborn screening (NBS) of six conditions for inborn errors of metabolism: citrullinemia type II (MIM #605814), systemic primary carnitine deficiency (MIM #212140), glutaric acidemia type I (MIM #231670), beta-ketothiolase deficiency (#203750), holocarboxylase synthetase deficiency (MIM #253270) and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MIM # 246450). The custom-designed NGS panel can detect sequence variants in the relevant genes and also specifically screen for the presence of the hotspot variant IVS16ins3kb of SLC25A13 by the copy number variant calling algorithm. Genetic second-tier tests were performed for 1.8% of a total of 22,883 NBS samples. The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. The confirmed true positive cases were citrullinemia type II (n = 2) and systemic primary carnitine deficiency (n = 1). The false positives were later confirmed to be carrier of citrullinemia type II (n = 2), carrier of glutaric acidemia type I (n = 1) and carrier of systemic primary carnitine deficiency (n = 1). There were no false negatives reported. The incorporation of a second-tier genetic screening test by NGS greatly enhanced our program's performance with 5-working days turn-around time maintained as before. In addition, early genetic information is available at the time of recall to facilitate better clinical management and genetic counseling.

The Toronto Adolescent and Youth Cohort Study: Study Design and Early Data Related to Psychosis Spectrum Symptoms, Functioning, and Suicidality.

BACKGROUND: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality. METHODS: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data. RESULTS: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs. CONCLUSIONS: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality.

Neuroimaging and Biosample Collection in the Toronto Adolescent and Youth Cohort Study: Rationale, Methods, and Early Data.

BACKGROUND: The Toronto Adolescent and Youth (TAY) Cohort Study will characterize the neurobiological trajectories of psychosis spectrum symptoms, functioning, and suicidality (i.e., suicidal thoughts and behaviors) in youth seeking mental health care. Here, we present the neuroimaging and biosample component of the protocol. We also present feasibility and quality control metrics for the baseline sample collected thus far. METHODS: The current study includes youths (ages 11-24 years) who were referred to child and youth mental health services within a large tertiary care center in Toronto, Ontario, Canada, with target recruitment of 1500 participants. Participants were offered the opportunity to provide any or all of the following: 1) 1-hour magnetic resonance imaging (MRI) scan (electroencephalography if ineligible for or declined MRI), 2) blood sample for genomic and proteomic data (or saliva if blood collection was declined or not feasible) and urine sample, and 3) heart rate recording to assess respiratory sinus arrhythmia. RESULTS: Of the first 417 participants who consented to participate between May 4, 2021, and February 2, 2023, 412 agreed to participate in the imaging and biosample protocol. Of these, 334 completed imaging, 341 provided a biosample, 338 completed respiratory sinus arrhythmia, and 316 completed all 3. Following quality control, data usability was high (MRI: T1-weighted 99%, diffusion-weighted imaging 99%, arterial spin labeling 90%, resting-state functional MRI 95%, task functional MRI 90%; electroencephalography: 83%; respiratory sinus arrhythmia: 99%). CONCLUSIONS: The high consent rates, good completion rates, and high data usability reported here demonstrate the feasibility of collecting and using brain imaging and biosamples in a large clinical cohort of youths seeking mental health care.

Cognition and Educational Achievement in the Toronto Adolescent and Youth Cohort Study: Rationale, Methods, and Early Data.

BACKGROUND: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data. METHODS: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023. RESULTS: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p < .05) and also had more academic/educational problems. CONCLUSIONS: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use.

More Than a Perioperative Surgical Home: An Opportunity for Anesthesiologists to Advance Public Health.

Public health and the medical specialty of anesthesiology have been closely intertwined throughout history, dating back to the 1800s when Dr. John Snow used contact tracing methods to identify the Broad Street Pump as the source of a cholera outbreak in London. During the COVID-19 pandemic, leaders in anesthesiology and anesthesia patient safety came forward to develop swift recommendations in the face of rapidly changing evidence to help protect patients and healthcare workers. While these high-profile examples may seem like uncommon events, there are many common modern-day public health issues that regularly intersect with anesthesiology and surgery. These include, but are not limited to, smoking; chronic opioid use and opioid use disorder; and obstructive sleep apnea. As an evolving medical specialty that encompasses pre- and postoperative care and acute and chronic pain management, anesthesiologists are uniquely positioned to improve patient care and outcomes and promote long-lasting behavioral changes to improve overall health. In this article, we make the case for advancing the role of the anesthesiologist beyond the original perioperative surgical home model into promoting public health initiatives within the perioperative period.

