Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Mortality from leading cancers in districts of England from 2002 to 2019: a population-based, spatiotemporal study.

BACKGROUND: Cancers are the leading cause of death in England. We aimed to estimate trends in mortality from leading cancers from 2002 to 2019 for the 314 districts in England. METHODS: We did a high-resolution spatiotemporal analysis of vital registration data from the UK Office for National Statistics using data on all deaths from the ten leading cancers in England from 2002 to 2019. We used a Bayesian hierarchical model to obtain robust estimates of age-specific and cause-specific death rates. We used life table methods to calculate the primary outcome, the unconditional probability of dying between birth and age 80 years by sex, cancer cause of death, local district, and year. We reported Spearman rank correlations between the probability of dying from a cancer and district-level poverty in 2019. FINDINGS: In 2019, the probability of dying from a cancer before age 80 years ranged from 0·10 (95% credible interval [CrI] 0·10-0·11) to 0·17 (0·16-0·18) for women and from 0·12 (0·12-0·13) to 0·22 (0·21-0·23) for men. Variation in the probability of dying was largest for lung cancer among women, being 3·7 times (95% CrI 3·2-4·4) higher in the district with the highest probability than in the district with the lowest probability; and for stomach cancer for men, being 3·2 times (2·6-4·1) higher in the district with the highest probability than in the one with the lowest probability. The variation in the probability of dying was smallest across districts for lymphoma and multiple myeloma (95% CrI 1·2 times [1·1-1·4] higher in the district with the highest probability than the lowest probability for women and 1·2 times [1·0-1·4] for men), and leukaemia (1·1 times [1·0-1·4] for women and 1·2 times [1·0-1·5] for men). The Spearman rank correlation between probability of dying from a cancer and district poverty was 0·74 (95% CrI 0·72-0·76) for women and 0·79 (0·78-0·81) for men. From 2002 to 2019, the overall probability of dying from a cancer declined in all districts: the reductions ranged from 6·6% (95% CrI 0·3-13·1) to 30·1% (25·6-34·5) for women and from 12·8% (7·1-18·8) to 36·7% (32·2-41·2) for men. However, there were increases in mortality for liver cancer among men, lung cancer and corpus uteri cancer among women, and pancreatic cancer in both sexes in some or all districts with posterior probability greater than 0·80. INTERPRETATION: Cancers with modifiable risk factors and potential for screening for precancerous lesions had heterogeneous trends and the greatest geographical inequality. To reduce these inequalities, factors affecting both incidence and survival need to be addressed at the local level. FUNDING: Wellcome Trust, Imperial College London, UK Medical Research Council, and the National Institute of Health Research.

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

Targeted long-read sequencing identifies missing disease-causing variation.

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.

Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3.

Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.

Acting on non-communicable diseases in low- and middle-income tropical countries.

The classical portrayal of poor health in tropical countries is one of infections and parasites, contrasting with wealthy Western countries, where unhealthy diet and behaviours cause non-communicable diseases (NCDs) such as heart disease and cancer. Using international mortality data, we show that most NCDs cause more deaths at every age in low- and middle-income tropical countries than in high-income Western countries. Causes of NCDs in low- and middle-income countries include poor nutrition and living environment, infections, insufficient taxation and regulation of tobacco and alcohol, and under-resourced and inaccessible healthcare. We identify a comprehensive set of actions across health, social, economic and environmental sectors that could confront NCDs in low- and middle-income tropical countries and reduce global health inequalities.

Does a Preoperative Mental Health Diagnosis Affect Pain Management in Patients With Adolescent Idiopathic Scoliosis Undergoing Surgery?

BACKGROUND: Patients with adolescent idiopathic scoliosis (AIS) are typically treated surgically with posterior spinal fusion (PSF) when the curve continues to progress beyond 45 to 50 degrees. In adult patients, studies have shown that preoperative psychiatric diagnoses are associated with poorer clinical outcomes after lumbar spine surgery. This study aims to address whether a preoperative mental health disorder affects outcomes in pediatric patients with AIS treated with PSF. METHODS: We conducted a retrospective study of pediatric patients with a history of AIS requiring operative treatment with PSF at a single center with a minimum of 2-year follow-up. These patients were split into 2 groups: a subset that had a mental health disorder (MHD), and a control group. The MHD subset included patients with anxiety disorder, major depressive disorder, bipolar disorder, manic disorder, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and stress disorder. The 2 groups were compared using independent student t -test and χ 2 analysis. RESULTS: A total of 417 patients were included in the study. Ninety-three patients were included in the MHD group, and 324 patients were included in the control group. The mean pain score for the MHD group was greater (3.93) compared with the control group (3.34). The PCA demands during inpatient stay for the MHD group were also greater (236.7) compared with the control group (140.0). There was no significant difference in the length of stay in the hospital between the MHD group (4.7 days) and the control group (4.6 days). There was a greater number of patients in the MHD cohort (25.8%) still using narcotic pain medication at first follow-up compared with the control group (12.0%). CONCLUSION: This study suggests that patients with AIS with a preoperative mental health disorder undergoing PSF experience more pain after surgery and require more pain medication during their recovery. LEVEL OF EVIDENCE: III. This is a retrospective review of pediatric patients with adolescent idiopathic scoliosis and a preoperative mental health diagnosis and their pain management requirements during the recovery period from posterior spinal fusion.

