Citations

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.

Abstract Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART ) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Hedgehog (HH) signaling participates in hepatobiliary repair after injury and is activated in patients with cholangiopathies. Cholangiopathies are associated with bile duct (BD) hyperplasia, including expansion of peribiliary glands, the niche for biliary progenitor cells. The inflammation‐associated cytokine interleukin (IL)‐33 is also up‐regulated in cholangiopathies, including cholangiocarcinoma. We hypothesized that HH signaling synergizes with IL‐33 in acute inflammation‐induced BD hyperplasia. We measured extrahepatic BD (EHBD) thickness and cell proliferation with and without an IL‐33 challenge in wild‐type mice, mice overexpressing Sonic HH ( pCMV‐Shh ), and mice with loss of the HH pathway effector glioma‐associated oncogene 1 ( Gli1lacZ/lacZ ). LacZ reporter mice were used to map the expression of HH effector genes in mouse EHBDs. An EHBD organoid (BDO) system was developed to study biliary progenitor cells in vitro . EHBDs from the HH overexpressing pCMV‐Shh mice showed increased epithelial cell proliferation and hyperplasia when challenged with IL‐33. In Gli1lacZ/lacZ mice, we observed a decreased proliferative response to IL‐33 and decreased expression of Il6 . The HH ligands Shh and Indian HH ( Ihh ) were expressed in epithelial cells, whereas the transcriptional effectors Gli1 , Gli2 , and Gli3 and the HH receptor Patched1 ( Ptch1 ) were expressed in stromal cells, as assessed by in situ hybridization and lacZ reporter mice. Although BDO cells lacked canonical HH signaling, they expressed the IL‐33 receptor suppression of tumorigenicity 2. Accordingly, IL‐33 treatment directly induced BDO cell proliferation in a nuclear factor κB‐dependent manner. Conclusion: HH ligand overexpression enhances EHBD epithelial cell proliferation induced by IL‐33. This proproliferative synergism of HH and IL‐33 involves crosstalk between HH ligand‐producing epithelial cells and HH‐responding stromal cells.

As a follow‐up to genome‐wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well‐known ovarian cancer risk factors and their interactions with 28 genome‐wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10−4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.

ObjectiveLaryngotracheal stenosis (LTS) is resource‐intensive disease. The cost‐effectiveness of LTS treatments has not been adequately explored. We aimed to conduct a cost‐effectiveness analysis comparing open reconstruction (cricotracheal/tracheal resection [CTR/TR]) with endoscopic dilation in the treatment of LTS.Study DesignRetrospective cohort.SettingTertiary referral center (2013‐2017).Subjects and MethodsThirty‐four LTS patients were recruited. Annual costs were derived from the Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University. Cost‐effectiveness analysis compared CTR/TR versus endoscopic dilation at a willingness‐to‐pay threshold of $50,000 per quality‐adjusted life year (QALY) over 5‐ and 10‐year time horizons. The incremental cost‐effectiveness ratio (ICER) was calculated with deterministic analysis and tested for sensitivity with univariate and probabilistic sensitivity analysis.ResultsMean LTS costs were $4080.09 (SE, $569.29) annually for related health care visits. The major risk factor for increased cost was etiology of stenosis. As compared with idiopathic patients, patients with intubation‐related stenosis had significantly higher annual costs ($5286.56 vs $2873.62, P =. 03). The cost of CTR/TR was $8583.91 (SE, $2263.22). Over a 5‐year time horizon, CTR/TR gained $896 per QALY over serial dilations and was cost‐effective. Over a 10‐year time horizon, CTR/TR dominated dilations with a lower cost and higher QALY.ConclusionThe cost of treatment for LTS is significant. Patients with intubation‐related stenosis have significantly higher annual costs than do idiopathic patients. CTR/TR contributes significantly to cost in LTS but is cost‐effective versus endoscopic dilations for appropriately selected patients over a 5‐ and 10‐year horizon.

Key Clinical MessageLymphoma often presents with extranodal manifestations. However, pancreatic involvement resulting in pancreatitis is rare. CD20‐negative variants of diffuse large B‐cell lymphoma are also rare and are more likely to present with extranodal involvement. Lymphoma should be considered in patients presenting with pancreatitis without traditional risk factors.

