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Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Objective To investigate the incidence and risk factors for hypogammaglobulinaemia and infectious complications associated with rituximab treatment in childhood-onset rheumatic diseases. Methods We performed a single-centre retrospective study of patients (n = 85) treated at Boston Children’s Hospital (BCH) from 2009 to 2019. Study subjects included patients (ages 6–24 years) who received rituximab for the treatment of a childhood-onset rheumatic disease. Results New-onset hypogammaglobulinaemia developed in 23 (27.1%) patients within 18 months of rituximab induction treatment. Twenty-two patients (25.9%) developed at least one infectious complication in the 18 months following the first rituximab infusion; of these, 11 (50%) had serious infections requiring inpatient treatment. After adjusting for potential confounders, exposure to pulse corticosteroid therapy in the month prior to rituximab use was a significant predictor of both new-onset hypogammaglobulinaemia (odds ratio [OR] 3.94; 95% CI: 1.07, 16.0; P = 0.044) and infectious complications (OR 15.3; 95% CI: 3.04, 126.8; P = 0.003). Post-rituximab hypogammaglobulinaemia was the strongest predictor of serious infectious complications (OR 7.89; 95% CI: 1.41, 65.6; P = 0.028). Younger age at rituximab use was also a significant predictor of new-onset hypogammaglobulinaemia (OR 0.83; 95% CI: 0.70, 0.97; P = 0.021). Compared with other rheumatic diseases, patients with vasculitis had a higher likelihood of developing infectious complications, including serious infections. Conclusion Although rituximab was well tolerated in terms of infectious complications in the majority of patients with childhood-onset rheumatic diseases, a substantial proportion developed new-onset hypogammaglobulinaemia and infectious complications following treatment. Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinaemia and infections in paediatric patients with rheumatic conditions.

Background Suicide is a leading cause of death among children, adolescents, and young adults (AYA), and mental health disorders are a major contributing factor. Yet, suicidal behaviors among children and AYA with mental health concerns remain understudied and age-specific risk factors are poorly understood. We examined the risk factors for suicide attempt in children and AYA with mental health disorders across three age groups: pre-adolescent children (aged ≤ 12), adolescents (aged 13-17), and young adults (aged 18-25). Methods A cross-sectional study of children and AYA hospitalized for a mental health disorder (n = 18,018) at a private hospital system with 141 facilities across the United States (year 2014). Results Suicide attempts six months prior to hospitalization were reported in 12.1% (n = 177) pre-adolescent children, 22% (n = 1476) adolescents, and 17.9% (n = 1766) young adults. Evidence of psychological trauma was present in 55.4% of pre-adolescent children, 51.2% of adolescents, and 44.5% of young adults. Predictors for suicide attempt observed across all three age groups included the following: female sex, depressive disorder, and being a victim of bullying. Risk factors for suicide attempt specific to pre-adolescent children included being uninsured and having an unsafe home or school environment. Among AYA, suicide attempt was associated with non-Hispanic white, family history of suicide, emotional traumas, and other traumatic experiences. Alcohol use disorder was also a significant predictor of suicide attempt in young adults. Conclusions Suicide attempts among children and AYA admitted to a hospital with mental health concerns are highly prevalent. Socioeconomic stressors appeared to be an important contributing factor of suicidal behavior in pre-adolescent children but not in older AYA. Effective suicide prevention strategies targeting children and AYA would need to consider age-specific risk factors.

BACKGROUND: Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics datasets are available to interrogate their biological effects. OBJECTIVE: We sought to identify functionally relevant ICS response genetic associations by integrating complementary multiomics datasets. METHODS: Variants with p-values

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an “Eastern Slavic NBS hot spot.” The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions. © Copyright © 2021 Sharapova, Pashchenko, Bondarenko, Vakhlyarskaya, Prokofjeva, Fedorova, Savchak, Mareika, Valiev, Popa, Tuzankina, Vlasova, Sakovich, Polyakova, Rumiantseva, Naumchik, Kulyova, Aleshkevich, Golovataya, Minakovskaya, Belevtsev, Latysheva, Latysheva, Beznoshchenko, Akopyan, Makukh, Kozlova, Varabyou, Ballow, Ong, Walter, Kondratenko, Kostyuchenko and Aleinikova. We thank all doctors for clinical help for patients. We also appreciate the support of patient and their parents for agreeing to take part in this study. TP thanks Sergey?Nikulshin, Marika Grutupa, and Zanna Kovalova. We thank Joseph Dasso for editing this manuscript, primarily for proper English.