Waveguide-integrated chip-scale optomechanical magnetometer.

Optomechanical magnetometers enable highly sensitive magnetic field sensing. However, all such magnetometers to date have been optically excited and read-out either via free space or a tapered optical fiber. This limits their scalability and integrability, and ultimately their range of applications. Here, we present an optomechanical magnetometer that is excited and read-out via a suspended optical waveguide fabricated on the same silicon chip as the magnetometer. Moreover, we demonstrate that thermomechanical noise limited sensitivity is possible using portable electronics and laser. The magnetometer employs a silica microdisk resonator selectively sputtered with a magnetostrictive film of galfenol (FeGa) which induces a resonant frequency shift in response to an external magnetic field. Experimental results reveal the retention of high quality-factor optical whispering gallery mode resonances whilst also demonstrating high sensitivity and dynamic range in ambient conditions. The use of off-the-shelf portable electronics without compromising sensor performance demonstrates promise for applications.

Continuous Optical-to-Mechanical Quantum State Transfer in the Unresolved Sideband Regime.

Optical-to-mechanical quantum state transfer is an important capability for future quantum networks, quantum communication, and distributed quantum sensing. However, existing continuous state transfer protocols operate in the resolved sideband regime, necessitating a high-quality optical cavity and a high mechanical resonance frequency. Here, we propose a continuous protocol that operates in the unresolved sideband regime. The protocol is based on feedback cooling, can be implemented with current technology, and is able to transfer non-Gaussian quantum states with high fidelity. Our protocol significantly expands the kinds of optomechanical devices for which continuous optical-to-mechanical state transfer is possible, paving the way toward quantum technological applications and the preparation of macroscopic superpositions to test the fundamentals of quantum science.

Exposed Intramedullary Fixation Produces Similar Outcomes to Buried Fixation for Acute Pediatric Monteggia Fractures.

BACKGROUND: Treatment of acute pediatric Monteggia fractures requires ulnar length stability to maintain reduction of the radiocapitellar joint. When operative care is indicated, intramedullary ulna fixation can be buried or left temporarily exposed through the skin while under a cast. The authors hypothesized that treatment with exposed fixation yields equivalent results to buried fixation for Monteggia fractures while avoiding secondary surgery for hardware removal. METHODS: A retrospective review of children with acute Monteggia fractures at our Level 1 pediatric trauma center was performed. Patient charts and radiographs were evaluated for age, fracture type, fracture location, Bado classification, type of treatment, complications, cast duration, time to fracture union, time to hardware removal, and range of motion. RESULTS: Out of 59 acute Monteggia fractures surgically treated (average age 6 y, range 2 to 14), 15 (25%) patients were fixed with buried intramedullary fixation and 44 (75%) with exposed intramedullary fixation under a cast. There were no significant differences between buried and exposed intramedullary fixation in cast time after surgery (39 vs. 37 d; P =0.55), time to fracture union (37 vs. 35 d; P =0.67), pronation/supination (137 vs. 134 degrees; P =0.68) or flexion/extension (115 vs. 114 degrees; P =0.81) range of motion. The exposed fixation had a return to OR of 4.5% (2 out of 44), and the buried fixation returned to the OR for removal on all patients. CONCLUSION: Exposed intramedullary fixation yielded equivalent clinical outcomes to buried devices in the treatment of acute pediatric Monteggia fractures while eliminating the need for a second surgery to remove hardware, reducing the associated risks and costs of surgery and anesthesia, but had a higher complication rate. Open Monteggia fractures or patterns with a known risk of delayed union may benefit from buried instead of exposed intramedullary fixation for earlier mobilization. LEVEL OF EVIDENCE: III.

Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons. Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.

Redefining the Etiologic Landscape of Cerebellar Malformations.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth.

