A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors.

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.

Chalk Talks for the Clinical Setting: Evaluation of a Medical Education Workshop for Fellows.

Introduction: Chalk talks are effective teaching tools in the clinical setting. However, data on optimal strategies for teaching medical educators how to develop and deliver them are limited. We designed and implemented two 50-minute workshops to help subspecialty fellows across GME create and deliver a chalk talk. Methods: The first workshop comprised a demonstration of an effective chalk talk and a discussion of best practices for creating chalk talks; the second was a practice session where fellows presented their chalk talks and received feedback from faculty and peers. We evaluated pre- and postworkshop confidence in the ability to create and deliver a chalk talk and develop learning objectives. Secondary outcomes were faculty and peer evaluations of the chalk talks. Results: Eighteen of 33 participants (54% response rate) completed both pre- and postsession surveys. Fellows reported improved confidence in their ability to create a chalk talk (22% vs. 83%, p < .001), deliver a chalk talk (17% vs. 83%, p < .001), and develop well-written learning objectives (11% vs. 83%, p < .001). After the workshop, participants were more likely to correctly identify a chalk talk that made use of an advanced organizer (67% vs. 89%, p < .05). Thirty-eight faculty and peers completed feedback evaluations of participants' chalk talks; most rated fellows' chalk talks highly in domains of content, delivery, design, learning objectives, and engagement. Discussion: The incorporation of these workshop within a course on medical education can effectively develop clinical teaching skills among subspecialty fellows in GME.

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth). DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all-cause mortality; secondary outcome measures were late-onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all-cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late-onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants. AUTHORS' CONCLUSIONS: Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.

Prebiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Dietary supplementation with prebiotic oligosaccharides to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or very low birth weight (VLBW) infants. OBJECTIVES: To assess the benefits and harms of enteral supplementation with prebiotics (versus placebo or no treatment) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care database and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing prebiotics with placebo or no prebiotics in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. The primary outcomes were NEC and all-cause mortality, and the secondary outcomes were late-onset invasive infection, duration of hospitalisation since birth, and neurodevelopmental impairment. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference (MD), with associated 95% confidence intervals (CIs). The primary outcomes of interest were NEC and all-cause mortality; our secondary outcome measures were late-onset (> 48 hours after birth) invasive infection, duration of hospitalisation, and neurodevelopmental impairment. We used the GRADE approach to assess the level of certainty of the evidence. MAIN RESULTS: We included seven trials in which a total of 705 infants participated. All the trials were small (mean sample size 100). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were potential sources of bias in three of the trials. The studied prebiotics were fructo- and galacto-oligosaccharides, inulin, and lactulose, typically administered daily with enteral feeds during birth hospitalisation. Meta-analyses of data from seven trials (686 infants) suggest that prebiotics may result in little or no difference in NEC (RR 0.97, 95% CI 0.60 to 1.56; RD none fewer per 1000, 95% CI 50 fewer to 40 more; low-certainty evidence), all-cause mortality (RR 0.43, 95% CI 0.20 to 0.92; 40 per 1000 fewer, 95% CI 70 fewer to none fewer; low-certainty evidence), or late-onset invasive infection (RR 0.79, 95% CI 0.60 to 1.06; 50 per 1000 fewer, 95% CI 100 fewer to 10 more; low-certainty evidence) prior to hospital discharge. The certainty of this evidence is low because of concerns about the risk of bias in some trials and the imprecision of the effect size estimates. The data available from one trial provided only very low-certainty evidence about the effect of prebiotics on measures of neurodevelopmental impairment (Bayley Scales of Infant Development (BSID) Mental Development Index score < 85: RR 0.84, 95% CI 0.25 to 2.90; very low-certainty evidence; BSID Psychomotor Development Index score < 85: RR 0.24, 95% 0.03 to 2.00; very low-certainty evidence; cerebral palsy: RR 0.35, 95% CI 0.01 to 8.35; very low-certainty evidence). AUTHORS' CONCLUSIONS: The available trial data provide low-certainty evidence about the effects of prebiotics on the risk of NEC, all-cause mortality before discharge, and invasive infection, and very low-certainty evidence about the effect on neurodevelopmental impairment for very preterm or VLBW infants. Our confidence in the effect estimates is limited; the true effects may be substantially different. Large, high-quality trials are needed to provide evidence of sufficient validity to inform policy and practice decisions.

