Social Frailty Index: Development and validation of an index of social attributes predictive of mortality in older adults.

While social characteristics are well-known predictors of mortality, prediction models rely almost exclusively on demographics, medical comorbidities, and function. Lacking an efficient way to summarize the prognostic impact of social factor, many studies exclude social factors altogether. Our objective was to develop and validate a summary measure of social risk and determine its ability to risk-stratify beyond traditional risk models. We examined participants in the Health and Retirement Study, a longitudinal, survey of US older adults. We developed the model from a comprehensive inventory of 183 social characteristics using least absolute shrinkage and selection operator, a penalized regression approach. Then, we assessed the predictive capacity of the model and its ability to improve on traditional prediction models. We studied 8,250 adults aged ≥65 y. Within 4 y of the baseline interview, 22% had died. Drawn from 183 possible predictors, the Social Frailty Index included age, gender, and eight social predictors: neighborhood cleanliness, perceived control over financial situation, meeting with children less than yearly, not working for pay, active with children, volunteering, feeling isolated, and being treated with less courtesy or respect. In the validation cohort, predicted and observed mortality were strongly correlated. Additionally, the Social Frailty Index meaningfully risk-stratified participants beyond the Charlson score (medical comorbidity index) and the Lee Index (comorbidity and function model). The Social Frailty Index includes age, gender, and eight social characteristics and accurately risk-stratifies older adults. The model improves upon commonly used risk prediction tools and has application in clinical, population health, and research settings.

Recent Advances in Liver Transplantation for Hepatocellular Carcinoma.

OPINION STATEMENT: Liver transplantation for hepatocellular carcinoma (HCC) remains an evolving field. Major challenges HCC transplant patients face today include liver organ donor shortages and the need for both better pre-transplant bridging/downstaging therapies and post-transplant HCC recurrence treatment options. The advent of immunotherapy and the demonstrated efficacy of immune checkpoint inhibitors in multiple solid tumors including advanced/unresectable HCC hold promise in expanding both the neoadjuvant and adjuvant HCC transplant treatment regimen, though caution is needed with these immune modulating agents leading up to and following transplant. New options for pre-transplant HCC management will expand access to this curative option as well as ensure patients have adequate control of their HCC prior to transplant to maximize the utility of a liver donor. Machine perfusion has been an active area of investigation in recent years and could expand the organ donor pool, helping address current liver donor shortages. Finally, additional HCC biomarkers such as AFP-L3 and DCP have shown promise in improving risk stratification of HCC patients. Together, these three recent advancements will likely alter HCC transplant guidelines in the coming years.

Collaborative Innovations in Childhood Cancer Therapies.

The outcome for children with cancer has improved significantly over the past 60 years, with more than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States and Europe, with significant short- and long-term toxicity of treatment continuing to impact most children. While the past 15 years have witnessed dramatic scientific innovation for certain cancers in adult patients, pediatric cancer treatment innovation lags increasingly behind. To help bridge the adult-pediatric therapeutic development gap, collaborative efforts are essential among stakeholders within and outside the pediatric oncology community. Prioritizing collaboration in areas such as cancer characterization, target identification and validation, drug discovery, and approaches to currently "undruggable" targets is imperative to improving the outcomes for children with cancer.

Pragmatic Clinical Trial of Population Health, Portal-Based Depression Screening: the PORTAL-Depression Study.

BACKGROUND: A population health approach to depression screening using patient portals may be a promising strategy to proactively engage and identify patients with depression. OBJECTIVE: To determine whether a population health approach to depression screening is more effective than screening during clinic appointments alone for identifying patients with depression. DESIGN: A pragmatic clinical trial at an adult outpatient internal medicine clinic at an urban, academic, tertiary care center. PATIENTS: Eligible patients (n = 2713) were adults due for depression screening with active portal accounts. Patients with documented depression or bipolar disorder and those who had been screened in the year prior to the study were excluded. INTERVENTION: Patients were randomly assigned to usual (n = 1372) or population healthcare (n = 1341). For usual care, patients were screened by medical assistants during clinic appointments. Population healthcare patients were sent letters through the portal inviting them to fill out an online screener regardless of whether they had a scheduled appointment. The same screening tool, the Computerized Adaptive Test for Mental Health (CAT-MH™), was used for clinic- and portal-based screening. MAIN MEASURES: The primary outcome was the depression screening rate. KEY RESULTS: The depression screening rate in the population healthcare arm was higher than that in the usual care arm (43% (n = 578) vs. 33% (n = 459), p < 0.0001). The rate of positive screens was also higher in the population healthcare arm compared to that in the usual care (10% (n = 58) vs. 4% (n = 17), p < 0.001). CONCLUSION: Findings suggest depression screening via a portal as part of a population health approach can increase screening and case identification, compared to usual care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03832283.