Rituximab is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following rituximab treatment. However, this phenomenon has not been well delineated in the pediatric population.This study sought to determine the prevalence, risk factors, and clinical significance of hypogammaglobulinemia following rituximab therapy in children.This was a multicenter, retrospective cohort study that extracted clinical and immunological data from pediatric patients who received rituximab.The cohort comprised 207 patients (median age, 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-rituximab therapy, with an increase in prevalence of hypo-IgG (28.7%-42.6%; P = .009), hypo-IgA (11.1%-20.4%; P = .02), and hypo-IgM (20.0%-62.0%; P .0001). Additionally, low IgG levels at any time post-rituximab therapy were associated with a higher risk of serious infections (34.4% vs 18.9%; odds ratio, 2.3; 95% CI, 1.1-4.8; P = .03). Persistent IgG hypogammaglobulinemia was observed in 27 of 101 evaluable patients (26.7%). Significant risk factors for persistent IgG hypogammaglobulinemia included low IgG and IgA levels pre-rituximab therapy. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency, 7 of which received rituximab for autoimmune cytopenias.Hypogammaglobulinemia post-rituximab treatment is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying primary immunodeficiencies are relatively common in children receiving rituximab, thus highlighting the importance of immunologic monitoring both before and after rituximab therapy.

OBJECTIVE To investigate the effects of early introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) on the disease course in untreated polyarticular juvenile idiopathic arthritis (JIA). METHODS We analyzed data on patients with polyarticular JIA participating in the Start Time Optimization of Biologics in Polyarticular JIA (STOP-JIA) study (n = 400) and a comparator cohort (n = 248) from the Childhood Arthritis and Rheumatology Research Alliance Registry. Latent class trajectory modeling (LCTM) was applied to identify subgroups of patients with distinct disease courses based on disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints) over 12 months from baseline. RESULTS In the STOP-JIA study, 198 subjects (49.5%) received bDMARDs within 3 months of baseline assessment. LCTM analyses generated 3 latent classes representing 3 distinct disease trajectories, characterized by slow, moderate, or rapid disease activity improvement over time. Subjects in the rapid improvement trajectory attained inactive disease within 6 months from baseline. Odds of being in the rapid improvement trajectory versus the slow improvement trajectory were 3.6 times as high (95% confidence interval 1.32-10.0; P = 0.013) for those treated with bDMARDs ≤3 months from baseline compared with subjects who started bDMARDs >3 months after baseline, after adjusting for demographic characteristics, clinical attributes, and baseline disease activity. Shorter disease duration at first rheumatology visit approached statistical significance as a predictor of favorable trajectory without bDMARD treatment. CONCLUSION Starting bDMARDs within 3 months of baseline assessment is associated with more rapid achievement of inactive disease in subjects with untreated polyarticular JIA. These results demonstrate the utility of trajectory analysis of disease course as a method for determining treatment efficacy.

Background Real‐world healthcare data are an important resource for epidemiologic research. However, accurate identification of patient cohorts—a crucial first step underpinning the validity of research results—remains a challenge. We developed and evaluated claims‐based case ascertainment algorithms for pulmonary hypertension (PH), comparing conventional decision rules with state‐of‐the‐art machine‐learning approaches. Methods and Results We analyzed an electronic health record‐Medicare linked database from two large academic tertiary care hospitals (years 2007–2013). Electronic health record charts were reviewed to form a gold standard cohort of patients with (n=386) and without PH (n=164). Using health encounter data captured in Medicare claims (including patients’ demographics, diagnoses, medications, and procedures), we developed and compared 2 approaches for identifying patients with PH: decision rules and machine‐learning algorithms using penalized lasso regression, random forest, and gradient boosting machine. The most optimal rule‐based algorithm—having ≥3 PH‐related healthcare encounters and having undergone right heart catheterization—attained an area under the receiver operating characteristic curve of 0.64 (sensitivity, 0.75; specificity, 0.48). All 3 machine‐learning algorithms outperformed the most optimal rule‐based algorithm ( P Conclusions Research‐grade case identification algorithms for PH can be derived and rigorously validated using machine‐learning algorithms. Simple decision rules commonly applied in published literature performed poorly; more complex rule‐based algorithms may potentially address the limitation of this approach. PH research using claims data would be considerably strengthened through the use of validated algorithms for cohort ascertainment.