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) conditions of the head and neck are treatment challenges. Traditionally, these conditions require multiple invasive interventions, with incomplete malformation removal, disfigurement, and possible dysfunction. Use of the PI3K inhibitor alpelisib, previously shown to be effective in PROS, has not been reported in PIK3CA-associated head and neck lymphatic malformations (HNLMs) or facial infiltrating lipomatosis (FIL). We describe prospective treatment of 5 children with PIK3CA-associated HNLMs or head and neck FIL with alpelisib monotherapy. METHODS: A total of 5 children with PIK3CA-associated HNLMs (n = 4) or FIL (n = 1) received alpelisib monotherapy (aged 2-12 years). Treatment response was determined by parental report, clinical evaluation, diary/questionnaire, and standardized clinical photography, measuring facial volume through 3-dimensional photos and magnetic resonance imaging. RESULTS: All participants had reduction in the size of lesion, and all had improvement or resolution of malformation inflammation/pain/bleeding. Common invasive therapy was avoided (ie, tracheotomy). After 6 or more months of alpelisib therapy, facial volume was reduced (range 1%-20%) and magnetic resonance imaging anomaly volume (range 0%-23%) were reduced, and there was improvement in swallowing, upper airway patency, and speech clarity. CONCLUSION: Individuals with head and neck PROS treated with alpelisib had decreased malformation size and locoregional overgrowth, improved function and symptoms, and fewer invasive procedures.

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis.

OBJECTIVE: Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non­platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. METHODS: In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. RESULTS: Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. CONCLUSIONS: Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

Spatial modelling and inequalities of environmental noise in Accra, Ghana.

Noise pollution is a growing environmental health concern in rapidly urbanizing sub-Saharan African (SSA) cities. However, limited city-wide data constitutes a major barrier to investigating health impacts as well as implementing environmental policy in this growing population. As such, in this first of its kind study in West Africa, we measured, modelled and predicted environmental noise across the Greater Accra Metropolitan Area (GAMA) in Ghana, and evaluated inequalities in exposures by socioeconomic factors. Specifically, we measured environmental noise at 146 locations with weekly (n = 136 locations) and yearlong monitoring (n = 10 locations). We combined these data with geospatial and meteorological predictor variables to develop high-resolution land use regression (LUR) models to predict annual average noise levels (LAeq24hr, Lden, Lday, Lnight). The final LUR models were selected with a forward stepwise procedure and performance was evaluated with cross-validation. We spatially joined model predictions with national census data to estimate population levels of, and potential socioeconomic inequalities in, noise levels at the census enumeration-area level. Variables representing road-traffic and vegetation explained the most variation in noise levels at each site. Predicted day-evening-night (Lden) noise levels were highest in the city-center (Accra Metropolis) (median: 64.0 dBA) and near major roads (median: 68.5 dBA). In the Accra Metropolis, almost the entire population lived in areas where predicted Lden and night-time noise (Lnight) surpassed World Health Organization guidelines for road-traffic noise (Lden <53; and Lnight <45). The poorest areas in Accra also had significantly higher median Lden and Lnight compared with the wealthiest ones, with a difference of ∼5 dBA. The models can support environmental epidemiological studies, burden of disease assessments, and policies and interventions that address underlying causes of noise exposure inequalities within Accra.

Treatments and Sequelae of Pediatric Pathologic Proximal Femur Fractures Due to Benign Bone Cyst.

BACKGROUND: The proximal femur is a common location for pathologic fractures in children, yet there is little published information regarding this injury. The purpose of this study was to investigate the outcomes of pediatric pathologic proximal femur fractures due to benign bone tumors. METHODS: A retrospective review of patients treated for pathologic proximal femur fractures from 2004 to 2018 was conducted. Inclusion criteria were age below 18 years and pathologic proximal femur fracture secondary to a benign bone tumor. Patients were excluded if they had <1 year of follow-up. Medical charts and serial radiographs were reviewed for fracture classification, underlying pathology, treatment, complications, and time to fracture healing. RESULTS: A total of 14 patients were included. Mean age was 6±3 (3 to 11) years, and mean follow-up was 44±21 (22 to 86) months. Index treatment was spica casting in 9/14 (68%) patients, while 5/14 (32%) were treated with internal fixation. Of the 9 patients initially treated with casting, 22% (2/9) required repeat spica casting at a mean of 0.6 months after index treatment, 67% (6/9) required internal fixation at a mean of 20.3 months after index treatment, and 11% (1/9) did not require revision treatment. Eighty-eight percent (8/9) of patients treated with casting required revision treatment compared with 40% (2/5) of those treated with internal fixation (P=0.05). Nonunion occurred after 1 refracture, malunion with coxa vara occurred in 2 fractures, and the remaining 11/14 (84%) fractures had a union at a mean of 4.9±3.0 months All cases of malunion occurred in patients initially treated nonoperatively. There were 19 distinct complications in 10/14 (71%) patients. The incidence of any revision surgery was 64% (9/14). CONCLUSIONS: In this series, pediatric pathologic proximal femur fractures demonstrated prolonged time to union, high incidence of revision surgery (64%), and substantial complication rate (71%). In children with pathologic proximal femur fractures, treatment with internal fixation is recommended as this series showed a 78% failure rate of initial conservative management. LEVEL OF EVIDENCE: Level IV.

