Citations

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

Restless legs syndrome (RLS) affects about 20% of all pregnant women. RLS symptoms are usually moderate to severe in intensity during pregnancy and can result in insomnia, depression, and other adverse outcomes. Although iron deficiency has been implicated as a potential etiological factor, other mechanisms can also play a role. Nonpharmacologic methods are the primary recommended form of treatment for RLS in pregnancy and lactation. Iron supplementation may be considered when the serum ferritin is low; however, several patients are unable to tolerate iron or have severe symptoms despite oral iron replacement. Here, we describe a case of severe RLS in pregnancy and illustrate the dilemmas in diagnosis and management. We review the literature on the prevalence, diagnosis, course, possible underlying pathophysiologic mechanisms and complications of RLS in pregnancy. We describe current best evidence on the efficacy, and safety of nonpharmacologic therapies, oral and intravenous iron supplementation, as well as other medication treatments for RLS in pregnancy and lactation. We highlight gaps in the literature and provide a practical guide for the clinical management of RLS in pregnancy and during breastfeeding.

PURPOSEThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.PATIENTS AND METHODSI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.RESULTSMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).CONCLUSIONThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

BACKGROUND: Outcomes after total abdominal colectomy with ileosigmoid or ileorectal anastomosis for Crohn’s colitis and risk factors for requirement of a permanent ileostomy remain poorly understood, particularly in the biologic era. OBJECTIVE: This study aimed to determine long-term ostomy-free survival after ileosigmoid or ileorectal anastomosis for Crohn’s colitis and potential risk factors for requirement of an ileostomy. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted at a single-institution IBD tertiary referral center. PATIENTS: Patients diagnosed with Crohn’s disease and undergoing ileosigmoid or ileorectal anastomosis between 2006 and 2018 were selected. MAIN OUTCOME MEASURE: Long-term ostomy-free survival and hazard ratios of potential predictors of ileostomy requirement were the primary outcomes measured. RESULTS: One hundred nine patients (56% female) underwent ileosigmoid or ileorectal anastomosis for Crohn’s disease. The majority of surgical procedures were completed in 2 or 3 stages (53%). The indication for total abdominal colectomy was predominantly medically refractory disease (77%), with dysplasia the second leading indication (13%). At an overall mean follow-up of 3 years, 16 patients had undergone either proctectomy or diversion with the rectum in situ. This resulted in ostomy-free survival estimates at 5 and 10 years of 78% (95% CI, 68-90) and 58% (95% CI, 35–94). A positive distal microscopic margin was the only risk factor for later requirement of a permanent ileostomy (HR, 5.4; 95% CI, 1.7–17.2). LIMITATIONS: This study is limited because it is a retrospective study at a tertiary referral center. CONCLUSIONS: Long-term ostomy-free survival can be achieved in the majority of patients who undergo restoration of intestinal continuity after total abdominal colectomy for Crohn’s colitis. A positive distal microscopic margin was independently associated with long-term anastomotic failure, and it should be accounted for when risk stratifying patients for postoperative prophylactic medical therapy. See Video Abstract at http://links.lww.com/DCR/B111. ¿QUÉ FACTORES ESTÁN ASOCIADOS CON LA EVENTUAL NECESIDAD DE UNA ILEOSTOMÍA DESPUÉS DE UNA COLECTOMÍA ABDOMINAL TOTAL Y UNA ANASTOMOSIS ILEOSIGMOIDEA O ILEORRECTAL PARA LA COLITIS DE CROHN EN LA ERA BIOLÓGICA? ANTECEDENTES: Los resultados después de la colectomía abdominal total con anastomosis ileosigmoidea o ileorrectal para la colitis de Crohn y los factores de riesgo para el requerimiento de una ileostomía permanente siguen siendo poco conocidos, particularmente en la era biológica. OBJETIVO: Determinar la supervivencia a largo plazo sin ostomía después de una anastomosis ileosigmoidea o ileorrectal para la colitis de Crohn y los factores de riesgo potenciales para la necesidad de una ileostomía. DISEÑO: Estudio de cohorte retrospectivo. AJUSTE: Centro de referencia de tercel nivel para enfermedad inflamatoria intestinal de una sola institución. PACIENTES: Pacientes diagnosticados con enfermedad de Crohn y sometidos a anastomosis ileosigmoidea o ileorrectal entre 2006 y 2018 MEDIDA DE RESULTADO PRINCIPAL: Supervivencia a largo plazo sin ostomías y cocientes de riesgo de predictores potenciales de requerimiento de ileostomía RESULTADOS: 109 pacientes (56% mujeres) se sometieron a anastomosis ileosigmoidea o ileorrectal por enfermedad de Crohn. La mayoría de los procedimientos quirúrgicos se completaron en 2 o 3 etapas (53%). La indicación de colectomía abdominal total fue predominantemente enfermedad médicamente refractaria (77%), con displasia la segunda indicación principal (13%). En un seguimiento medio general de 3 años, 16 pacientes se habían sometido a una proctectomía o a una derivación con el recto in situ. Esto dio como resultado estimaciones de supervivencia sin ostomía a los 5 y 10 años de 78% (intervalo de confianza del 95%: 68–90) y 58% (intervalo de confianza del 95%: 35–94), respectivamente. Un margen microscópico distal positivo fue el único factor de riesgo para el requerimiento posterior de una ileostomía permanente (razón de riesgo: 5.4; intervalo de confianza del 95%, 1.7–17.2). LIMITACIONES: Estudio retrospectivo en un centro de referencia de tercer nivel. CONCLUSIONES: La supervivencia a largo plazo sin ostomía se puede lograr en la mayoría de los pacientes que se someten a la restauración de la continuidad intestinal después de la colectomía abdominal total por colitis de Crohn. Un margen microscópico distal positivo se asoció de forma independiente con la insuficiencia anastomótica a largo plazo, y debe tenerse en cuenta cuando se trata de pacientes con estratificación de riesgo para el tratamiento médico profiláctico postoperatorio. Consulte Video Resumen en http://links.lww.com/DCR/B111.