In-the-Wild Affect Analysis of Children with ASD Using Heart Rate.

Recognizing the affective state of children with autism spectrum disorder (ASD) in real-world settings poses challenges due to the varying head poses, illumination levels, occlusion and a lack of datasets annotated with emotions in in-the-wild scenarios. Understanding the emotional state of children with ASD is crucial for providing personalized interventions and support. Existing methods often rely on controlled lab environments, limiting their applicability to real-world scenarios. Hence, a framework that enables the recognition of affective states in children with ASD in uncontrolled settings is needed. This paper presents a framework for recognizing the affective state of children with ASD in an in-the-wild setting using heart rate (HR) information. More specifically, an algorithm is developed that can classify a participant's emotion as positive, negative, or neutral by analyzing the heart rate signal acquired from a smartwatch. The heart rate data are obtained in real time using a smartwatch application while the child learns to code a robot and interacts with an avatar. The avatar assists the child in developing communication skills and programming the robot. In this paper, we also present a semi-automated annotation technique based on facial expression recognition for the heart rate data. The HR signal is analyzed to extract features that capture the emotional state of the child. Additionally, in this paper, the performance of a raw HR-signal-based emotion classification algorithm is compared with a classification approach based on features extracted from HR signals using discrete wavelet transform (DWT). The experimental results demonstrate that the proposed method achieves comparable performance to state-of-the-art HR-based emotion recognition techniques, despite being conducted in an uncontrolled setting rather than a controlled lab environment. The framework presented in this paper contributes to the real-world affect analysis of children with ASD using HR information. By enabling emotion recognition in uncontrolled settings, this approach has the potential to improve the monitoring and understanding of the emotional well-being of children with ASD in their daily lives.

Five Years of Sacubitril/Valsartan-a Safety Analysis of Randomized Clinical Trials and Real-World Pharmacovigilance.

PURPOSE: In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use. METHODS: We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0. RESULTS: Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice. CONCLUSION: With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.

Use of Vasopressin as Rescue Therapy in Refractory Hypoxia and Refractory Systemic Hypotension in Term Neonates with Severe Persistent Pulmonary Hypertension-A Prospective Observational Study.

OBJECTIVE: Persistent pulmonary hypertension of the newborn (PPHN) is a serious cardiorespiratory problem. PPHN is frequently associated with refractory hypoxia and hypotension, and optimal management has the potential to improve important clinical outcomes including mortality. The primary objective is to evaluate the efficacy and safety of rescue vasopressin (VP) therapy in the management of severe (refractory) hypoxia and refractory systemic hypotension in term neonates with severe PPHN. STUDY DESIGN: Neonates with refractory hypoxia and refractory hypotension due to severe PPHN needing VP were prospectively enrolled in the study. Refractory hypoxia was defined as oxygenation index (OI) ≥ 25 for at least 4 hours after the commencement of high-frequency oscillatory ventilation and nitric oxide at 20 ppm. Refractory hypotension was defined as mean blood pressure lesser than mean gestational age lasting for more than 15 minutes in spite of dopamine infusion at 10 µg/kg/min, adrenaline infusion at 0.3 µg/kg/min, and noradrenaline infusion at 0.1 µg/kg/min. RESULTS: Thirty-two neonates with PPHN were recruited. The baseline OI (mean ± standard deviation [SD]) before starting VP was 33.43 ± 16.54 which started decreasing significantly between 1 and 6 hours after the commencement of VP (p < 0.05). The mean blood pressure also increased concomitantly with a significant effect seen by 1 hour (p < 0.05). The vasoactive infusion score before the commencement of VP was mean 46.07 (SD = 25.72) and started decreasing after 12 to 24 hours of commencement of VP (p < 0.05). Lactate levels (mean ± SD) before starting VP were 7.8 ± 8.6 mmol/L and started decreasing between 6 and 12 hours (p < 0.05). Two neonates died due to refractory hypoxia and refractory hypotension (overall mortality 6.2%) CONCLUSION: Rescue VP therapy is a useful adjunct in the management of neonates with severe PPHN with refractory hypoxia and/or refractory hypotension. Improvement in oxygenation and hemodynamics with the use of VP results in reduced mortality. KEY POINTS: · Rescue vasopressin is a useful adjunct in the management of neonates with severe PPHN.. · Vasopressin helps reduce OI.. · Vasopressin reduces the vasoactive inotrope score..