Bubble devices versus other pressure sources for nasal continuous positive airway pressure in preterm infants.

BACKGROUND: Several types of pressure sources, including underwater bubble devices, mechanical ventilators, and the Infant Flow Driver, are used for providing continuous positive airway pressure (CPAP) to preterm infants with respiratory distress. It is unclear whether the use of bubble CPAP versus other pressure sources is associated with lower rates of CPAP treatment failure, or mortality and other morbidity.  OBJECTIVES: To assess the benefits and harms of bubble CPAP versus other pressure sources (mechanical ventilators or Infant Flow Driver) for reducing treatment failure and associated morbidity and mortality in newborn preterm infants with or at risk of respiratory distress. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 1); MEDLINE (1946 to 6 January 2023), Embase (1974 to 6 January 2023), Maternity & Infant Care Database (1971 to 6 January 2023), and the Cumulative Index to Nursing and Allied Health Literature (1982 to 6 January 2023). We searched clinical trials databases and the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials comparing bubble CPAP with other pressure sources (mechanical ventilators or Infant Flow Driver) for the delivery of nasal CPAP to preterm infants. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of the evidence for effects on treatment failure, all-cause mortality, neurodevelopmental impairment, pneumothorax, moderate-severe nasal trauma, and bronchopulmonary dysplasia. MAIN RESULTS: We included 15 trials involving a total of 1437 infants. All trials were small (median number of participants 88). The methods used to generate the randomisation sequence and ensure allocation concealment were unclear in about half of the trial reports. Lack of measures to blind caregivers or investigators was a potential source of bias in all of the included trials. The trials took place during the past 25 years in care facilities internationally, predominantly in India (five trials) and Iran (four trials). The studied pressure sources were commercially available bubble CPAP devices versus a variety of mechanical ventilator (11 trials) or Infant Flow Driver (4 trials) devices.  Meta-analyses suggest that the use of bubble CPAP compared with mechanical ventilator or Infant Flow Driver CPAP may reduce the rate of treatment failure (RR 0.76, 95% confidence interval (CI) 0.60 to 0.95; (I² = 31%); RD -0.05, 95% CI -0.10 to -0.01; number needed to treat for an additional beneficial outcome 20, 95% CI 10 to 100; 13 trials, 1230 infants; low certainty evidence). The type of pressure source may not affect mortality prior to hospital discharge (RR 0.93, 95% CI 0.64 to 1.36 (I² = 0%); RD -0.01, 95% CI -0.04 to 0.02; 10 trials, 1189 infants; low certainty evidence). No data were available on neurodevelopmental impairment. Meta-analysis suggests that the pressure source may not affect the risk of pneumothorax (RR 0.73, 95% CI 0.40 to 1.34 (I² = 0%); RD -0.01, 95% CI -0.03 to 0.01; 14 trials, 1340 infants; low certainty evidence). Bubble CPAP likely increases the risk of moderate-severe nasal injury (RR 2.29, 95% CI 1.37 to 3.82 (I² = 17%); RD 0.07, 95% CI 0.03 to 0.11; number needed to treat for an additional harmful outcome 14, 95% CI 9 to 33; 8 trials, 753 infants; moderate certainty evidence). The pressure source may not affect the risk of bronchopulmonary dysplasia (RR 0.76, 95% CI 0.53 to 1.10 (I² = 0%); RD -0.04, 95% CI -0.09 to 0.01; 7 trials, 603 infants; low certainty evidence).  AUTHORS' CONCLUSIONS: Given the low level of certainty about the effects of bubble CPAP versus other pressure sources on the risk of treatment failure and most associated morbidity and mortality for preterm infants, further large, high-quality trials are needed to provide evidence of sufficient validity and applicability to inform context- and setting-relevant policy and practice.

Mechanisms affecting the gut of preterm infants in enteral feeding trials: a nested cohort within a randomised controlled trial of lactoferrin.

OBJECTIVE: To determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants. DESIGN: Cohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation. SETTING: Thirteen UK hospitals participating in a RCT of lactoferrin. PATIENTS: 479 infants born <32 weeks' gestation between June 2016 and September 2017. RESULTS: 10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition. CONCLUSIONS: This multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design.