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an “Eastern Slavic NBS hot spot.” The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.

To investigate racial and ethnic differences in pulmonary hypertension subtypes and survival differences in a pediatric population.This was a retrospective analysis of a cohort of patients with pulmonary hypertension (aged ≤18 years) enrolled in the Pediatric Pulmonary Hypertension Network registry between 2014 and 2018, comprising patients at eight Pediatric Centers throughout North America (n = 1417).Among children diagnosed after the neonatal period, pulmonary arterial hypertension was more prevalent among Asians (OR, 1.83; 95% CI, 1.21-2.79; P = .0045), lung disease-associated pulmonary hypertension among blacks (OR, 2.09; 95% CI, 1.48-2.95; P .0001), idiopathic pulmonary arterial hypertension among whites (OR, 1.58; 95% CI, 1.06-2.41; P = .0289), and pulmonary veno-occlusive disease among Hispanics (OR, 6.11; 95% CI, 1.34-31.3; P = .0184). Among neonates, persistent pulmonary hypertension of the newborn (OR, 4.07; 95% CI, 1.54-10.0; P = .0029) and bronchopulmonary dysplasia (OR, 8.11; 95% CI, 3.28-19.8; P .0001) were more prevalent among blacks, and congenital diaphragmatic hernia was more prevalent among whites (OR, 2.29; 95% CI, 1.25-4.18; P = .0070). An increased mortality risk was observed among blacks (HR, 1.99; 95% CI, 1.03-3.84; P = .0396), driven primarily by the heightened mortality risk among those with lung disease-associated pulmonary hypertension (HR, 2.84; 95% CI, 1.15-7.04; P = .0241).We found significant racial variability in the prevalence of pulmonary hypertension subtypes and survival outcomes among children with pulmonary hypertension. Given the substantial burden of this disease, further studies to validate phenotypic differences and to understand the underlying causes of survival disparities between racial and ethnic groups are warranted.

Human diseases are historically categorized into groups based on the specific organ or tissue affected. Over the past two decades, advances in high-throughput genomic and proteomic technologies have generated substantial evidence demonstrating that many diseases are in fact markedly heterogeneous, comprising multiple clinically and molecularly distinct subtypes that simply share an anatomical location. Here, a Bayesian network analysis is applied to study comorbidity patterns that define disease subtypes in pediatric pulmonary hypertension. The analysis relearned established subtypes, thus validating the approach, and identified rare subtypes that are difficult to discern through clinical observations, providing impetus for deeper investigation of the disease subtypes that will enrich current disease classifications. Further advances linking disease subtypes to therapeutic response, disease outcomes, as well as the molecular profiles of individual subtypes will provide impetus for the development of more effective and targeted therapies.

BACKGROUND Prophylactic treatment of postoperative Crohn's disease (CD) plays a critical role in maintaining clinical remission. We performed the first study in the last decade to examine secular trends in the use of pharmacologic interventions after ileocolonic resection in the United States, to understand whether clinical practice converges with recent advances in scientific knowledge. METHODS A retrospective study of a U.S. national claims database was performed. The study cohort included 106 CD patients in the years 1999 to 2001 (prebiologic era) and 294 CD patients in the years 2009 to 2011 (postbiologic era), who underwent ileocolonic resection. Medication use in the 12 months after the surgery was examined. RESULTS Significant variations in care were evident in both study periods. Across the 2 study periods, there was an increased use of biologics (from 0% to 36.4%) and a substantial reduction in the use of 5-aminosalicylic acid (from 50.9% to 28.2%; P < 0.0001). Therapeutic interventions that have been found ineffective in published studies continued to be widely applied: one-third of patients were prescribed corticosteroids, and several cases of prolonged use of corticosteroids or antibiotics were observed in both cohorts. Disease behavior (penetrating, stricturing, or nonpenetrating and nonstricturing) was not associated with the choice of postoperative therapeutic interventions, with the exception of an increased use of antibiotics among patients with penetrating disease. CONCLUSIONS There is a substantial gap between advances in postoperative care for ileocolonic CD and clinical practice. Strategies to expedite the integration of new knowledge and evidence into practice are urgently needed.

