Management of neonatal pulmonary hypertension-a survey of neonatal intensive care units in India.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs). METHODS: A questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed. RESULTS: There were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1-3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation. CONCLUSION: We found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

The Approach to Performance of Quality Upper Endoscopy in Lynch Syndrome (QUELS): An International Expert Statement.

Strong evidence demonstrates the protective benefit of frequent colonoscopy surveillance for colorectal cancer prevention in Lynch Syndrome (LS) and is endorsed by many guidelines. Until recently, the evidence supporting the utility of upper endoscopy [esophagogastroduodenoscopy (EGD)] for upper gastrointestinal (UGI) cancer surveillance was limited. Over the last 3 years, multiple studies have demonstrated that EGD surveillance in LS is associated with the detection of both precancerous lesions and early-stage UGI cancers. On the basis of the emerging favorable evidence derived from EGD surveillance programs, the 2022 National Comprehensive Cancer Network (NCCN) Guidelines for LS recommend UGI surveillance with EGD starting between age 30 and 40 years with repeat EGDs every 2 to 4 years, preferably in conjunction with colonoscopy, in all patients with a germline pathogenic variant (PV) in MLH1, MSH2, EPCAM, and MSH6 and, because of the lack of data, consideration in PMS2. Standardization of the approach to performing EGD surveillance in LS and reporting clinically actionable findings is requisite for both improving quality and understanding the cost efficiency and outcomes of patients undergoing EGD as a surveillance tool. Accordingly, the primary objective of this Quality of Upper Endoscopy in Lynch Syndrome (QUELS) statement is to articulate a framework for standardizing the approach to performing and reporting EGD findings in patients with LS by introducing emerging quality metrics. The recommendations presented herein were developed from available evidence and consensus-based expert opinion and provide a practical approach for clinicians applying EGD surveillance in accordance with the most recent and existing LS guidelines.

Review article: Lynch Syndrome-a mechanistic and clinical management update.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers. AIM: To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS. METHODS: A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted. RESULTS: LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene. CONCLUSIONS: As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.

Effect of opaque wraps for pulse oximeter sensors: randomised cross-over trial.

BACKGROUND: Evidence is lacking as to whether ambient light or phototherapy light could interfere with pulse oximeter performance. METHODS: In this randomised cross-over trial, we recruited neonates of gestation >24 weeks. Consented infants were randomly assigned to either pulse oximeter sensor with opaque wrap or without opaque wrap. Nellcor and Masimo sensors were applied simultaneously to different feet for 10 min of recording. Infants were crossed over to the other intervention for a further 10 min, totalling 20 min recording per infant. Primary outcome was faster acquisition of data with shielding of pulse oximeter sensor as compared with not shielding. RESULTS: A total of 96 babies were recruited. There was no difference in primary outcome of time taken to display valid data between the two groups (opaque wrap: 12.73±3.1 s vs no opaque wrap: 13.16±3.3 s, p=0.27). There was no difference in any of the secondary outcomes (percentage of valid data points, percentage of time saturation below target, and so on) between the two groups in both pulse oximeters. Masimo sensor readings displayed a higher mean oxygen saturation (mean difference of 2.85, p=0.001) and lower percentage of time saturation below 94% (mean difference of -27.8, p=0.001) than Nellcor in both groups. There was no difference in any of the outcomes in babies receiving phototherapy (n=21). CONCLUSION: In this study, shielding the pulse oximeter sensor from ambient light or phototherapy light did not yield faster data acquisition or better data quality. TRIAL REGISTRATION NUMBER: ISRCTN10302534.

Sorafenib in Hepatopulmonary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.

Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis.