Implementing two-stage consent pathway in neonatal trials.

Perinatal trials sometimes require rapid recruitment processes to facilitate inclusion of participants when interventions are time-critical. A two-stage consent pathway has been used in some trials and is supported by national guidance. This pathway includes seeking oral assent for participation during the time-critical period followed by informed written consent later. This approach is being used in the fluids exclusively enteral from day one (FEED1) trial where participants need to be randomised within 3 hours of birth. There is some apprehension about approaching parents for participation via the oral assent pathway. The main reasons for this are consistent with previous research: lack of a written record, lack of standardised information and unfamiliarity with the process. Here, we describe how the pathway has been implemented in the FEED1 trial and the steps the trial team have taken to support sites. We provide recommendations for future trials to consider if they are considering implementing a similar pathway. Trial registration number: ISRCTN89654042.

Masks versus prongs as interfaces for nasal continuous positive airway pressure in preterm infants.

BACKGROUND: Nasal masks and nasal prongs are used as interfaces for providing continuous positive airway pressure (CPAP) for preterm infants with or at risk of respiratory distress, either as primary support after birth or as ongoing support after endotracheal extubation from mechanical ventilation. It is unclear which type of interface is associated with lower rates of CPAP treatment failure, nasal trauma, or mortality and other morbidity. OBJECTIVES: To assess the benefits and harms of nasal masks versus nasal prongs for reducing CPAP treatment failure, nasal trauma, or mortality and other morbidity in newborn preterm infants with or at risk of respiratory distress. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was October 2021. SELECTION CRITERIA: We included randomised controlled trials comparing masks versus prongs as interfaces for delivery of nasal CPAP in newborn preterm infants (less than 37 weeks' gestation) with or at risk of respiratory distress. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. treatment failure, 2. all-cause mortality, and 3. neurodevelopmental impairment. Our secondary outcomes were 4. pneumothorax, 5. moderate-severe nasal trauma, 6. bronchopulmonary dysplasia, 7. duration of CPAP use, 8. duration of oxygen supplementation, 9. duration of hospitalisation, 10. patent ductus arteriosus receiving medical or surgical treatment, 11. necrotising enterocolitis, 12. severe intraventricular haemorrhage, and 13. severe retinopathy of prematurity. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 12 trials with 1604 infants. All trials were small (median number of participants 118). The trials occurred after 2001 in care facilities internationally, predominantly in India (eight trials). Most participants were preterm infants of 26 to 34 weeks' gestation who received nasal CPAP as the primary form of respiratory support after birth. The studied interfaces included commonly used commercially available masks and prongs. Lack of measures to blind caregivers or investigators was a potential source of performance and detection bias in all the trials. Meta-analyses suggested that use of masks compared with prongs may reduce CPAP treatment failure (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 8 trials, 919 infants; low certainty). The type of interface may not affect mortality prior to hospital discharge (RR 0.83, 95% CI 0.56 to 1.22; 7 trials, 814 infants; low certainty). There are no data on neurodevelopmental impairment. Meta-analyses suggest that the choice of interface may result in little or no difference in the risk of pneumothorax (RR 0.93, 95% CI 0.45 to 1.93; 5 trials, 625 infants; low certainty). Use of masks rather than prongs may reduce the risk of moderate-severe nasal injury (RR 0.55, 95% CI 0.44 to 0.71; 10 trials, 1058 infants; low certainty). The evidence is very uncertain about the effect on bronchopulmonary dysplasia (RR 0.69, 95% CI 0.46 to 1.03; 7 trials, 843 infants; very low certainty). AUTHORS' CONCLUSIONS: The available trial data provide low-certainty evidence that use of masks compared with prongs as the nasal CPAP interface may reduce treatment failure and nasal injury, and may have little or no effect on mortality or the risk of pneumothorax in newborn preterm infants with or at risk of respiratory distress. The effect on bronchopulmonary dysplasia is very uncertain. Large, high-quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.

Penalties for industrial accidents: The impact of the Deepwater Horizon accident on BP's reputation and stock market returns.

