Mortality rates in people with first diagnosis of schizophrenia-spectrum disorders: A 5-year population-based cohort study.

OBJECTIVE: Schizophrenia-spectrum disorder (SSD) is associated with increased premature death, with emerging data suggesting early illness course as a high-risk period for excess mortality. This study aimed to examine mortality rate in patients with incident SSD and differential mortality risk between inpatient-diagnosed and outpatient-diagnosed subsamples within 5 years of first diagnosis. METHOD: This population-based cohort study identified 8826 patients aged 18-39 years receiving first-recorded SSD diagnosis upon service entry, comprising 3877 inpatient-diagnosed and 4949 outpatient-diagnosed patients, between 2006 and 2012 in Hong Kong using a territory-wide medical record database of public health care services. All-cause, natural-cause, and unnatural-cause mortality risks within 5 years after first diagnosis were quantified by standardized mortality ratios (SMRs) relative to the general population. We also directly compared mortality rates between inpatient and outpatient subsamples over 5-year follow-up. RESULTS: SSD patients exhibited markedly elevated all-cause (SMR: 12.28, 95% confidence interval [CI]: [10.83, 13.88]), natural-cause (SMR: 3.76, 95% CI: [2.77, 4.98]) and unnatural-cause (SMR: 20.64, 95% CI: [17.49, 24.20]) mortality during first 5 years of diagnosis. Increased mortality rate was most pronounced in the first year of treatment, especially for unnatural deaths (SMR 32.2, 95% CI: [24.08, 42.22]). Discharged inpatient-diagnosed patients displayed significantly higher all-cause and unnatural-cause mortality rates than outpatient-diagnosed counterparts within first 3 years of treatment, and differential mortality risks on all-cause (adjusted hazard ratio [aHR]: 7.05, 95% CI: [2.02, 24.64]) and unnatural-cause (aHR: 5.15, 95% CI: [1.38, 19.19]) deaths were the highest in the first month of follow-up. CONCLUSIONS: Substantial increase in early mortality risk among people with incident SSD, particularly in the first year of diagnosis and the time shortly after discharge, underscores an urgent need of targeted early intervention for effective suicide prevention and physical health improvement to minimize mortality gap.

Pre-existing chronic physical morbidity and excess mortality in people with schizophrenia: a population-based cohort study.

PURPOSE: Schizophrenia is associated with increased premature mortality and physical morbidity. This study aimed to examine prevalence of pre-existing chronic physical diseases, and association between physical multimorbidity burden and mortality rates among patients with newly diagnosed schizophrenia. METHODS: This population-based cohort study investigated patients with first-recorded diagnosis of schizophrenia between January 2006 and December 2016, using territory-wide medical-record database of public healthcare service in Hong Kong. Physical morbidities were measured by Charlson Comorbidity Index (CCI), taking into consideration both number and severity of physical diseases, and were grouped into nine broad disease categories for analyses. Physical multimorbidity burden was stratified into three levels according to CCI of 0, 1 or ≥ 2. Cox proportional hazards regression models were used to examine associations of physical multimorbidity with mortality rates. RESULTS: Of the 13,945 patients, 8.6% (n = 1207) had pre-existing physical morbidity. Patients with physical morbidity exhibited elevated all-cause mortality rate relative to those without physical morbidity [adjusted HR 2.38 (95% CI 2.04-2.77)]. Gastrointestinal/liver diseases, diabetes and cardiovascular diseases constituted the three most frequently diagnosed physical morbidities, whereas cancers displayed the highest all-cause mortality rate. An increase in physical multimorbidity burden was associated with increased all-cause mortality rate [CCI = 1: 1.98 (1.64-2.40); CCI ≥ 2: 3.08 (2.51-3.77), CCI = 0 as reference]. CONCLUSION: Schizophrenia patients with pre-existing physical morbidity had two-fold increased risk of premature mortality compared to those without physical morbidity. Physical multimorbidity confers incremental impact on excess mortality. Early detection and intervention of physical morbidity in the initial phase of schizophrenia is necessary to reduce avoidable mortality.

Establishing an Association between Polycystic Ovarian Syndrome and Pilonidal Disease in Adolescent Females.