Author's Response to an Unusual Presentation of Spontaneous Chylothorax.

How to cite this article: Kaul A, Fursule A, Shah S. Author's Response to an Unusual Presentation of Spontaneous Chylothorax. Indian J Crit Care Med 2022;26(11):1226.

An Unusual Presentation of Spontaneous Chylothorax.

True bilateral spontaneous chylothorax without any etiology has been reported rarely in the pediatric literature. A 3-year-old male child was detected to have incidental moderate chylothorax on USG thorax done for scrotal swelling. Investigations for infectious, malignant, cardiac, and congenital etiology were unremarkable. Effusion was drained by securing bilateral intercostal drains (ICD) and confirmed to be chyle on biochemical evaluation. The child was discharged with ICD in situ, but there was non-resolution of bilateral pleural effusion. Because of the failure of conservative treatment, video-assisted thoracoscopy (VATS) with pleurodesis was done. Thereafter, the child improved symptomatically and was discharged. On follow-up, there is no recurrence of pleural effusion, and the child has been growing well, albeit the etiology remains elusive. Chylothorax should not be missed in children presenting with scrotal swelling. In children with spontaneous chylothorax, VATS should be done after a fair trial of conservative medical management (thoracic drainage) along with continued nutritional management. How to cite this article: Kaul A, Fursule A, Shah S. An Unusual Presentation of Spontaneous Chylothorax. Indian J Crit Care Med 2022;26(7):871-873.

Clinical experience of use of percutaneous peripheral arterial cannulation in sick neonates in a developing country.

BACKGROUND: Continuous invasive arterial monitoring is necessary in sick neonates needing hemodynamic and ventilatory support. The primary objective of our study was to describe clinical experience with percutaneous peripheral arterial cannulation (PAC) in sick neonates. METHODS: Neonates needing PAC were prospectively enrolled in the study. Inclusion criteria were: neonates needing respiratory support (invasive or non-invasive), neonates requiring vasoactive medications or neonate likely to need more than 5 sampling pricks in 24 h. RESULTS: One hundred eight neonates (93.1%) needed cannulation of one arterial site while 8 (6.9%) needed cannulation of 2 arterial sites, thus giving a total of 124 cannulations. Out of the 124 cannulations, 102 (82%) were performed in first attempt, while 22 (18%) cannulations needed 2 or more attempts. Serious complications like discolouration of digits, blanching of skin or bleeding were seen in 6 (4.9%) cannulations. These resolved after removal of arterial line and no long term consequences were noted. On comparing neonates having radial arterial cannulation(n = 108) with posterior tibial arterial cannulation (n = 16) there was no difference in duration of arterial line between radial artery group (mean, SD 53.30 ± 22.56) and posterior tibial artery group (mean, SD 48.25 ± 27.39). However, more attempts were needed to cannulate post tibial artery (mean, SD 2.25 ± 1.32) as compared to radial artery (mean 1.22 ± 0.789) and this difference was statistically significant (MD -1.02, 95% CI - 1.75 to - 0.30). There was no difference in incidence of serious complications between the radial artery group (3.7%, n = 4) as compared to posterior tibial group (5.5%, n = 1, OR 0.57, 95% CI 0.06-5.51, p = 0.63). CONCLUSIONS: Peripheral arterial cannulation is a safe method for hemodynamic monitoring and blood sampling in sick neonates. Complications can be minimized by diligent monitoring and proactive removal of line if there is damping of tracing.