Do visible industrial accidents damage firms' reputations and depress their stock market returns, and do these penalties spill over to other firms in the industry? On April 20, 2010, the Deepwater Horizon offshore oil rig in the Gulf of Mexico leased by BP exploded and sank, causing 11 deaths and the largest marine oil spill in US history. We examine the impact of this accident on BP's reputation and stock market performance using data from YouGov's BrandIndex and Capital IQ's financial data for the period 2007-2017. We employ a synthetic control analysis to examine the extent and duration of these penalties. We find that in the aftermath of the Deepwater accident, BP's reputation declined by approximately 50% relative to the synthetic control, and this decline persisted through the end of 2017. Yet, in terms of financial market returns, though the stock price dropped drastically in the first two months, we do not find a statistically significant decline in the stock market returns either in the mid-term (1-2 years) or the long term (2-7 years). In terms of spillover effects, we find no evidence of reputational damage or a decline in stock market returns for other oil and gas firms. These findings suggest that while environmental accidents invite swift and lasting reputational penalties, they might not depress the stock market performance in the long run. Moreover, the impact either on reputation or stock market returns does not necessarily spill over to other firms in the same industry.

Synbiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with synbiotics (probiotic micro-organisms combined with prebiotic oligosaccharides) to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity. OBJECTIVES: To assess the effect of enteral supplementation with synbiotics (versus placebo or no treatment, or versus probiotics or prebiotics alone) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Maternity and Infant Care database and CINAHL, from earliest records to 17 June 2021. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing prophylactic synbiotics supplementation with placebo or no synbiotics in very preterm (< 32 weeks' gestation) or very low birth weight (< 1500 g) infants. DATA COLLECTION AND ANALYSIS: Two review authors separately performed the screening and selection process,  evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference, with associated 95% confidence intervals (CIs). We used the GRADE approach to assess the level of certainty for effects on NEC, all-cause mortality, late-onset invasive infection, and neurodevelopmental impairment. MAIN RESULTS: We included six trials in which a total of 925 infants participated. Most trials were small (median sample size 200). Lack of clarity on methods used to conceal allocation and mask caregivers or investigators were potential sources of bias in four of the trials. The studied synbiotics preparations contained lactobacilli or bifidobacteria (or both) combined with fructo- or galacto-oligosaccharides (or both).  Meta-analyses suggested that synbiotics may reduce the risk of NEC (RR 0.18, 95% CI 0.09 to 0.40; RD 70 fewer per 1000, 95% CI 100 fewer to 40 fewer; number needed to treat for an additional beneficial outcome (NNTB) 14, 95% CI 10 to 25; six trials (907 infants); low certainty evidence); and all-cause mortality prior to hospital discharge (RR 0.53, 95% CI 0.33 to 0.85; RD 50 fewer per 1000, 95% CI 120 fewer to 100 fewer; NNTB 20, 95% CI 8 to 100; six trials (925 infants); low-certainty evidence). Synbiotics may have little or no effect on late-onset invasive infection, but the evidence is very uncertain (RR 0.84, 95% CI 0.58 to 1.21; RD 20 fewer per 1000, 95% CI 70 fewer to 30 more; five trials (707 infants); very low-certainty evidence). None of the trials assessed neurodevelopmental outcomes. In the absence of high levels of heterogeneity, we did not undertake any subgroup analysis (including the type of feeding). AUTHORS' CONCLUSIONS: The available trial data provide only low-certainty evidence about the effects of synbiotics on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants. Our confidence in the effect estimates is limited; the true effects may be substantially different from these estimates. Large, high-quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.

The FEED1 trial: protocol for a randomised controlled trial of full milk feeds versus intravenous fluids with gradual feeding for preterm infants (30-33 weeks gestational age).