STUDY OBJECTIVE: We sought to determine whether pilonidal disease (PD) is associated with polycystic ovarian syndrome (PCOS) in adolescent females. DESIGN: Retrospective cohort study SETTING: Urban tertiary children's hospital PARTICIPANTS: All girls aged 12 to 21 who received a diagnosis of PD and/or PCOS from 2012 to 2019 INTERVENTIONS: Treatment for PCOS and PD MAIN OUTCOME MEASURES: The variables analyzed included age, race/ethnicity, body mass index, age at menarche, tobacco use, payer status, treatment of PCOS and PD, and serum markers of hyperandrogenism and metabolic syndrome. RESULTS: During the study period, 100,043 patients presented to an urban tertiary medical center. Of these patients, 966 were diagnosed with PD, and 219 were diagnosed with both PD and PCOS. Compared with patients with only PD, patients with both diagnoses had a higher body mass index (31.4 vs 27.4 kg/m2; P < .01) and were older (18.76 vs 18.30 years; P = .003). The prevalence ratio for patients with PD having PCOS per the original Rotterdam criteria was 26.1 (CI, 22.0-31.0) and 28.7 (CI, 24.3-33.9) for having PCOS per the modified Rotterdam criteria. Patients with both diagnoses were less likely to receive intervention for PD (OR = 0.22; CI, 0.13-0.37; P < .001). CONCLUSIONS: Adolescent females diagnosed with PD are likely to demonstrate features of PCOS. PCOS treatment could positively alter the disease course of PD. As such, surgical providers should consider referring adolescent females with PD to endocrinologists, gynecologists, and adolescent medicine specialists for evaluation of PCOS.

In utero delivery of miRNA induces epigenetic alterations and corrects pulmonary pathology in congenital diaphragmatic hernia.

Structural fetal diseases, such as congenital diaphragmatic hernia (CDH) can be diagnosed prenatally. Neonates with CDH are healthy in utero as gas exchange is managed by the placenta, but impaired lung function results in critical illness from the time a baby takes its first breath. MicroRNA (miR) 200b and its downstream targets in the TGF-ß pathway are critically involved in lung branching morphogenesis. Here, we characterize the expression of miR200b and the TGF-ß pathway at different gestational times using a rat model of CDH. Fetal rats with CDH are deficient in miR200b at gestational day 18. We demonstrate that novel polymeric nanoparticles loaded with miR200b, delivered in utero via vitelline vein injection to fetal rats with CDH results in changes in the TGF-ß pathway as measured by qRT-PCR; these epigenetic changes improve lung size and lung morphology, and lead to favorable pulmonary vascular remodeling on histology. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development in a pre-clinical model. With refinement, this technique could be applied to fetal cases of CDH or other forms of impaired lung development in a minimally invasive fashion.

Intra-amniotic Injection of Poly(lactic-co-glycolic Acid) Microparticles Loaded with Growth Factor: Effect on Tissue Coverage and Cellular Apoptosis in the Rat Model of Myelomeningocele.

BACKGROUND: Myelomeningocele (MMC) is a devastating congenital neurologic disorder that can lead to lifelong morbidity and has limited treatment options. This study investigates the use of poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) loaded with fibroblast growth factor (FGF) as a platform for in utero treatment of MMC. STUDY DESIGN: Intra-amniotic injections of PLGA MPs were performed on gestational day 17 (E17) in all-trans retinoic acid-induced MMC rat dams. MPs loaded with fluorescent dye (DiO) were evaluated 3 hours after injection to determine incidence of binding to the MMC defect. Fetuses were then treated with PBS or PLGA particles loaded with DiO, bovine serum albumin, or FGF and evaluated at term (E21). Fetuses with MMC defects were evaluated for gross and histologic evidence of soft tissue coverage. The effect of PLGA-FGF treatment on spinal cord cell death was evaluated using an in situ cell death kit. RESULTS: PLGA-DiO MPs had a binding incidence of 86% and 94% 3 hours after injection at E17 for doses of 0.1 mg and 1.2 mg, respectively. Incidence of soft tissue coverage at term was 19% (4 of 21), 22% (2 of 9), and 83% (5 of 6) for PLGA-DiO, PLGA-BSA, and PLGA-FGF, respectively. At E21, the percentage of spinal cord cells positive for in situ cell death was significantly higher in MMC controls compared with wild-type controls or MMC pups treated with PLGA-FGF. CONCLUSION: PLGA MPs are an innovative minimally invasive platform for induction of soft tissue coverage in the rat model of MMC and may reduce cellular apoptosis.