Altered connectivity of default mode and executive control networks among female patients with persistent post-concussion symptoms.

OBJECTIVE: To examine the roles of the default mode network (DMN) and executive control network (ECN) in prolonged recovery after mild traumatic brain injury (mTBI), and relationships with indices of white matter microstructural injury. METHODS: Seventeen mTBI patients with persistent symptoms were imaged an average of 21.5 months post-injury, along with 23 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to evaluate functional connectivity (FC) of the DMN and ECN. Diffusion tensor imaging (DTI) quantified fractional anisotropy, along with mean, axial and radial diffusivity of white matter tracts. RESULTS: Compared to controls, patients with mTBI had increased functional connectivity of the DMN and ECN to brain regions implicated in salience and frontoparietal networks, and increased white matter diffusivity within the cerebrum and brainstem. Among the patients, FC was correlated with better neurocognitive test scores, while diffusivity was correlated with more severe self-reported symptoms. The FC and diffusivity values within abnormal brain regions were not significantly correlated. CONCLUSION: For female mTBI patients with prolonged symptoms, hyper-connectivity may represent a compensatory response that helps to mitigate the effects of mTBI on cognition. These effects are unrelated to indices of microstructural injury, which are correlated with symptom severity, suggesting that rs-fMRI and DTI may capture distinct aspects of pathophysiology.

Cortical Gyrification Morphology in ASD and ADHD: Implication for Further Similarities or Disorder-Specific Features?

Shared etiological pathways are suggested in ASD and ADHD given high rates of comorbidity, phenotypic overlap and shared genetic susceptibility. Given the peak of cortical gyrification expansion and emergence of ASD and ADHD symptomology in early development, we investigated gyrification morphology in 539 children and adolescents (6-17 years of age) with ASD (n=197) and ADHD (n=96) compared to typically developing controls (n=246) using the local Gyrification Index (lGI) to provide insight into contributing etiopathological factors in these two disorders. We also examined IQ effects and functional implications of gyrification by exploring the relation between lGI and ASD and ADHD symptomatology beyond diagnosis. General Linear Models yielded no group differences in lGI, and across groups, we identified an age-related decrease of lGI and greater lGI in females compared to males. No diagnosis-by-age interactions were found. Accounting for IQ variability in the model (n=484) yielded similar results. No significant associations were found between lGI and social communication deficits, repetitive and restricted behaviours, inattention or adaptive functioning. By examining both disorders and controls using shared methodology, we found no evidence of atypicality in gyrification as measured by the lGI in these conditions.

Lessons from a system-wide response to a measles outbreak, Canterbury, February-April 2019.

Despite New Zealand's "measles elimination" status, the risk of measles outbreaks persists, due to ongoing measles importation and sub-optimal vaccination coverage, including specific sub-populations with higher proportions of susceptible people. From February to April 2019, Canterbury experienced a measles outbreak with 38 local cases and an unidentified index case. The outbreak strain was linked to a large outbreak in the Philippines. The whole-of-health-system response included active case and contact follow-up by public health and hospital staff, and a prioritised vaccination campaign in primary care. Important features of a measles outbreak response in an "elimination" context include cross-system liaison, co-ordination of communications, careful prioritisation of use of available resources, and support for households affected by isolation and/or quarantine requests. Closer analysis of the effectiveness of outbreak control measures would help prioritise use of scarce public health and health care resources during outbreaks. Future measles outbreaks could be prevented by a systematic primary care-based MMR catch-up campaign.

A Multidisciplinary Perioperative Intervention to Improve Positive Airway Pressure Adherence in Patients With Obstructive Sleep Apnea: A Case Series.