BACKGROUND: In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units' workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition. METHODS: FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30+0 to 32+6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother's expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births. DISCUSSION: This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner. TRIAL REGISTRATION: ISRCTN ISRCTN89654042 . Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Enteral feeding for very preterm or very low birth weight (VLBW) infants is often delayed for several days after birth due to concern that early introduction of feeding may not be tolerated and may increase the risk of necrotising enterocolitis. Concerns exist, however, that delaying enteral feeding may diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effects of delayed introduction of progressive enteral feeds on the risk of necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants. SEARCH METHODS: Search strategies were developed by an information specialist in consultation with the review authors. The following databases were searched in October 2021 without date or language restrictions: CENTRAL (2021, Issue 10), MEDLINE via OVID (1946 to October 2021), Embase via OVID (1974 to October 2021), Maternity and Infant Care via OVID (1971 to October 2021), CINAHL (1982 to October 2021). We also searched for eligible trials in clinical trials databases, conference proceedings, previous reviews, and reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials that assessed the effects of delayed (four or more days after birth) versus earlier introduction of progressive enteral feeds on necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated trial risk of bias, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on necrotising enterocolitis, mortality,  feed intolerance, and invasive infection. MAIN RESULTS: We included 14 trials in which a total of 1551 infants participated. Potential sources of bias were lack of clarity on methods to generate random sequences and conceal allocation in half of the trials, and lack of masking of caregivers or investigators in all of the trials. Trials typically defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or fewer after birth. Infants in six trials (accounting for about half of all of the participants) had intrauterine growth restriction or circulatory redistribution demonstrated by absent or reversed end-diastolic flow velocities in the fetal aorta or umbilical artery.  Meta-analyses showed that delayed introduction of progressive enteral feeds may not reduce the risk of necrotising enterocolitis (RR 0.81, 95% confidence interval (CI) 0.58 to 1.14; RD -0.02, 95% CI -0.04 to 0.01; 13 trials, 1507 infants; low-certainty evidence due risk of bias and imprecision) nor all-cause mortality before hospital discharge (RR 0.97, 95% CI 0.70 to 1.36; RD -0.00, 95% CI -0.03 to 0.03; 12 trials, 1399 infants; low-certainty evidence due risk of bias and imprecision). Delayed introduction of progressive enteral feeds may slightly reduce the risk of feed intolerance (RR 0.81, 95% CI 0.68 to 0.97; RD -0.09, 95% CI -0.17 to -0.02; number needed to treat for an additional beneficial outcome = 11, 95% CI 6 to 50; 6 trials, 581 infants; low-certainty evidence due to risk of bias and imprecision) and probably increases the risk of invasive infection (RR 1.44, 95% CI 1.15 to 1.80; RD 0.10, 95% CI 0.04 to 0.15; number needed to treat for a harmful outcome = 10, 95% CI 7 to 25; 7 trials, 872 infants; moderate-certainty evidence due to risk of bias).  AUTHORS' CONCLUSIONS: Delaying the introduction of progressive enteral feeds beyond four days after birth (compared with earlier introduction) may not reduce the risk of necrotising enterocolitis or death in very preterm or VLBW infants. Delayed introduction may slightly reduce feed intolerance, and probably increases the risk of invasive infection.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, it is unclear whether slow feed advancement may delay establishment of full enteral feeding, and if it could be associated with infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effects of slow rates of enteral feed advancement on the risk of NEC, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We searched CENTRAL (2020, Issue 10), Ovid MEDLINE (1946 to October 2020), Embase via Ovid (1974 to October 2020), Maternity and Infant Care database (MIDIRS) (1971 to October 2020), CINAHL (1982 to October 2020), and clinical trials databases and reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that assessed effects of slow (up to 24 mL/kg/d) versus faster rates of advancement of enteral feed volumes on the risk of NEC in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated trial risk of bias, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence. Outcomes of interest were NEC, all-cause mortality, feed intolerance, and invasive infection. MAIN RESULTS: We included 14 trials involving a total of 4033 infants (2804 infants participated in one large trial). None of the trials masked parents, caregivers, or investigators. Risk of bias was otherwise low. Most infants were stable very preterm or VLBW infants of birth weight appropriate for gestation. About one-third of all infants were extremely preterm or extremely low birth weight (ELBW), and about one-fifth were small for gestational age, growth-restricted, or compromised as indicated by absent or reversed end-diastolic flow velocity in the foetal umbilical artery. Trials typically defined slow advancement as daily increments of 15 to 24 mL/kg, and faster advancement as daily increments of 30 to 40 mL/kg. Meta-analyses showed that slow advancement of enteral feed volumes probably has little or no effect on the risk of NEC (RR 1.06, 95% confidence interval (CI) 0.83 to 1.37; RD 0.00, 95% CI -0.01 to 0.02; 14 trials, 4026 infants; moderate-certainty evidence) or all-cause mortality prior to hospital discharge (RR 1.13, 95% CI 0.91 to 1.39; RD 0.01, 95% CI -0.01 to 0.02; 13 trials, 3860 infants; moderate-certainty evidence). Meta-analyses suggested that slow advancement may slightly increase feed intolerance (RR 1.18, 95% CI 0.95 to 1.46; RD 0.05, 95% CI -0.02 to 0.12; 9 trials, 719 infants; low-certainty evidence) and may slightly increase the risk of invasive infection (RR 1.14, 95% CI 0.99 to 1.31; RD 0.02, 95% CI -0.00 to 0.05; 11 trials, 3583 infants; low-certainty evidence). AUTHORS' CONCLUSIONS: The available trial data indicate that advancing enteral feed volumes slowly (daily increments up to 24 mL/kg) compared with faster rates probably does not reduce the risk of NEC, death, or feed intolerance in very preterm or VLBW infants. Advancing the volume of enteral feeds at a slow rate may slightly increase the risk of invasive infection.