A narrative review of in utero gene therapy: advances, challenges, and future considerations.

The field of in utero gene therapy (IUGT) represents a crossroad of technologic advancements and medical ethical boundaries. Several strategies have been developed for IUGT focusing on either modifying endogenous genes, replacing missing genes, or modifying gene transcription products. The list of candidate diseases such as hemoglobinopathies, cystic fibrosis, lysosomal storage disorders continues to grow with new strategies being developed as our understanding of their respective underlying molecular pathogenesis increases. Treatment in utero has several distinct advantages to postnatal treatment. Biologic and physiologic phenomena enable the delivery of a higher effective dose, generation of immune tolerance, and the prevention of phenotypic onset for genetic diseases. Therapeutic technology for IUGT including CRISPR-Cas9 systems, zinc finger nucleases (ZFN), and peptide nucleic acids (PNAs) has already shown promise in animal models and early postnatal clinical trials. While the ability to detect fetal diagnoses has dramatically improved with developments in ultrasound and next-generation sequencing, treatment options remain experimental, with several translational gaps remaining prior to implementation in the clinical realm. Complicating this issue, the potential diseases targeted by this approach are often debilitating and would otherwise prove fatal if not treated in some manner. The leap from small animals to large animals, and subsequently, to humans will require further vigorous testing of safety and efficacy.

Laparoscopy is increasingly used for pediatric inguinal hernia repair.

INTRODUCTION: Inguinal hernia repairs (IHR) are commonly performed by pediatric surgeons in the United States. The operative approach depends on surgeon preference with no definitive prospective studies comparing laparoscopic inguinal hernia repair (LIHR) versus traditional inguinal hernia repair (TIHR). We aim to assess current practice, hypothesizing that laparoscopy is increasingly used for pediatric IHR. MATERIAL & METHODS: The Children's Hospital Association (CHA) Pediatric Health Information System was queried for IHRs performed between 01/01/2009 and 12/31/2018. Demographics, procedure type, hernia laterality, and cost were obtained. Patients were grouped by procedure type (laparoscopic/traditional). RESULTS: 125,249 IHRs were performed at 32 CHA hospitals during the ten-year study period. 115,782 (92.4%) were TIHR and 9467 (7.6%) LIHR. Use of laparoscopy increased 5-fold from 3% to 15% over the study period. When comparing laparoscopic to traditional IHR groups, there were more females (28.3% vs 12.6%), African-Americans (19.7% vs 14.4%), government-insured (50% vs 45.2%), younger patients (4.2 vs 4.4 years), bilateral IHRs (11.4% vs 7.9%), and higher adjusted total hospital cost ($3,791 vs $2995) in the laparoscopic group (p<0.0001, all comparisons). CONCLUSIONS: Laparoscopy for pediatric IHR is increasing at CHA hospitals where nearly 1 in 6 children currently undergoes a laparoscopic repair. The long-term outcomes with laparoscopic repair are worthy of future study.

Diffusion weighted imaging as a biomarker of retinoic acid induced myelomeningocele.

Neural tube defects are a common congenital anomaly involving incomplete closure of the spinal cord. Myelomeningocele (MMC) is a severe form in which there is complete exposure of neural tissue with a lack of skin, soft tissue, or bony covering to protect the spinal cord. The all-trans retinoic acid (ATRA) induced rat model of (MMC) is a reproducible, cost-effective means of studying this disease; however, there are limited modalities to objectively quantify disease severity, or potential benefits from experimental therapies. We sought to determine the feasibility of detecting differences between MMC and wild type (WT) rat fetuses using diffusion magnetic resonance imaging techniques (MRI). Rat dams were gavage-fed ATRA to produce MMC defects in fetuses, which were surgically delivered prior to term. Average diffusion coefficient (ADC) and fractional anisotropy (FA) maps were obtained for each fetus. Brain volumes and two anatomically defined brain length measurements (D1 and D2) were significantly decreased in MMC compared to WT. Mean ADC signal was significantly increased in MMC compared to WT, but no difference was found for FA signal. In summary, ADC and brain measurements were significantly different between WT and MMC rat fetuses. ADC could be a useful complementary imaging biomarker to current histopathologic analysis of MMC models, and potentially expedite therapeutic research for this disease.