Impact of a medical scribe on clinical efficiency and quality in an academic general internal medicine practice.

BACKGROUND: Scribes have been proposed as an intervention to decrease physician electronic health record (EHR) workload and improve clinical quality. We aimed to assess the impact of a scribe on clinical efficiency and quality in an academic internal medicine practice. METHODS: Six faculty physicians worked with one scribe at an urban academic general internal medicine clinic April through June 2017. Patient visits during the 3 months prior to intervention (baseline, n = 789), unscribed visits during the intervention (concurrent control, n = 605), and scribed visits (n = 579) were included in the study. Clinical efficiency outcomes included time to close encounter, patient time in clinic, and number of visits per clinic session. Quality outcomes included EHR note quality, rates of medication and immunization review, population of patient instructions, reconciliation of outside information, and completion of preventative health recommendations. RESULTS: Median time to close encounter (IQR) was lower for scribed visits [0.4 (4.8) days] compared to baseline and unscribed visits [1.2 (5.9) and 2.9 (5.4) days, both p < 0.001]. Scribed notes were more likely to have a clear history of present illness (HPI) [OR = 7.30 (2.35-22.7), p = 0.001] and sufficient HPI information [OR = 2.21 (1.13-4.35), p = 0.02] compared to unscribed notes. Physicians were more likely to review the medication list during scribed vs. baseline visits [OR = 1.70 (1.22-2.35), p = 0.002]. No differences were found in the number of visits per clinic session, patient time in clinic, completion of preventative health recommendations, or other outcomes. CONCLUSIONS: Working with a scribe in an academic internal medicine practice was associated with more timely documentation.

A prospective observational real world feasibility study assessing the role of app-based remote patient monitoring in reducing primary care clinician workload during the COVID pandemic.

BACKGROUND: The novel coronavirus disease in 2019 (COVID-19) has placed unprecedented strain on healthcare providers, in particular, primary care services. General practitioners (GP) have to effectively manage patients remotely preserving social distancing. We aim to assess an app-based remote patient monitoring solution in reducing the workload of a clinician and reflect this as time-saved in an economic context. Primary care COVID patients in West London deemed medium risk were recruited into the virtual ward. Patients were monitored for 14 days by telephone or by both the Huma app and telephone. Information on number of phone calls, duration of phone calls and duration of time spent reviewing the app data was recorded. RESULTS: The amount of time spent reviewing one patient in the telephone only arm of the study was 490 min, compared with 280 min spent reviewing one patient who was monitored via both the Huma app and telephone. Based on employed clinicians monitoring patients, this equates to a 0.04 reduction of full-time equivalent staffing I.e. for every 100 patients, it would require 4 less personnel to remotely monitor them. There was no difference in mortality or adverse events between the two groups. CONCLUSION: App-based remote patient monitoring potentially holds large economic benefit to COVID-19 patients. In wake of further waves or future pandemics, and even in routine care, app-based remote monitoring patients could free up vital resources in terms of clinical team's time, allowing a better reallocation of services.

Comparison of Invasive Arterial Blood Pressure Monitoring vs. Non-Invasive Blood Pressure Monitoring in Preterm Infants < 37 Weeks in the Neonatal Intensive Care Unit- A Prospective Observational Study.