Topical emollient for preventing infection in preterm infants.

BACKGROUND: Breakdown of the developmentally immature epidermal barrier may permit entry for micro-organisms leading to invasive infection in preterm infants. Topical emollients may improve skin integrity and barrier function and thereby prevent invasive infection, a major cause of mortality and morbidity in preterm infants. OBJECTIVES: To assess the effect of topical application of emollients (ointments, creams, or oils) on the risk of invasive infection and mortality in preterm infants. SEARCH METHODS: We searched CENTRAL via Cochrane Register of Studies (CRS) Web and MEDLINE via Ovid (updated 08 January 2021) and the reference lists of retrieved articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of prophylactic application of topical emollient on the risk of invasive infection, mortality, other morbidity, and growth and development in preterm infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on mortality and invasive infection. MAIN RESULTS: We included 22 trials with a total of 5578 infant participants. The main potential sources of bias were lack of clarity on the methods used to generate random sequences and conceal allocation in half of the trials, and lack of masking of parents, caregivers, clinicians, and investigators in all of the trials. Eight trials (2086 infants) examined the effect of topical ointments or creams. Most participants were very preterm infants cared for in healthcare facilities in high-income countries. Meta-analyses suggested that topical ointments or creams may have little or no effect on invasive infection (RR 1.13, 95% confidence interval (CI) 0.97 to 1.31; low certainty evidence) or mortality (RR 0.94, 95% CI 0.82 to 1.08; low certainty evidence). Fifteen trials (3492 infants) assessed the effect of topical plant or vegetable oils. Most of these trials were undertaken in low- or middle-income countries and were based in healthcare facilities. One large (2249 infants) community-based trial occurred in a rural field practice in India. Meta-analyses suggested that topical oils may reduce invasive infection (RR 0.71, 95% CI 0.52 to 0.96; I² = 52%; low certainty evidence) but have little or no effect on mortality (RR 0.94, 95% CI 0.82 to 1.08, I² = 3%; low certainty evidence). One trial (316 infants) that compared petroleum-based ointment versus sunflower seed oil in very preterm infants in Bangladesh showed little or no effect on invasive infection (RR 0.91, 95% CI 0.57 to 1.46; low certainty evidence), but suggested that ointment may lower mortality slightly (RR 0.82, 95% CI 0.68 to 0.98; RD -0.12, 95% CI -0.23 to -0.01; number needed to treat for an additional beneficial outcome 8, 95% CI 4 to 100; low certainty evidence). One trial (64 infants) that assessed the effect of coconut oil versus mineral oil in preterm infants with birth weight 1500 g to 2000 g in India reported no episodes of invasive infection or death in either group (very low certainty evidence). AUTHORS' CONCLUSIONS: The level of certainty about the effects of emollient therapy on invasive infection or death in preterm infants is low. Since these interventions are mostly inexpensive, readily accessible, and generally acceptable, further good-quality randomised controlled trials in healthcare facilities, and in community settings in low- or middle-income countries, may be justified.

Evaluation of the Quality of Perinatal Trials: Making the GRADE.