The parental journey of fetal care: a systematic review and metasynthesis.

OBJECTIVE: This study aimed to synthesize the qualitative literature on parental experiences of fetal care to reflect events that happened across the continuum of care and to better understand parents' positive and negative experiences with care delivery. DATA SOURCES: Eligible studies published until June 2020 were retrieved from MEDLINE, Embase, Cochrane Central Register of Controlled Trials, EBSCO CINAHL, Web of Science, and ProQuest. STUDY ELIGIBILITY CRITERIA: Studies must have been: (1) published in English in a peer-reviewed journal or in ProQuest, (2) available in full text, (3) contained a qualitative component, and (4) focused on expectant parents' experiences of tertiary, coordinated, multidisciplinary prenatal diagnosis and care related to a fetal anomaly. STUDY APPRAISAL AND SYNTHESIS METHODS: Researchers used the Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research. A metastudy and an interpretive description approach was taken to synthesize the events that happened across the continuum of care and the themes associated with a positive care experience. RESULTS: The metasynthesis included 13 studies and 217 patients from 11 different multidisciplinary fetal diagnosis and intervention practices across North America and Europe. We identified key events that influenced parental experience of fetal care across the continuum. The themes associated with a positive care experience are parents (1) gaining understanding and feeling understood, (2) realizing agency and control, and (3) finding hope and meaning. We identified aspects of healthcare delivery that served as barriers or facilitators to these positive experiences. CONCLUSION: Understanding the commonalities of the parental experience of fetal care across diverse settings creates a foundation for improving care and better meeting the needs of parents undergoing a painful and life-defining event. Although health outcomes are not always positive, a positive experience of care is possible and can assist parents to cope with their grief, manage their expectations, and engage in their care. The findings of this study illustrate the ways in which healthcare delivery can facilitate or obstruct a positive care experience.

Excess Mortality and Life-Years Lost in People With Schizophrenia and Other Non-affective Psychoses: An 11-Year Population-Based Cohort Study.

Psychotic disorders are associated with premature mortality, but research was primarily based on Western countries and rarely examined non-affective psychoses other than schizophrenia (ONAP). This population-based cohort study investigated excess mortality in 46 896 schizophrenia and 20 651 ONAP patients between January 2006 and December 2016 in Hong Kong (HK), by estimating all-cause and cause-specific standardized mortality ratios (SMRs), and life-years lost (LYLs), a recently developed, more precise reduced life expectancy measure taking into account the illness onset (age at first-recorded diagnosis). Changes in mortality metrics over the study period were assessed. Study data were retrieved from a territory-wide medical-record database of public healthcare services to 7.5 million HK residents. Results showed that schizophrenia and ONAP patients had higher all-cause (schizophrenia: SMR: 2.49 [95% CI: 2.43-2.55]; ONAP: 2.00 [1.92-2.09]), natural-cause (1.80 [1.74-1.85]; 1.47 [1.40-1.54]), and unnatural-cause (6.97 [6.47-7.49]; 8.53 [7.61-9.52]) mortality rates than general population. Respiratory diseases, cardiovascular diseases, and cancers accounted for the majority of deaths in patient cohorts. Men and women with schizophrenia had 9.53 years and 8.07 years of excess LYLs, respectively. For ONAP, excess LYLs was 8.18 years for men and 5.44 years for women. The overall mortality gap remained similar for both patient groups over time despite their improved longevity and declined unnatural-cause mortality rates. Taken together, schizophrenia and ONAP are associated with increased premature mortality and substantially reduced lifespan in a predominantly Chinese population, with excess deaths mainly attributed to a natural cause. Persistent mortality gap highlights an urgent need for targeted interventions to improve the physical health of patients with psychotic disorders.

Nanoparticles for delivery of agents to fetal lungs.

Fetal treatment of congenital lung disease, such as cystic fibrosis, surfactant protein syndromes, and congenital diaphragmatic hernia, has been made possible by improvements in prenatal diagnostic and interventional technology. Delivery of therapeutic agents to fetal lungs in nanoparticles improves cellular uptake. The efficacy and safety of nanoparticle-based fetal lung therapy depends on targeting of necessary cell populations. This study aimed to determine the relative distribution of nanoparticles of a variety of compositions and sizes in the lungs of fetal mice delivered through intravenous and intra-amniotic routes. Intravenous delivery of particles was more effective than intra-amniotic delivery for epithelial, endothelial and hematopoietic cells in the fetal lung. The most effective targeting of lung tissue was with 250nm Poly-Amine-co-Ester (PACE) particles accumulating in 50% and 44% of epithelial and endothelial cells. This study demonstrated that route of delivery and particle composition impacts relative cellular uptake in fetal lung, which will inform future studies in particle-based fetal therapy.

Closing the gap in care of blunt solid organ injury in children.

INTRODUCTION: Cross-sectional data of pediatric blunt solid organ injury demonstrates higher rates of nonoperative management and shorter lengths of stay (LOSs) in pediatric trauma centers (PTCs) versus adult trauma centers (ATCs) or dual trauma centers (DTCs). Recent iterations of guidelines (McVay 2008, J Pediatr Surg 2008;43(6):1072-1076 J Trauma Acute Care Surg 2015;79(4):683-693) have emphasized physiologic parameters rather than injury grade in clinical decision making, improving resource allocation and decreasing LOS. We sought to evaluate how these guidelines have influenced care. METHODS: The National Trauma Data Bank (2007-2016) was queried for isolated spleen and liver injuries in patients younger than 19 years. Linear regression, odds ratio (OR), and χ test were used to determine significance between operative intervention or LOS among different trauma center types and grade of injury. RESULT: A total of 55,036 blunt spleen or liver injuries were identified. Although operative rates decreased in ATCs over time (p = 0.037), patients treated at ATCs or DTCs continued to demonstrate higher ORs of operative intervention (OR, 4.43 and 2.88, respectively) compared with PTCs. Mean LOS decreased by 1.52 (p < 0.001), 0.49 (p = 0.26), and 1.31 (p = 0.05) days at ATC, DTC, and PTC to 6.43, 6.68, and 5.16 days. Improvement in LOS for ATCs was distributed across injury Grades I, II, and IV, while there was no correlation among PTCs for injury grade. CONCLUSION: Despite more than a decade of guidelines in pediatric solid organ injury supporting nonoperative management and accelerated discharge pathways based on physiologic parameters, rates of operative intervention remain much higher in ATCs versus PTCs, and all centers appear to fall short of consensus guidelines for discharge. LEVEL OF EVIDENCE: Care management study, level IV.

Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study.

Evidence shows that schizophrenia is associated with increased incidence of stroke. However, relationship between schizophrenia and short-term mortality risk is understudied, and mixed findings were observed. In this retrospective population-based cohort study, we identified individuals admitted for incident ischemic stroke between 2006 and 2016 using a territory-wide electronic medical record database of public healthcare system in Hong Kong to examine 30-day and 1-year mortality rates in 817 schizophrenia patients compared with 8170 patients without psychotic disorder (10:1 matched to schizophrenia patients on demographics, treatment sites and calendar-period for index admission). Multivariate regression analyses adjusting for medical comorbidities revealed that schizophrenia patients experienced elevated 1-year (16.9% vs 12.1%; p < 0.001) and 30-day mortality (7.2% vs 5.3%; p = 0.053) relative to control group. Additional age- and gender-stratified analyses revealed even more pronounced effect of schizophrenia on raised mortality risk, as indicated by higher odds, in younger-age (<65 years) group and men. Our results indicate that schizophrenia is associated with heightened short-term mortality following incident ischemic stroke. Further research is warranted to identify factors contributing to excess post-stroke deaths among schizophrenia patients to facilitate development of effective interventions for mortality risk reduction.