Small area variations and factors associated with blood pressure and body-mass index in adult women in Accra, Ghana: Bayesian spatial analysis of a representative population survey and census data.

BACKGROUND: Body-mass index (BMI) and blood pressure (BP) levels are rising in sub-Saharan African cities, particularly among women. However, there is very limited information on how much they vary within cities, which could inform targeted and equitable health policies. Our study aimed to analyse spatial variations in BMI and BP for adult women at the small area level in the city of Accra, Ghana. METHODS AND FINDINGS: We combined a representative survey of adult women's health in Accra, Ghana (2008 to 2009) with a 10% random sample of the national census (2010). We applied a hierarchical model with a spatial term to estimate the associations of BMI and systolic blood pressure (SBP) and diastolic blood pressure (DBP) with demographic, socioeconomic, behavioural, and environmental factors. We then used the model to estimate BMI and BP for all women in the census in Accra and calculated mean BMI, SBP, and DBP for each enumeration area (EA). BMI and/or BP were positively associated with age, ethnicity (Ga), being currently married, and religion (Muslim) as their 95% credible intervals (95% CrIs) did not include zero, while BP was also negatively associated with literacy and physical activity. BMI and BP had opposite associations with socioeconomic status (SES) and alcohol consumption. In 2010, 26% of women aged 18 and older had obesity (BMI ≥ 30 kg/m2), and 21% had uncontrolled hypertension (SBP ≥ 140 and/or DBP ≥ 90 mm Hg). The differences in mean BMI and BP between EAs at the 10th and 90th percentiles were 2.7 kg/m2 (BMI) and in BP 7.9 mm Hg (SBP) and 4.8 mm Hg (DBP). BMI was generally higher in the more affluent eastern parts of Accra, and BP was higher in the western part of the city. A limitation of our study was that the 2010 census dataset used for predicting small area variations is potentially outdated; the results should be updated when the next census data are available, to the contemporary population, and changes over time should be evaluated. CONCLUSIONS: We observed that variation of BMI and BP across neighbourhoods within Accra was almost as large as variation across countries among women globally. Localised measures are needed to address this unequal public health challenge in Accra.

A Bayesian mixture modeling approach for public health surveillance.

Spatial monitoring of trends in health data plays an important part of public health surveillance. Most commonly, it is used to understand the etiology of a public health issue, to assess the impact of an intervention, or to provide detection of unusual behavior. In this article, we present a Bayesian mixture model for public health surveillance, which is able to provide estimates of the disease risk in space and time, and also to detect areas with unusual behavior. The model is designed to deal with a range of spatial and temporal patterns in the data, and with time series of different lengths. We carry out a simulation study to assess the performance of the model under different scenarios, and we compare it against a recently proposed Bayesian model for short time series. Finally, the proposed model is used for surveillance of road traffic accidents data in England over the years 2005-2015.

Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations.

PURPOSE: Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM. METHODS: cfDNA was isolated from plasma or cyst fluid from patients with arteriovenous malformations (AVM), venous malformations (VeM), or lymphatic malformations (LM), and assayed for known pathogenic variants using droplet digital polymerase chain reaction (ddPCR). Cyst fluid cfDNA from an independent cohort of LM patients was prospectively screened for variants using a multiplex ddPCR assay. RESULTS: Variants were detected in plasma cfDNA in patients with AVM (2/8) and VeM (1/3). Variants were detected in cyst fluid cfDNA (7/7) but not plasma (0/26) in LM patients. Prospective testing of cyst fluid cfDNA with multiplex ddPCR identified variants in LM patients who had never undergone surgery (4/5). CONCLUSION: Variants were detected in plasma from AVM and VeM patients, and in cyst fluid from patients with LM. These data support investigation of cfDNA-based molecular diagnostics for VM patients, which may provide opportunities to initiate targeted pharmacotherapies without prior surgery.