BACKGROUND: Assessing the quality of clinical research is a key evidence-based practice skill. Clinicians, guideline producers, policy makers, service commissioners, and families need to have a sense of the validity, applicability, and certainty of research evidence when determining how it should inform their decision-making and practice. METHODS: We consider the various methodological and study design factors that contribute to the validity and applicability of clinical research findings. We describe the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methodology and discuss how this approach is used to assess and report certainty of evidence and strength of recommendations. RESULTS: The randomized controlled trial (RCT) is the gold standard method for assessing interventions because randomization balances prognostic characteristics between comparison groups. The GRADE approach considers evidence from RCTs as high quality, but acknowledges that the quality and level of certainty of trial evidence may be "downgraded" based on consideration of threats across 5 domains: risk of bias in included trials, inconsistency between trials in outcome estimates, indirectness of the evidence, imprecision of estimates, and likelihood of publication bias. CONCLUSIONS: Structured critical appraisal using GRADE methods to assess risk of bias and other threats to the internal and external validity of RCTs and systematic reviews and meta-analyses of their data facilitates transparency and consistency in using evidence to inform policy and practice.

Population-Based Prostate Cancer Screening With Magnetic Resonance Imaging or Ultrasonography: The IP1-PROSTAGRAM Study.

IMPORTANCE: Screening for prostate cancer using prostate-specific antigen (PSA) testing can lead to problems of underdiagnosis and overdiagnosis. Short, noncontrast magnetic resonance imaging (MRI) or transrectal ultrasonography might overcome these limitations. OBJECTIVE: To compare the performance of PSA testing, MRI, and ultrasonography as screening tests for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This prospective, population-based, blinded cohort study was conducted at 7 primary care practices and 2 imaging centers in the United Kingdom. Men 50 to 69 years of age were invited for prostate cancer screening from October 10, 2018, to May 15, 2019. INTERVENTIONS: All participants underwent screening with a PSA test, MRI (T2 weighted and diffusion), and ultrasonography (B-mode and shear wave elastography). The tests were independently interpreted without knowledge of other results. Both imaging tests were reported on a validated 5-point scale of suspicion. If any test result was positive, a systematic 12-core biopsy was performed. Additional image fusion-targeted biopsies were performed if the MRI or ultrasonography results were positive. MAIN OUTCOMES AND MEASURES: The main outcome was the proportion of men with positive MRI or ultrasonography (defined as a score of 3-5 or 4-5) or PSA test (defined as PSA ≥3 µg/L) results. Key secondary outcomes were the number of clinically significant and clinically insignificant cancers detected if each test was used exclusively. Clinically significant cancer was defined as any Gleason score of 3+4 or higher. RESULTS: A total of 2034 men were invited to participate; of 411 who attended screening, 408 consented to receive all screening tests. The proportion with positive MRI results (score, 3-5) was higher than the proportion with positive PSA test results (72 [17.7%; 95% CI, 14.3%-21.8%] vs 40 [9.9%; 95% CI, 7.3%-13.2%]; P < .001). The proportion with positive ultrasonography results (score, 3-5) was also higher than the proportion of those with positive PSA test results (96 [23.7%; 95% CI, 19.8%-28.1%]; P < .001). For an imaging threshold of score 4 to 5, the proportion with positive MRI results was similar to the proportion with positive PSA test results (43 [10.6%; 95% CI, 7.9%-14.0%]; P = .71), as was the proportion with positive ultrasonography results (52 [12.8%; 95% CI, 9.9%-16.5%]; P = .15). The PSA test (≥3 ng/mL) detected 7 clinically significant cancers, an MRI score of 3 to 5 detected 14 cancers, an MRI score of 4 to 5 detected 11 cancers, an ultrasonography score of 3 to 5 detected 9 cancer, and an ultrasonography score of 4 to 5 detected 4 cancers. Clinically insignificant cancers were diagnosed by PSA testing in 6 cases, by an MRI score of 3 to 5 in 7 cases, an MRI score of 4 to 5 in 5 cases, an ultrasonography score of 3 to 5 in 13 cases, and an ultrasonography score of 4 to 5 in 7 cases. CONCLUSIONS AND RELEVANCE: In this cohort study, when screening the general population for prostate cancer, MRI using a score of 4 or 5 to define a positive test result compared with PSA alone at 3 ng/mL or higher was associated with more men diagnosed with clinically significant cancer, without an increase in the number of men advised to undergo biopsy or overdiagnosed with clinically insignificant cancer. There was no evidence that ultrasonography would have better performance compared with PSA testing alone.