Positive airway pressure (PAP) adherence in patients with obstructive sleep apnea (OSA) remains low despite known benefits. The postoperative inpatient period may represent a unique opportunity to address technical issues and promote self-efficacy, 2 important factors determining adherence, which may result in patients' seeking outpatient sleep medicine follow-up. We report our experience in developing a perioperative multidisciplinary intervention of reintroducing PAP therapy to nonadherent OSA patients with the intent of motivating patients to return to their outpatient sleep medicine clinics.

Networks of face-to-face social contacts in Niakhar, Senegal.

We present the first analysis of face-to-face contact network data from Niakhar, Senegal. Participants in a cluster-randomized influenza vaccine trial were interviewed about their contact patterns when they reported symptoms during their weekly household surveillance visit. We employ a negative binomial model to estimate effects of covariates on contact degree. We estimate the mean contact degree for asymptomatic Niakhar residents to be 16.5 (95% C.I. 14.3, 18.7) in the morning and 14.8 in the afternoon (95% C.I. 12.7, 16.9). We estimate that symptomatic people make 10% fewer contacts than asymptomatic people (95% C.I. 5%, 16%; p = 0.006), and those aged 0-5 make 33% fewer contacts than adults (95% C.I. 29%, 37%; p < 0.001). By explicitly modelling the partial rounding pattern observed in our data, we make inference for both the underlying (true) distribution of contacts as well as for the reported distribution. We created an estimator for homophily by compound (household) membership and estimate that 48% of contacts by symptomatic people are made to their own compound members in the morning (95% CI, 45%, 52%) and 60% in the afternoon/evening (95% CI, 56%, 64%). We did not find a significant effect of symptom status on compound homophily. We compare our findings to those from other countries and make design recommendations for future surveys.

Are Case Volume and Facility Complexity Level Associated With Postoperative Complications After Hip Fracture Surgery in the Veterans Affairs Healthcare System?

BACKGROUND: Hospital-related factors associated with mortality and morbidity after hip fracture surgery are not completely understood. The Veterans Health Administration (VHA) is the largest single-payer, networked healthcare system in the country serving a relatively homogenous patient population with facilities that vary in size and resource availability. These characteristics provide some degree of financial and patient-level controls to explore the association, if any, between surgical volume and facility resource availability and hospital performance regarding postoperative complications after hip fracture surgery. QUESTIONS/PURPOSES: (1) Do VHA facilities with the highest complexity level designation (Level 1a) have a disproportionate number of better-than-expected performance outliers for major postoperative complications compared with lower-complexity level facilities? (2) Do VHA facilities with higher hip fracture surgical volume have a disproportionate number of better-than-expected performance outliers for major postoperative complications compared with lower-volume facilities? METHODS: We explored the Veterans Affairs Surgical Quality Improvement Project (VASQIP) database from October 2001 to September 2012 for records of hip fracture surgery performed. Data reliability of the VASQIP database has been previously validated. We excluded nine of the 98 VHA facilities for contributing fewer than 30 records. The remaining 89 VHA facilities provided 23,029 records. The VHA designates a complexity level to each facility based on multiple criteria. We labeled facilities with a complexity Level 1a (38 facilities)-the highest achievable VHA designated complexity level-as high complexity; we labeled all other complexity level designations as low complexity (51 facilities). Facility volume was divided into tertiles: high (> 277 hip fracture procedures during the sampling frame), medium (204 to 277 procedures), and low (< 204 procedures). The patient population treated by low-complexity facilities was older, had a higher prevalence of severe chronic obstructive pulmonary disease (26% versus 22%, p < 0.001), and had a higher percentage of patients having surgery within 2 days of hospital admission (83% versus 76%, p < 0.001). High-complexity facilities treated more patients with recent congestive heart failure exacerbation (4% versus 3%, p < 0.001). We defined major postoperative complications as having at least one of the following: death within 30 days of surgery, cardiac arrest requiring cardiopulmonary resuscitation, new q-wave myocardial infarction, deep vein thrombosis and/or pulmonary embolism, ventilator dependence for at least 48 hours after surgery, reintubation for respiratory or cardiac failure, acute renal failure requiring renal replacement therapy, progressive renal insufficiency with a rise in serum creatinine of at least 2 mg/dL from preoperative value, pneumonia, or surgical site infection. We used the observed-to-expected ratio (O/E ratio)-a risk-adjusted metric to classify facility performance-for major postoperative complications to assess the performance of VHA facilities. Outlier facilities with 95% confidence intervals (95% CI) for O/E ratio completely less than 1.0 were labeled "exceed expectation;" those that were completely greater than 1.0 were labeled "below expectation." We compared differences in the distribution of outlier facilities between high and low-complexity facilities, and between high-, medium-, and low-volume facilities using Fisher's exact test. RESULTS: We observed no association between facility complexity level and the distribution of outlier facilities (high-complexity: 5% exceeded expectation, 5% below expectation; low-complexity: 8% exceeded expectation, 2% below expectation; p = 0.742). Compared with high-complexity facilities, the adjusted odds ratio for major postoperative complications for low-complexity facilities was 0.85 (95% CI, 0.67-1.09; p = 0.108).We observed no association between facility volume and the distribution of outlier facilities: 3% exceeded expectation and 3% below expectation for high-volume; 10% exceeded expectation and 3% below expectation for medium-volume; and 7% exceeded expectation and 3% below expectation for low-volume; p = 0.890). The adjusted odds ratios for major postoperative complications were 0.87 (95% CI, 0.73-1.05) for low- versus high-volume facilities and 0.89 (95% CI, 0.79-1.02] for medium- versus high-volume facilities (p = 0.155). CONCLUSIONS: These results do not support restricting facilities from treating hip fracture patients based on historical surgical volume or facility resource availability. Identification of consistent performance outliers may help health care organizations with multiple facilities determine allocation of services and identify characteristics and processes that determine outlier status in the interest of continued quality improvement. LEVEL OF EVIDENCE: Level III, therapeutic study.