SummaryNon‐endemic Burkitt lymphoma (BL) is a rare germinal centre B‐cell‐derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic‐based and population‐based lymphoma registries from six countries were used to identify 264 real‐world patients. The median age was 47 years and the majority had advanced‐stage disease and elevated LDH. Treatment protocols were R‐CODOX‐M/IVAC (47%), R‐hyper‐CVAD (16%), DA‐EPOCH‐R (11%), R‐BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two‐year overall survival and event‐free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two‐year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post‐remission event‐free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real‐world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow‐up strategies with increased focus on survivorship and less focus on routine disease surveillance.

AbstractBackgroundAdvanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging.MethodsWe describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine.ResultsSerum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P &lt; 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P &lt; 0.001).ConclusionsThese mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.

Abstract Background: Close associations between insomnia with other clinical factors have been identified in migraine, but there have been few studies investigating associations between insomnia and clinical factors in patients with persistent post-traumatic headache (PPTH). The study objective was to contrast the severity of insomnia symptoms in PPTH, migraine, and healthy controls, and to identify factors associated with insomnia in patients with PPTH vs. migraine. Methods: In this cross-sectional cohort study, 57 individuals with PPTH attributed to mild traumatic brain injury, 39 with migraine, and 39 healthy controls were included. Participants completed a detailed headache characteristics questionnaire, the Migraine Disability Assessment Scale (MIDAS), Insomnia Severity Index (ISI), Hyperacusis Questionnaire (HQ), Allodynia Symptom Checklist, Photosensitivity Assessment Questionnaire, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory, Post-Traumatic Stress Disorder (PTSD) checklist, Ray Auditory Verbal Learning Test, and the Trail Making Test A and B to assess headache characteristics, disability, insomnia symptoms, sensory hypersensitivities, and neuropsychological factors. Fisher’s test and one-way ANOVA were used to assess group differences of categorical and continuous data. Stepwise logistic regression analyses were conducted to identify clinical variables associated with insomnia symptoms. Results: Those with PPTH had significantly higher ISI scores (16.72 ± 6.58) compared to migraine patients (11.28 ± 6.42) and healthy controls (4.05 ± 4.80) (p < 0.001). For those with PPTH, insomnia severity was most strongly correlated with the BDI (Spearman's rho (ρ) = 0.634, p < 0.01), followed by Trait Anxiety (ρ = 0.522, p < 0.01), PTSD (ρ = 0.505, p < 0.01), HQ (ρ = 0.469, p < 0.01), State Anxiety (ρ = 0.437, p < 0.01), and MIDAS scores (ρ = 0.364, p < 0.01). According to linear regression models, BDI, headache intensity, and hyperacusis scores were significantly positively associated with insomnia severity in those with PPTH, while only delayed memory recall was negatively associated with insomnia severity in those with migraine. Conclusions: Insomnia symptoms were more severe in those with PPTH compared to migraine and healthy control cohorts. Depression, headache intensity, and hyperacusis were associated with insomnia in individuals with PPTH. Future studies should determine the bidirectional impact of treating insomnia and its associated symptoms.