Congenital leptin deficiency and leptin gene missense mutation found in two colombian sisters with severe obesity

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

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

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

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Congenital leptin deficiency and leptin gene missense mutation found in two colombian sisters with severe obesity

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Colombian surgical outcomes study insights on perioperative mortality rate, a main indicator of the lancet commission on global surgery – a prospective cohort studyResearch in context

Summary: Background: Surgical care holds significant importance in healthcare, especially in low and middle-income countries, as at least 50% of the 4.2 million deaths within the initial 30 days following surgery take place in these countries. The Lancet Commission on Global Surgery proposed six indicators to enhance surgical care. In Colombia, studies have been made using secondary data. However, strategies to reduce perioperative mortality have not been implemented. This study aims to describe the fourth indicator, perioperative mortality rate (POMR), with primary data in Colombia. Methods: A multicentre prospective cohort study was conducted across 54 centres (hospitals) in Colombia. Each centre selected a 7-day recruitment period between 05/2022 and 01/2023. Inclusion criteria involved patients over 18 years of age undergoing surgical procedures in operating rooms. Data quality was ensured through a verification guideline and statistical analysis using mixed-effects multilevel modelling with a case mix analysis of mortality by procedure-related, patient-related, and hospital-related conditions. Findings: 3807 patients were included with a median age of 48 (IQR 32–64), 80.3% were classified as ASA I or II, and 27% of the procedures had a low-surgical complexity. Leading procedures were Orthopedics (19.2%) and Gynaecology/Obstetrics (17.7%). According to the Clavien–Dindo scale, postoperative complications were distributed in major complications (11.7%, 10.68–12.76) and any complication (31.6%, 30.09–33.07). POMR stood at 1.9% (1.48–2.37), with elective and emergency surgery mortalities at 0.7% (0.40–1.23) and 3% (2.3–3.89) respectively. Interpretation: The POMR was higher than the ratio reported in previous national studies, even when patients had a low–risk profile and low-complexity procedures. The present research represents significant public health progress with valuable insights for national decision-makers to improve the quality of surgical care. Funding: This work was supported by Universidad del Rosario and Fundación Cardioinfantil-Instituto de Cardiología grant number CTO-057-2021, project-ID IV-FGV017

A Survey of Empirical Results on Program Slicing

International audienceBACKGROUND:Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS:This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS:Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION:Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding

The role of centre and country factors on process and outcome indicators in critically ill patients with hospital-acquired bloodstream infections

Purpose: The primary objective of this study was to evaluate the associations between centre/country-based factors and two important process and outcome indicators in patients with hospital-acquired bloodstream infections (HABSI). Methods: We used data on HABSI from the prospective EUROBACT-2 study to evaluate the associations between centre/country factors on a process or an outcome indicator: adequacy of antimicrobial therapy within the first 24&nbsp;h or 28-day mortality, respectively. Mixed logistical models with clustering by centre identified factors associated with both indicators. Results: Two thousand two hundred nine patients from two hundred one intensive care units (ICUs) were included in forty-seven countries. Overall, 51% (n = 1128) of patients received an adequate antimicrobial therapy and the 28-day mortality was 38% (n = 839). The availability of therapeutic drug monitoring (TDM) for aminoglycosides everyday [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.03-2.14] or within a few hours (OR 1.79, 95% CI 1.34-2.38), surveillance cultures for multidrug-resistant organism carriage performed weekly (OR 1.45, 95% CI 1.09-1.93), and increasing Human Development Index (HDI) values were associated with adequate antimicrobial therapy. The presence of intermediate care beds (OR 0.63, 95% CI 0.47-0.84), TDM for aminoglycoside available everyday (OR 0.66, 95% CI 0.44-1.00) or within a few hours (OR 0.51, 95% CI 0.37-0.70), 24/7 consultation of clinical pharmacists (OR 0.67, 95% CI 0.47-0.95), percentage of vancomycin-resistant enterococci (VRE) between 10% and 25% in the ICU (OR 1.67, 95% CI 1.00-2.80), and decreasing HDI values were associated with 28-day mortality. Conclusion: Centre/country factors should be targeted for future interventions to improve management strategies and outcome of HABSI in ICU patients