Post-traumatic stress disorder and chronic hyperconnectivity in emotional processing.

Post-traumatic stress disorder (PTSD) is associated with heightened responses to threatening stimuli, particularly aggression-related emotional facial expressions. The stability over time of this neurophysiological 'hyperactive' threat response has not been determined. We studied implicit emotional face processing in soldiers with and without PTSD at two time-points (roughly 2 years apart) using magnetoencephalography to determine the response of oscillations and synchrony to happy and angry faces, and the reliability of this marker for PTSD over time. At the initial time-point we had 20 soldiers with and 25 without PTSD; 35 returned for follow-up testing 2 years later, and included 13 with and 22 without PTSD. A mixed-effects analysis was used. There were no significant differences (albeit a slight reduction) in the severity of PTSD between the two time-points. MEG contrasts of the neurophysiological networks involved in the processing of angry vs. happy faces showed that the PTSD group had elevated oscillatory connectivity for angry faces. Maladaptive hypersynchrony in PTSD for threatening faces was seen in subcortical regions, including the thalamus, as well as the ventromedial prefrontal cortex, cingulum gyri, inferior temporal and parietal regions. These results are generally consistent with prior studies and our own, and we demonstrate that this hyperconnectivity was stable over a two year period, in line with essentially stable symptomatology. Together, these results are consistent with the theory that hypervigilance in PTSD is driven by bottom-up, rapid processing of threat-related stimuli that engage a widespread network working in synchrony.

Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model.

Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, ß-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.

A survey of older Hong Kong people's perceptions of telecommunication technologies and telecare devices.

We investigated how older Hong Kong people perceive the application of telecommunication technologies in products that could enhance their safety at home. The telecare devices in the present study were: (1) the Personal Emergency Link Service (PELS), a 24-hour personal emergency link service; (2) a home-based non-intrusive motion monitoring system; and (3) a wearable vital signs monitoring system. Data were collected from a convenience sample of 368 elderly persons aged 65 years or above from 15 District Elderly Community Centres in Hong Kong, through a structured questionnaire administered during face-to-face interviews by trained interviewers. All three telecare devices were generally perceived as useful by the elderly participants: the PELS by 96% of them, the home-based non-intrusive monitoring system by 91% and the wearable vital signs monitoring system by 84%. However, although many respondents were positive about the function and usefulness of these devices, they stated that they would not personally use them. Technological innovations need to be perceived by the elderly as relevant to their everyday lives.