OBJECTIVE:  To assess the comparative efficacy and safety of candidate agents (low and high dose aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), calcium, vitamin D, folic acid, alone or in combination) for prevention of advanced metachronous neoplasia (that is, occurring at different times after resection of initial neoplasia) in individuals with previous colorectal neoplasia, through a systematic review and network meta-analysis. DATA SOURCES:  Medline, Embase, Web of Science, from inception to 15 October 2015; clinical trial registries. STUDY SELECTION:  Randomized controlled trials in adults with previous colorectal neoplasia, treated with candidate chemoprevention agents, and compared with placebo or another candidate agent. Primary efficacy outcome was risk of advanced metachronous neoplasia; safety outcome was serious adverse events. DATA EXTRACTION:  Two investigators identified studies and abstracted data. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities (ranging from 1, indicating that the treatment has a high likelihood to be best, to 0, indicating the treatment has a high likelihood to be worst). Quality of evidence was appraised with GRADE criteria. RESULTS:  15 randomized controlled trials (12 234 patients) comparing 10 different strategies were included. Compared with placebo, non-aspirin NSAIDs were ranked best for preventing advanced metachronous neoplasia (odds ratio 0.37, 95% credible interval 0.24 to 0.53; SUCRA=0.98; high quality evidence), followed by low-dose aspirin (0.71, 0.41 to 1.23; SUCRA=0.67; low quality evidence). Low dose aspirin, however, was ranked the safest among chemoprevention agents (0.78, 0.43 to 1.38; SUCRA=0.84), whereas non-aspirin NSAIDs (1.23, 0.95 to 1.64; SUCRA=0.26) were ranked low for safety. High dose aspirin was comparable with low dose aspirin in efficacy (1.12, 0.59 to 2.10; SUCRA=0.58) but had an inferior safety profile (SUCRA=0.51). Efficacy of agents for reducing metachronous colorectal cancer could not be estimated. CONCLUSIONS:  Among individuals with previous colorectal neoplasia, non-aspirin NSAIDs are the most effective agents for the prevention of advanced metachronous neoplasia, whereas low dose aspirin has the most favorable risk:benefit profile. REGISTRATION:  PROSPERO (CRD42015029598).

A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice.

BACKGROUND: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of high-dose integrase inhibitors. METHODS: C57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. RESULTS: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir = 0.25 mg/dl, dolutegravir = 0.30 mg/dl versus CTRL = 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. CONCLUSION: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.

Pathway to dry skin prevention and treatment.

BACKGROUND: This article presents an evidence-supported clinical pathway for dry skin prevention and treatment. OBJECTIVE: The development of the pathway involved the following: a literature review was conducted and demonstrated that literature on dry skin is scarce. To compensate for the gap in the available literature, a modified Delphi method was used to collect information on prevention and treatment practice through a panel, which included 10 selected dermatologists who currently provide medical care for dermatology patients in Ontario. An advisor experienced in this therapeutic area guided the process, including a central meeting. Panel members completed a questionnaire regarding their individual practice in caring for these patients and responded to questions on assessment of dry skin etiology, frequency of skin care visits for consultation and follow-up, assessment, and referral to other specialties. The panel members reviewed a summary of all responses and reached a consensus. The result was presented as a clinical pathway. CONCLUSION: The panel concluded that our current awareness of dry skin and therefore prevention and effective treatment is limited; that identifying dry skin and its clinical issues requires tools such as clinical pathways, which may improve patient outcomes; and that additional research on dry skin etiology, prevention, and treatment is necessary.

Increased serum vitamin A and E levels after lung transplantation.

BACKGROUND: Adult cystic fibrosis (CF) patients experience significant increases in serum vitamin A and E levels after lung transplantation. It is unclear whether this finding is specific to the CF population or inherent to the lung transplantation process. METHODS: The objectives of this study were to assess pre- and postlung transplantation serum vitamin A and E levels in subjects with end-stage lung disease secondary to all causes. The study population consisted of adults who received a lung transplant at the Toronto Lung Transplant Program between 2004 and 2009. The mean change in serum vitamin A and E levels pre- and postlung transplant was evaluated using a paired t test, while differences in vitamin A and E levels between CF and non-CF subjects were determined using a Student's t test. RESULTS: Thirty-two CF and 21 non-CF subjects who underwent lung transplantation were included in the study. Mean serum vitamin A and vitamin E levels increased significantly after transplant, from 1.2 to 3.5 µmol/L (P<0.0001) and from 21.9 to 33.2 µmol/L (P<0.0001), respectively. The proportion of individuals with serum levels above the upper limit of normal increased from 7.6% to 88.7% (P<0.0001) and from 11.3% to 24.5% (P=0.02) for vitamin A and vitamin E, respectively. The dosage of vitamin supplementation did not increase after transplant. CONCLUSIONS: Significant increases in serum vitamin A and E levels were seen in both CF and non-CF subjects after lung transplantation. Further research is needed to understand the cause and clinical implications of these findings.