Human diseases are historically categorized into groups based on the specific organ or tissue affected. Over the past two decades, advances in high-throughput genomic and proteomic technologies have generated substantial evidence demonstrating that many diseases are in fact markedly heterogeneous, comprising multiple clinically and molecularly distinct subtypes that simply share an anatomical location. Here, a Bayesian network analysis is applied to study comorbidity patterns that define disease subtypes in pediatric pulmonary hypertension. The analysis relearned established subtypes, thus validating the approach, and identified rare subtypes that are difficult to discern through clinical observations, providing impetus for deeper investigation of the disease subtypes that will enrich current disease classifications. Further advances linking disease subtypes to therapeutic response, disease outcomes, as well as the molecular profiles of individual subtypes will provide impetus for the development of more effective and targeted therapies.

Key Points Question In patients receiving rituximab, what are the current rates of screening and recognition of hypogammaglobulinemia, and what are the infectious risks and predictors for increased mortality? Findings In a cohort study of 4479 patients receiving rituximab, many patients were found as not being screened or not being properly identified as having hypogammaglobulinemia. Following rituximab therapy, there was a significant increase in severe infections in the overall study cohort, increased mortality was associated with severe infections in the 6 months before and after rituximab therapy, and higher cumulative doses of immunoglobulin replacement therapy were associated with a reduced risk of severe infections. Meaning Many patients are not being screened or properly identified as having hypogammaglobulinemia before or after rituximab therapy, which may contribute to inferior outcomes with excess morbidity and mortality; monitoring routine serum immunoglobulin levels before and after rituximab therapy may help identify patients at high risk for developing infections and who may benefit from immunoglobulin replacement therapy., Importance Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality. Objective To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality. Design, Setting, and Participants A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System). Exposures Rituximab administration. Main Outcomes and Measures The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use. Results Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P, This cohort study examines the association of screening for hypogammaglobulinemia with the risk of infection and mortality in patients who received rituximab therapy.

Populationwide mammography screening has been associated with a substantial rise in false-positive mammography findings and breast cancer overdiagnosis. However, there is a lack of current data on the associated costs in the United States. We present costs due to false-positive mammograms and breast cancer overdiagnoses among women ages 40-59, based on expenditure data from a major US health care insurance plan for 702,154 women in the years 2011-13. The average expenditures for each false-positive mammogram, invasive breast cancer, and ductal carcinoma in situ in the twelve months following diagnosis were $852, $51,837 and $12,369, respectively. This translates to a national cost of $4 billion each year. The costs associated with false-positive mammograms and breast cancer overdiagnoses appear to be much higher than previously documented. Screening has the potential to save lives. However, the economic impact of false-positive mammography results and breast cancer overdiagnoses must be considered in the debate about the appropriate populations for screening.

Figure S1. Average clinical read time (CRT) for tests ordered on a given day of admission. (DOCX 100 kb)

Background Debates about the benefits and harms of mammography continue despite the accumulation of evidence. We sought to quantify the disagreement across systematic reviews of mammography and determine whether author or design characteristics were associated with conclusions that were favourable to the use of mammography for routine breast cancer screening. Methods We identified systematic reviews of mammography published between January 2000 and November 2015, and extracted information about the selection of evidence, age groups, the use of meta-analysis, and authors’ professions and financial competing interest disclosures. Conclusions about specific age groups were graded as favourable if they stated that there were meaningful benefits, that benefits of mammography outweighed harms, or that harms were inconsequential. The main outcome measures were the proportions of favourable conclusions relative to review design and author characteristics. Results From 59 conclusions identified in 50 reviews, 42% (25/59) were graded as favourable by two investigators. Among the conclusions produced by clinicians, 63% (12/19) were graded as favourable compared to 32% (13/40) from other authors. In the 50–69 age group where the largest proportion of systematic reviews were focused, conclusions drawn by authors without financial competing interests (odds ratio 0.06; 95% CI 0.07–0.56) and non-clinicians (odds ratio 0.11; 95% CI 0.01–0.84) were less likely to be graded as favourable. There was no trend in the proportion of favourable conclusions over the period, and we found no significant association between review design characteristics and favourable conclusions. Conclusions Differences in the conclusions of systematic reviews of the evidence for mammography have persisted for 15 years. We found no strong evidence that design characteristics were associated with greater support for the benefits of mammography in routine breast cancer screening. Instead, the results suggested that the specific expertise and competing interests of the authors influenced the conclusions of systematic reviews. Electronic supplementary material The online version of this article (doi:10.1186/s13643-017-0495-6) contains supplementary material, which is available to authorized users.

Rationale: Pediatric pulmonary hypertension (PH) is a heterogeneous condition with varying natural history and therapeutic response. Precise classification of PH subtypes is, therefore, crucial for individualizing care. However, gaps remain in our understanding of the spectrum of PH in children. Objective: We seek to study the manifestations of PH in children and to assess the feasibility of applying a network-based approach to discern disease subtypes from comorbidity data recorded in longitudinal data sets. Methods and Results: A retrospective cohort study comprising 6 943 263 children (, National Institutes of Health (U.S.) (Award U01HL121518)

Multiple provider prescribing of interacting drugs is a preventable cause of morbidity and mortality, and fragmented care is a major contributing factor. We applied social network analysis to examine the impact of provider patient-sharing networks on the risk of multiple provider prescribing of interacting drugs. We performed a retrospective analysis of commercial healthcare claims (years 2008–2011), including all non-elderly adult beneficiaries (n = 88,494) and their constellation of care providers. Patient-sharing networks were derived based on shared patients, and care constellation cohesion was quantified using care density, defined as the ratio between the total number of patients shared by provider pairs and the total number of provider pairs within the care constellation around each patient. In our study, 2% (n = 1796) of patients were co-prescribed interacting drugs by multiple providers. Multiple provider prescribing of interacting drugs was associated with care density (odds ratio per unit increase in the natural logarithm of the value for care density 0.78; 95% confidence interval 0.74–0.83; p

Alongside their benefits health IT applications can pose new risks to patient safety. Problems with IT have been linked to many different types of clinical errors including prescribing and administration of medications; as well as wrong-patient, wrong-site errors, and delays in procedures. There is also growing concern about the risks of data breach and cyber-security. IT-related clinical errors have their origins in processes undertaken to design, build, implement and use software systems in a broader sociotechnical context. Safety can be improved with greater standardization of clinical software and by improving the quality of processes at different points in the technology life cycle, spanning design, build, implementation and use in clinical settings. Oversight processes can be set up at a regional or national level to ensure that clinical software systems meet specific standards. Certification and regulation are two mechanisms to improve oversight. In the absence of clear standards, guidelines are useful to promote safe design and implementation practices. Processes to identify and mitigate hazards can be formalised via a safety management system. Minimizing new patient safety risks is critical to realizing the benefits of IT.

Alongside all its benefits, the widespread adoption of health care information technology (HIT) is coupled with emerging risks to patient safety. Evidence about patient harms associated with HIT is mounting. Data breach and cyber-crime can also pose risks. Problems with the design, implementation and use of systems give rise to clinical errors. As safety is an emergent system property, it needs to be addressed throughout the life cycle of HIT systems including design, build, implementation, and use. Classification systems help to understand underlying causes of errors and to facilitate timely detection of new problems that can pose threats to patient safety.

The manner in which people preferentially interact with others like themselves suggests that information about social connections may be useful in the surveillance of opinions for public health purposes. We examined if social connection information from tweets about human papillomavirus (HPV) vaccines could be used to train classifiers that identify anti-vaccine opinions. From 42,533 tweets posted between October 2013 and March 2014, 2,098 were sampled at random and two investigators independently identified anti-vaccine opinions. Machine learning methods were used to train classifiers using the first three months of data, including content (8,261 text fragments) and social connections (10,758 relationships). Connection-based classifiers performed similarly to content-based classifiers on the first three months of training data, and performed more consistently than content-based classifiers on test data from the subsequent three months. The most accurate classifier achieved an accuracy of 88.6% on the test data set, and used only social connection features. Information about how people are connected, rather than what they write, may be useful for improving public health surveillance methods on Twitter.