Ovarian cancer is a heterogeneous disease having the highest gynecologic fatality in the United States with a 5-year survival rate of 46.5%. Poor overall prognosis is mostly attributed to inadequate screening tools, and the majority of diagnoses occur at late stages of the disease. Due to genetic and biological underpinnings, ovarian high-grade serous carcinomas (HGSC) have etiologic evidence in the distal fallopian tube. Fallopian tube screening modalities are aggressively investigated, but few describe cytological characteristics of benign tubal specimens to help in the comparative detection of HGSC precursor cells. Here, we describe fimbrial cytomorphological and nuclear features of tubal specimens (n = 75) from patients clinically indicated for salpingectomy, bilateral or unilateral salpingo-oophorectomy, and hysterectomies for any diagnosis other than ovarian or peritoneal cancer. Fallopian tube histology was used as the diagnostic reference. A total of 75 samples had benign diagnoses. The benign cytological characteristics of fimbrial tubal specimens included ciliated cells in clustered arrangements with mild nuclear membrane irregularity, mild anisonucleosis, round and/or oval nuclei, hyperchromatic chromatin, and mild nuclear membrane irregularity. In contrast, none of the cytology samples had spindle-shaped nuclei, significantly marked anisonucleosis (n = 1), nor had hypochromasia as a characteristic feature. These cytological characteristics could be a potential area of distinction from HGSC precursor cells. Our study establishes cytomorphological characteristics of nonmalignant tubal cells which help underscore the importance of distinguishing malignant HGSC precursors through fimbrial brush sampling in minimally invasive approach.

Myeloproliferative neoplasms (MPNs) are rare hematological malignancies with a significant symptom burden often left unresolved despite recent advances in pharmacological therapy. Yoga is a nonpharmacological strategy that has been shown to improve symptoms in other cancers and may be effective for improving symptoms in MPN patients. Online yoga helps address many of the commonly reported barriers of cancer patients to in-person interventions and may make yoga more accessible to MPNs. An exploration of MPN patient perceptions of participation in online yoga is needed to tailor interventions to patient needs and inform future studies. The purpose of this study was to explore the perceptions of MPN patients participating in a 12-week online yoga intervention. This article represents the combined qualitative interview data from two studies. Participants were asked to complete 60 min/wk of online, home-based yoga and were asked to participate in a 15- to 20-minute phone interview postintervention. The qualitative data was coded in NVivo 11 for content analysis. The total sample included 39 MPN patients. Online yoga was well accepted and liked among these patients. They reported physical (eg, improved sleep, reduced fatigue) and mental (eg, reduced stress) health benefits and liked the convenience of being able to do yoga at home. Online yoga provides a feasible and attractive format through which to deliver a nonpharmacological intervention among MPN patients. Randomized controlled trials are needed to confirm the effects of online yoga on MPN patient symptoms. The qualitative findings presented here help inform the development of these future trials.

Wolf‐Hirschhorn syndrome (WHS) is a microdeletion syndrome characterized by distinctive facial features consisting of “Greek warrior helmet” appearance, prenatal and postnatal growth deficiency, developmental disability, and seizures. This disorder is caused by heterozygous deletions on chromosome 4p16.3 often identified by cytogenetic techniques. Many groups have attempted to identify the critical region within this deletion to establish which genes are responsible for WHS. Herein, clinical whole exome sequencing (WES) was performed on a child with developmental delays, mild facial dysmorphisms, short stature, failure to thrive, and microcephaly, and revealed a de novo frameshift variant, c.1676_1679del (p.Arg559Tfs*38), in WHSC1 (NSD2). While WHSC1 falls within the WHS critical region, individuals with only disruption of this gene have only recently been described in the literature. Loss‐of‐function de novo variations in WHSC1 were identified in large developmental delay, autism, diagnostic, and congenital cardiac cohorts, as well as recent case reports, suggesting that de novo loss‐of‐function WHSC1 variants may be related to disease. These findings, along with our patient suggest that loss‐of‐function variation in WHSC1 may lead to a mild form of Wolf‐Hirschhorn syndrome, and also may suggest that the developmental delays, facial dysmorphisms, and short stature seen in WHS may be due to disruption of WHSC1 gene.