Identity-Based Motivation: Constraints and Opportunities in Consumer Research.

This commentary underscores the integrative nature of the identity-based motivation model (Oyserman, 2009). We situate the model within existing literatures in psychology and consumer behavior, and illustrate its novel elements with research examples. Special attention is devoted to, 1) how product- and brand-based affordances constrain identity-based motivation processes and, 2) the mindsets and action tendencies that can be triggered by specific cultural identities in pursuit of consumer goals. Future opportunities are suggested for researching the antecedents of product meanings and relevant identities.

Intraarticular neurofibroma of the hip.

Musculoskeletal involvement in neurofibromatosis type 1 is present in 33% to 50%, including tumors of neural origin, typically neurofibroma. While both osseous and soft tissue lesions are well recognized, articular involvement is rare. The aim of this case report is describe and discuss the intraarticular extension of a neurofibroma into the hip joint.

A simple device in shoulder arthroscopy: the suture assistant.

Arthroscopic reconstructive surgery in the shoulder is an extremely demanding. The advent of suture anchors, arthroscopic knot-tying techniques, and new arthroscopic instruments has greatly facilitated its development. Knowledge of the anatomy and surgical principles alone are not enough. Good visualization is critical. We describe a simple home-made device that can be very useful in improving visualization and in helping to retrieve sutures during the knot-tying stage, especially in smaller shoulders. We introduce the concept of "bringing the suture" to the instrument rather than "taking the instrument to the suture."

The peashooter device: an invaluable tool for bone grafting during revision anterior cruciate ligament surgery.

Anterior cruciate ligament (ACL) reconstruction is a commonly performed surgery. Despite the improved technique and understanding of the rehabilitation rationale, the long-term success rate of good or excellent results is 75% to 90%. That leaves 10% to 25% of reconstructed ACLs with unsatisfactory results. Certainly, revision ACL surgery is not required in every patient. It should be individualized according to symptoms, objective findings, and the expectations of the patients. Revision of a failed ACL reconstruction may be carried out either as a single-stage procedure or a staged procedure. A staged procedure is recommended in cases of tunnel enlargement and/or removal of the implants and the failed graft, which leaves large bone defects. Bone grafting of the tibial bone tunnel defect is usually not a problem. On the other hand, grafting the femoral bone tunnel defect can present a challenge. It is important to place enough bone graft into the femoral tunnel securely and tightly so that bone incorporation takes place before the second-stage surgery, when the new tunnel can be drilled and the new ligament graft placed. We describe a simple technique using the elasticity and transparent properties of a chest drain, which effectively delivers the bone graft to the femoral tunnel defect. We name it the "peashooter device."

Hemangioendothelioma with an epithelioid phenotype arising in hemangioma of the fibula.

The classification of certain vascular bone tumors that show an epithelioid cytologic appearance remains confusing, with overlap in features of epithelioid hemangioma, hemangioendothelioma and epithelioid hemangioendothelioma. Radiographs of a 27-year-old woman who presented with ankle pain showed an expanded lytic-sclerotic lesion in the distal left fibula. Magnetic resonance imaging showed an intramedullary lesion with a small lateral intracortical component. The lesion was hypo- to isointense to muscle on T1-weighted images and heterogeneously hyperintense on T2-weighted images. Initial incisional biopsy was inconclusive. Open biopsy showed hemangioendothelioma with epithelioid morphology, and the lesion was completely resected with reconstruction using a peroneal fibular rotation graft. Examination of the resected specimen showed focal hemangioendothelioma with an epithelioid phenotype arising in a hemangioma. This case illustrates the difficulty and pitfalls of making the correct diagnosis on the basis of a small biopsy specimen.

How to use cuff suture instruments: the concept of "concave in and concave out".

Arthroscopic reconstructive surgery of the shoulder is extremely demanding. The advent of suture anchors and knot-tying instruments has greatly facilitated its development. Knowledge of the anatomy and surgical principles alone is not enough. Familiarity with specific instruments is also important. We describe our experience with the Elite Cuff Stitch Suture Relay (Smith & Nephew, London, U.K.). We describe a new concept on how to use this suture passer or similar instrument. We advocate this new concept of "concave in and concave out."