Presentation, management, and outcomes of older compared to younger adults with hospital-acquired bloodstream infections in the intensive care unit: a multicenter cohort study

Purpose: Older adults admitted to the intensive care unit (ICU) usually have fair baseline functional capacity, yet their age and frailty may compromise their management. We compared the characteristics and management of older (≥ 75&nbsp;years) versus younger adults hospitalized in ICU with hospital-acquired bloodstream infection (HA-BSI). Methods: Nested cohort study within the EUROBACT-2 database, a multinational prospective cohort study including adults (≥ 18&nbsp;years) hospitalized in the ICU during 2019-2021. We compared older versus younger adults in terms of infection characteristics (clinical signs and symptoms, source, and microbiological data), management (imaging, source control, antimicrobial therapy), and outcomes (28-day mortality and hospital discharge). Results: Among 2111 individuals hospitalized in 219 ICUs with HA-BSI, 563 (27%) were ≥ 75&nbsp;years old. Compared to younger patients, these individuals had higher comorbidity score and lower functional capacity; presented more often with a pulmonary, urinary, or unknown HA-BSI source; and had lower heart rate, blood pressure and temperature at presentation. Pathogens and resistance rates were similar in both groups. Differences in management included mainly lower rates of effective source control achievement among aged individuals. Older adults also had significantly higher day-28 mortality (50% versus 34%, p &lt; 0.001), and lower rates of discharge from hospital (12% versus 20%, p &lt; 0.001) by this time. Conclusions: Older adults with HA-BSI hospitalized in ICU have different baseline characteristics and source of infection compared to younger patients. Management of older adults differs mainly by lower probability to achieve source control. This should be targeted to improve outcomes among older ICU patients

Epidemiology and outcomes of hospital-acquired bloodstream infections in intensive care unit patients: the EUROBACT-2 international cohort study

Purpose In the critically ill, hospital-acquired bloodstream infections (HA-BSI) are associated with significant mortality. Granular data are required for optimizing management, and developing guidelines and clinical trials. Methods We carried out a prospective international cohort study of adult patients (≥ 18 years of age) with HA-BSI treated in intensive care units (ICUs) between June 2019 and February 2021. Results 2600 patients from 333 ICUs in 52 countries were included. 78% HA-BSI were ICU-acquired. Median Sequential Organ Failure Assessment (SOFA) score was 8 [IQR 5; 11] at HA-BSI diagnosis. Most frequent sources of infection included pneumonia (26.7%) and intravascular catheters (26.4%). Most frequent pathogens were Gram-negative bacteria (59.0%), predominantly Klebsiella spp. (27.9%), Acinetobacter spp. (20.3%), Escherichia coli (15.8%), and Pseudomonas spp. (14.3%). Carbapenem resistance was present in 37.8%, 84.6%, 7.4%, and 33.2%, respectively. Difficult-to-treat resistance (DTR) was present in 23.5% and pan-drug resistance in 1.5%. Antimicrobial therapy was deemed adequate within 24 h for 51.5%. Antimicrobial resistance was associated with longer delays to adequate antimicrobial therapy. Source control was needed in 52.5% but not achieved in 18.2%. Mortality was 37.1%, and only 16.1% had been discharged alive from hospital by day-28. Conclusions HA-BSI was frequently caused by Gram-negative, carbapenem-resistant and DTR pathogens. Antimicrobial resistance led to delays in adequate antimicrobial therapy. Mortality was high, and at day-28 only a minority of the patients were discharged alive from the hospital. Prevention of antimicrobial resistance and focusing on adequate antimicrobial therapy and source control are important to optimize patient management and outcomes