BACKGROUND: Accurate measurement of blood pressure (BP) is extremely important in the management of sick preterm newborns. The primary objective of this study was to compare non-invasive blood pressure measurement (NIBP) with invasive blood pressure measurement (IBP) using peripheral arterial cannulation (PAC) in preterm neonates < 37 weeks in the neonatal intensive care unit. METHODS: Preterm neonates needing PAC were prospectively enrolled in the study. NIBP measurements were taken in the same limb as that of peripheral arterial line. Initially IBP was recorded followed by NIBP within 1 min using the same monitor. These were called as paired measurements since they are taken within 1 min of each other. RESULTS: Seventy-three preterm infants with 1703 paired measurements were included in the final analysis (median gestational age 32 weeks, IQR 30-34 weeks, median birth weight 1540 g, IQR 1160-2100 g). In preterm infants not receiving vasoactive agents (n = 51, 1428 paired measurements, Bland-Altman analysis for agreement between invasive mean blood pressure (MBP) and non-invasive mean BP revealed a bias of -2.9123 mmHg (SD 7.8074). The 95% limits of agreement were from -18.2157 to 12.3893 mmHg. In preterm infants with hypotension, we detected a bias of -3.9176 mmHg (SD 5.1135) between invasive MBP and non-invasive MBP. The 95% limits of agreement were from -13.9401 to 6.1048 mmHg. In normotensive preterm infants receiving vasoactive agents, we detected a bias of -0.7629 mmHg (SD 8.0539) between invasive MBP and non-invasive MBP. The 95% limits of agreement were from -16.5485 to 15.02274 mmHg. CONCLUSIONS: There is poor level of agreement between IBP and NIBP measurements in sick preterm neonates, leading to overestimation or underestimation of blood pressure. The bias was less for mean BP measurements as compared with systolic BP measurements and also for normotensive neonates as compared with hypotensive neonates. Hence, NIBP may be used as a screening method in haemodynamically stable preterm infants, but infants who are haemodynamically unstable and need to be commenced on vasoactive agents should have IBP monitoring.

Outcomes of COVID-19 in Patients With a History of Cancer and Comorbid Cardiovascular Disease.

BACKGROUND: Cancer and cardiovascular disease (CVD) are independently associated with adverse outcomes in patients with COVID-19. However, outcomes in patients with COVID-19 with both cancer and comorbid CVD are unknown. METHODS: This retrospective study included 2,476 patients who tested positive for SARS-CoV-2 at 4 Massachusetts hospitals between March 11 and May 21, 2020. Patients were stratified by a history of either cancer (n=195) or CVD (n=414) and subsequently by the presence of both cancer and CVD (n=82). We compared outcomes between patients with and without cancer and patients with both cancer and CVD compared with patients with either condition alone. The primary endpoint was COVID-19-associated severe disease, defined as a composite of the need for mechanical ventilation, shock, or death. Secondary endpoints included death, shock, need for mechanical ventilation, need for supplemental oxygen, arrhythmia, venous thromboembolism, encephalopathy, abnormal troponin level, and length of stay. RESULTS: Multivariable analysis identified cancer as an independent predictor of COVID-19-associated severe disease among all infected patients. Patients with cancer were more likely to develop COVID-19-associated severe disease than were those without cancer (hazard ratio [HR], 2.02; 95% CI, 1.53-2.68; P<.001). Furthermore, patients with both cancer and CVD had a higher likelihood of COVID-19-associated severe disease compared with those with either cancer (HR, 1.86; 95% CI, 1.11-3.10; P=.02) or CVD (HR, 1.79; 95% CI, 1.21-2.66; P=.004) alone. Patients died more frequently if they had both cancer and CVD compared with either cancer (35% vs 17%; P=.004) or CVD (35% vs 21%; P=.009) alone. Arrhythmias and encephalopathy were also more frequent in patients with both cancer and CVD compared with those with cancer alone. CONCLUSIONS: Patients with a history of both cancer and CVD are at significantly higher risk of experiencing COVID-19-associated adverse outcomes. Aggressive public health measures are needed to mitigate the risks of COVID-19 infection in this vulnerable patient population.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: Primary objectives To determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease. AUTHORS' CONCLUSIONS: This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended. A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.

BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-weight, or preterm and low-birth-weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 30 November 2017), Embase (1980 to 30 November 2017), and CINAHL (1982 to 30 November 2017). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 39 studies enrolling 2843 infants. Ibuprofen (IV) versus placebo: IV Ibuprofen (3 doses) reduced the failure to close a PDA compared with placebo (typical relative risk (RR); 0.62 (95% CI 0.44 to 0.86); typical risk difference (RD); -0.18 (95% CI -0.30 to -0.06); NNTB 6 (95% CI 3 to 17); I2 = 65% for RR and I2 = 0% for RD; 2 studies, 206 infants; moderate-quality the evidence). One study reported decreased failure to close a PDA after single or three doses of oral ibuprofen compared with placebo (64 infants; RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4; I2 test not applicable). Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure (typical RR 1.07, 95% CI 0.92 to 1.24; typical RD 0.02, 95% CI -0.02 to 0.06; I2 = 0% for both RR and RD; moderate-quality evidence). A reduction in NEC (necrotising enterocolitis) was noted in the ibuprofen (IV or oral) group (18 studies, 1292 infants; typical RR 0.68, 95% CI 0.49 to 0.94; typical RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; I2 = 0% for both RR and RD; moderate-quality evidence). There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies, 576 infants; typical RR 0.28, 95% CI 0.14 to 0.54; typical RD -0.09, 95% CI -0.14 to -0.05; NNTB 11, 95% CI 7 to 20; I2 = 24% for RR and I2 = 69% for RD; moderate-quality evidence). The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants; MD -8.12 µmol/L, 95% CI -10.81 to -5.43). For this comparison, there was high between-study heterogeneity (I2 = 83%) and low-quality evidence. Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09; I2 = 0% for both RR and RD). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was low-quality evidence for these two outcomes. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants; typical RR 0.38, 95% CI 0.26 to 0.56; typical RD -0.22, 95% CI -0.31 to -0.14; NNTB 5, 95% CI 3 to 7; moderate-quality evidence). There was a decreased risk of failure to close a PDA with high-dose versus standard-dose of IV ibuprofen (3 studies 190 infants; typical RR 0.37, 95% CI 0.22 to 0.61; typical RD - 0.26, 95% CI -0.38 to -0.15; NNTB 4, 95% CI 3 to 7); I2 = 4% for RR and 0% for RD); moderate-quality evidence). Early versus expectant administration of IV ibuprofen, echocardiographically-guided IV ibuprofen treatment versus standard IV ibuprofen treatment, continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, and rectal ibuprofen versus oral ibuprofen were studied in too few trials to allow for precise estimates of any clinical outcomes. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Therefore, of these two drugs, ibuprofen appears to be the drug of choice. The effectiveness of ibuprofen versus paracetamol is assessed in a separate review. Oro-gastric administration of ibuprofen appears as effective as IV administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically-guided versus standard IV ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.

Comparative effectiveness of long-term acute care hospital versus skilled nursing facility transfer.

BACKGROUND: Long-term acute care hospital (LTACH) use varies considerably across the U.S., which may reflect uncertainty about the effectiveness of LTACHs vs. skilled nursing facilities (SNF), the principal post-acute care alternative. Given that LTACHs provide more intensive care and thus receive over triple the reimbursement of SNFs for comparable diagnoses, we sought to compare outcomes and spending between LTACH versus SNF transfer. METHODS: Using Medicare claims linked to electronic health record (EHR) data from six Texas Hospitals between 2009 and 2010, we conducted a retrospective cohort study of patients hospitalized on a medicine service in a high-LTACH use region and discharged to either an LTACH or SNF and followed for one year. The primary outcomes included mortality, 60-day recovery without inpatient care, days at home, and healthcare spending RESULTS: Of 3503 patients, 18% were transferred to an LTACH. Patients transferred to LTACHs were younger (median 71 vs. 82 years), less likely to be female (50.5 vs 66.6%) and white (69.0 vs. 84.1%), but were sicker (24.3 vs. 14.2% for prolonged intensive care unit stay; median diagnosis resource intensity weight of 2.03 vs. 1.38). In unadjusted analyses, patients transferred to an LTACH vs. SNF were less likely to survive (59.1 vs. 65.0%) or recover (62.5 vs 66.0%), and spent fewer days at home (186 vs. 200). Adjusting for demographic and clinical confounders available in Medicare claims and EHR data, LTACH transfer was not significantly associated with differences in mortality (HR, 1.12, 95% CI, 0.94-1.33), recovery (SHR, 1.07, 0.93-1.23), and days spent at home (IRR, 0.96, 0.83-1.10), but was associated with greater Medicare spending ($16,689 for one year, 95% CI, $12,216-$21,162). CONCLUSION: LTACH transfer for Medicare beneficiaries is associated with similar clinical outcomes but with higher healthcare spending compared to SNF transfer. LTACH use should be reserved for patients who require complex inpatient care and cannot be cared for in SNFs.

Dipeptidyl Peptidase-4 Inhibitors and Inflammatory Bowel Disease Risk: A Meta-analysis.

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4) inhibitors are a popular second-line treatment for type 2 diabetes mellitus. Several studies have reported on the association between DPP-4 inhibitors and the risk of developing inflammatory bowel disease (IBD), with conflicting results. OBJECTIVE: This meta-analysis aims to elucidate the risk for IBD with DPP-4 inhibitor therapy. METHODS: A comprehensive search of PubMed/MEDLINE, CINAHL, the Cochrane Database, ClinicalTrials.gov, and the European Clinical Trials Database was performed (December 2018). All controlled clinical trials and observational studies of DPP-4 inhibitors that reported events of IBD, Crohn's disease (CD), ulcerative colitis (UC) or colitis and had a duration ≥52 weeks were included. The DerSimonian and Laird random-effects model was utilized to assess the relative risk (RR) for IBD post DPP-4 inhibitor exposure. RESULTS: A total of 16 individual studies evaluating a total of 198 404 patients were included for analysis. Studies ranged from 52 weeks through 5 years. In the primary random-effects analysis, DPP-4 inhibitor exposure resulted in a nonsignificant increase in the risk of IBD (RR = 1.52; 95% CI = 0.72 to 3.24; I2 = 54.2%). Sensitivity analysis using a fixed-effects model demonstrated significantly increased risk (RR = 3.01; 95% CI = 2.30-3.93). DPP-4 inhibitor use significantly increased the risk of CD (RR = 2.47; 95% CI = 1.36 to 4.48). All findings were driven by the inclusion of 1 large study. Conclusion and Relevance: Based on a conservative random-effects analysis, DPP-4 inhibitors do not appear to increase the risk of developing inflammatory bowel disease. However, long-term postmarketing surveillance is warranted.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: Primary objectivesTo determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease. AUTHORS' CONCLUSIONS: This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended.A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.

Effect of Variation in Published Stroke Rates on the Net Clinical Benefit of Anticoagulation for Atrial Fibrillation.

Background: Stroke rates in patients with nonvalvular atrial fibrillation (AF) who are not receiving anticoagulant therapy vary widely across published studies; the resulting effect on the net clinical benefit of anticoagulation in AF is unknown. Objective: To determine the effect of variation in published AF stroke rates on the net clinical benefit of anticoagulation. Design: Markov model decision analysis. Warfarin was the base case, and non-vitamin K antagonist oral anticoagulants (NOACs) were modeled in a secondary analysis. Setting: Community-dwelling adults. Patients: 33 434 adults with incident AF. Measurements: Quality-adjusted life-years (QALYs). Results: Of the 33 434 patients, 27 179 had a CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease) score of 2 or more. The population benefit of warfarin anticoagulation for these patients was least using stroke rates from the ATRIA (AnTicoagulation and Risk Factors In Atrial Fibrillation) study and greatest using those from the Danish National Patient Registry (6290 QALYs [95% CI, ±2.3%] vs. 24 110 QALYs [CI, ±1.9%]; P < 0.001). The optimal CHA2DS2-VASc score threshold for anticoagulation was 3 or more using stroke rates from ATRIA, 2 or more using those from the Swedish AF cohort study, 1 or more using those from the SPORTIF (Stroke Prevention using ORal Thrombin Inhibitor in atrial Fibrillation) study, and 0 or more using those from the Danish National Patient Registry. Accounting for lower rates of NOAC-associated intracranial hemorrhage decreased optimal CHA2DS2-VASc score thresholds, but these thresholds still varied widely. Limitation: Measured benefit may not generalize to other populations. Conclusion: Variation in published AF stroke rates for patients not receiving anticoagulant therapy results in multifold variation in the net clinical benefit of anticoagulation. Guidelines should better reflect the uncertainty in current thresholds of stroke risk score for recommending anticoagulation. Primary Funding Source: None.