Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Chronic Obstructive Pulmonary Disease and sexual functioning among Women in Egypt

Background: Sexuality has rarely been studied in Chronic Obstructive Pulmonary Disease female patients, nonetheless they do report several in dysfunction in their sexual life consequent to fear of pain, breathlessness or shortness of breathing and exacerbation. Hence, leading unsatisfactory sexual life. Objective: To assess the effect of Chronic Obstructive Pulmonary Disease on sexual functions of female patients at Suez Canal University Hospital as compared to healthy women. Patients and methods: The sample consisted of two groups each of 86 female subjects, with most common aged group from 30 to 40 respectively. The study group suffered Chronic Obstructive Pulmonary Disease and fulfilled the inclusion criteria. The comparison group was healthy women who were free of any pulmonary disease. Two instruments were used for data collection. The first to assess socio-demographic features of the two groups and the second to assess sexual functioning and satisfaction. Results: Socio-demographics revealed the following: Education level ranged from illiterate to university graduate in both groups and more than one third of the sample were working in dusty places. Body mass index of both groups showed over-weight measures in 87.2% of the study group and 79.1% of the other group with no statistical difference. Positive history of gynecological problems in both groups was 73.1% and 72% respectively. Reported sexual dysfunctions by female patients were statistically significantly different at (P < 0.05) as compared with the healthy group. Breathing disturbances interrupting sexual intercourse among the study group included: difficult breathing 91.9%, breathlessness 62%, fatigability 54%, particular sexual positions 97.6% and reduced quality of sexual performance 96.9% while the comparison group’s breathing disturbances interrupting sexual intercourse were 36.1%, 9.3%, 12.8%, 14%, 22.1% respectively. Results of Sexual Function Index revealed a negatively significant statistical difference between the study and comparison groups at P < 0.001 with regard to scores of “desire and arousal, and also showed a negative significant difference at P < 0.05 with regard to “sexual satisfaction”. Correlation of the Spirometry biological test “Forced Expiratory Volume in one second (FEV1) of the study group with regard to “desire, arousal and sexual satisfaction was positively statistically significant at (P < 0.05) i.e., powerful breezing is positively correlated with desire, arousal, and sexual satisfaction. Conclusion: Significant dysfunction in sexual life as attributed to symptoms of breathing difficulties and difficult sexual positions were found in a majority of the studied Egyptian female group with Chronic Obstructive Pulmonary Disease. Comparatively the healthy women group demonstrated significantly less sexual dysfunction

Incidence and Management of Proteasome Inhibitor-Related Cardiotoxicity in Multiple Myeloma Patients at Memorial Sloan Kettering Cancer Center

Abstract Introduction: Given that the rate of cardiovascular (CV) morbidity increases with age and the median age of patients with multiple myeloma (MM) is 65, CV complications can occur during MM treatment. The proteasome inhibitors (PIs), bortezomib and carfilzomib, may play a role in the development of treatment-related cardiotoxicity as suggested by phase 2 clinical studies and a phase 3 trial (Stewart AK et al. N Engl J Med 2015;372:142-52). Reported treatment-related cardiotoxicity includes hypertension, congestive heart failure (CHF), myocardial infarction, and cardiac arrest. The objectives of this study are to define the incidence of cardiotoxicity in MM patients treated with bortezomib and carfilzomib and to evaluate whether the dose and pre-existing cardiac history affects that incidence. Study design and methods:Using the pharmacy database, we identified all MM patients treated at Memorial Sloan Kettering Cancer Center between 1/2010 to 10/2014 who were treated with bortezomib or carfilzomib in the second-line and relapsed refractory setting. Of note, all patients in the carfilzomib arm received prior bortezomib; thus, MM patients in the carfilzomib arm were more heavily pretreated and the two arms should be compared with caution. Data collected included: baseline demographics, baseline disease status, treatment given including dose and number of cycles, baseline cardiovascular comorbidities and medications, and pre- and post-treatment ejection fraction. Cardiotoxicity recorded was defined as grade 3 or more (requiring intervention) and included: hypertension, CHF, coronary artery disease, pulmonary hypertension, myocardial infarction, stroke, and/or arrhythmias. Descriptive statistics were used to analyze baseline demographics, including median and range for continuous variables and frequency and percentage for categorical variables. Fisher's exact test was used to assess the association between clinical and treatment characteristics and cardiotoxicity. Results: 157 patients were eligible for analysis with 47 in the bortezomib arm and 110 in the carfilzomib arm. The overall incidence of cardiotoxicity across both arms was 17% with an incidence of 9% (n = 4) and 20% (n = 22) in the bortezomib and carfilzomib arms, respectively. The most common events reported were arrhythmias (n = 3) with bortezomib and CHF (n = 12) with carfilzomib. The incidence of CHF and cardiomyopathy was 4% and 19% in the bortezomib and the more heavily pretreated carfilzomib arms, respectively. Baseline cardiac comorbidities were not found to increase the risk of cardiotoxicity while on treatment with carfilzomib (p = 0.815); due to small numbers, we were unable to assess this aspect in the bortezomib arm. Based on a categorization of carfilzomib dose (≤20 mg/m2, 27 mg/m2, or ≥36 mg/m2) starting on cycle 2, there was a significant association between the dose level received and cardiotoxicity (p=0.003); patients treated at dose level ≥36 mg/m2 were most likely to have a cardiac-related event while on therapy. Patients receiving the higher doses were treated on a clinical trial (Lendvai et al. Blood 2014;124:899-906), and they were among the most heavily pretreated. Management of cardiac events with carfilzomib was largely supportive with all patients requiring pharmacological intervention, 64% (n= 14) requiring hospital admission, and 73% (n = 16) requiring treatment delays. Conclusion: Grade 3 or more cardiotoxicity is a potential complication of treatment with PIs. However, there is no increased risk of CV deaths noted in our study. The results show a higher risk of cardiac toxicity in heavily pretreated MM patients receiving higher doses (≥36 mg/m2) of carfilzomib. The number of prior lines of therapy is a major factor when defining CV events in relation to a given therapy. Importantly, both carfilzomib and bortezomib are highly efficacious anti-myeloma drugs; CV risks should be assessed for individual patients and in relation to benefits. Disclosures Landgren: BMJ Publishing: Honoraria; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy

Similar Incidence of Typhlitis in Patients Receiving Various Doses of Daunorubicin or Idarubicin as Induction for Acute Myeloid Leukemia

BACKGROUND: The current standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed by abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction chemotherapy with idarubicin 12 mg/m METHODS: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between January 1, 2009 and June 30, 2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum only, defined as non-tumoral bowel wall thickening with or without pericolonic fat infiltration and fluid, according to CTCAE version 4.03 along with clinical symptoms. The primary endpoint was to determine the incidence of typhlitis among IDA, DNA60, and DNA90. Secondary endpoints included characterizing the variability of doses used in induction therapy and identifying any potential risk factors for the development of typhlitis. RESULTS: The overall incidence of typhlitis was 2.5%. When the definition was broadened to include the colitis, enteritis, or enterocolitis, the incidence increased. The inter-reliability ratings of the 2 radiologists\u27 evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. In patients that developed typhlitis, all patients had clinical symptoms in addition to documented cecum inflammation on CT scan. All patients were managed conservatively with intravenous broad-spectrum antibiotics. CONCLUSION: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. The cumulative incidence of typhlitis was similar to the currently published literature, with the incidence being similar irrespective of the anthracycline chosen or dose. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy