Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

UK Patients of Bangladeshi Descent with Crohn's Disease Respond Less Well to TNF Antagonists Than Caucasian Patients.

BACKGROUND: Patients with inflammatory bowel disease are currently managed with the assumption that trial data are applicable to all ethnic groups. Previous studies demonstrate differences in disease severity and phenotype of Asian patients with Crohn's disease (CD), including Bangladeshi Asians within the UK. No study has evaluated the impact of ethnicity on response to anti-TNFs. AIM: Our primary endpoint was a comparison of failure-free survival on first prescribed anti-TNF (anti-tumor necrosis factor) therapy in UK Bangladeshi and Caucasian patients with CD. Our secondary aims were to evaluate disease phenotype, indication for anti-TNF prescription, and duration from diagnosis until first anti-TNF prescribed between groups. METHODS: The records of consecutive outpatient appointments over a 12-month period were used to identify Caucasian and Bangladeshi patients prescribed an anti-TNF for CD. Information on patient demographics, ethnicity, disease phenotype, immunomodulator use, outcome from first biologic, duration of therapy, and reason for cessation was recorded. RESULTS: In total, 224 Caucasian and Bangladeshi patients were prescribed an anti-TNF for CD. Bangladeshi patients started an anti-TNF 4.3 years earlier after diagnosis than Caucasian patients (3.9 years vs. 8.2 years: p < 0.01). Bangladeshi patients experienced shorter failure-free survival than Caucasian patients (1.8 vs. 4.8 years p < 0.01). By 2 years, significantly more Bangladeshi patients had stopped anti-TNF due to loss of response (OR 6.35, p < 0.01). CONCLUSIONS: This is the first study to suggest that Bangladeshi patients resident in the UK with CD respond less well to treatment with TNF antagonists than Caucasian patients.

The Speed of Increasing milk Feeds: a randomised controlled trial.

BACKGROUND: In the UK, 1-2% of infants are born very preterm (<32 weeks of gestation) or have very low birth weight (<1500 g). Very preterm infants are initially unable to be fed nutritional volumes of milk and therefore require intravenous nutrition. Milk feeding strategies influence several long and short term health outcomes including growth, survival, infection (associated with intravenous nutrition) and necrotising enterocolitis (NEC); with both infection and NEC being key predictive factors of long term disability. Currently there is no consistent strategy for feeding preterm infants across the UK. The SIFT trial will test two speeds of increasing milk feeds with the primary aim of determining effects on survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for prematurity. The trial will also examine many secondary outcomes including infection, NEC, time taken to reach full feeds and growth. METHODS/DESIGN: Two thousand eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a randomised controlled trial. Infants with severe congenital anomaly or no realistic chance of survival will be excluded. Infants will be randomly allocated to either a faster (30 ml/kg/day) or slower (18 ml/kg/day) rate of increase in milk feeds. Data will be collected during the neonatal hospital stay on weight, infection rates, episodes of NEC, length of stay and time to reach full milk feeds. Long term health outcomes comprising vision, hearing, motor and cognitive impairment will be assessed at 24 months of age (corrected for prematurity) using a parent report questionnaire. DISCUSSION: Extensive searches have found no active or proposed studies investigating the rate of increasing milk feeds. The results of this trial will have importance for optimising incremental milk feeding for very preterm and/or very low birth weight infants. No additional resources will be required to implement an optimal feeding strategy, and therefore if successful, the trial results could rapidly be adopted across the NHS at low cost. TRIAL REGISTRATION: ISRCTN Registry; ISRCTN76463425 on 5 March, 2013.

Parents' views on care of their very premature babies in neonatal intensive care units: a qualitative study.

BACKGROUND: The admission of a very premature infant to the neonatal intensive care unit (NICU) is often a difficult time for parents. This paper explores parents' views and experiences of the care for their very premature baby on NICU. METHODS: Parents were eligible if they had a baby born before 32 weeks gestation and cared for in a NICU, and spoke English well. 32 mothers and 7 fathers were interviewed to explore their experiences of preterm birth. Although parents' evaluation of care in the NICU was not the aim of these interviews, all parents spoke spontaneously and at length on this topic. Results were analysed using thematic analysis. RESULTS: Overall, parents were satisfied with the care on the neonatal unit. Three major themes determining satisfaction with neonatal care emerged: 1) parents' involvement; including looking after their own baby, the challenges of expressing breast milk, and easy access to their baby; 2) staff competence and efficiency; including communication, experience and confidence, information and explanation; and 3) interpersonal relationships with staff; including sensitive and emotional support, reassurance and encouragement, feeling like an individual. CONCLUSIONS: Determinants of positive experiences of care were generally consistent with previous research. Specifically, provision of information, support for parents and increasing their involvement in the care of their baby were highlighted by parents as important in their experience of care.

Effective palliation of refractory ascites in cirrhosis is challenging.

BACKGROUND: Palliative care is often suboptimal for patients with end-stage liver disease (ESLD). Ascites remains the most common complication in ESLD. Though long-term abdominal drains (LTAD) are commonly used in refractory malignant ascites, the standard care for ESLD is hospital drainage (large volume paracentesis (LVP)). There is an ongoing National Institute for Health and Care Research (NIHR) funded trial (REDUCe 2 Study) (ISRCTN269936824) comparing palliative LTAD to LVP in ESLD. This 35-site trial is being conducted in England, Scotland and Wales. AIM: To understand the views and experience of healthcare professionals (HCP) on the use of palliative LTAD in ESLD. METHODS: An electronic survey comprised of seven questions with fixed quantitative options and three exploratory questions was used between August-December 2019. The survey was distributed electronically via the British Association for Study of Liver newsletter and to relevant hospital departments in Southeast England and Northeast London. An email reminder was sent at 4 and 8 weeks after the initial invitation to the survey. RESULTS: There were 211 respondents (hepatologists (36.5%), specialist nurses (24.6%), gastroenterologists (16.6%), trainees (17%) and others (5.2%)). All respondents had access to LVP, 86% to a transjugular intrahepatic portosystemic shunt procedure for patients, 67% to LTADs and 10% to other options, such as the automated low-flow ascites (ALFA) pump. The majority of respondents to the survey (68%) reported their experience of using LTAD. Almost all respondents (91%) were willing to consider LTAD in ESLD. However, the main deterrents of this were the perceived risk of infection (90%), followed by LTAD management in community (57%). Some 51% of those with prior experience of using LTAD reported clinical complications for patients (including bleeding, infection and renal impairment), 41% reported technical issues and 35% inadequate community support. CONCLUSIONS: Almost all HCPs are willing to consider palliative LTAD in refractory ascites due to ESLD, but the main deterrents are the perceived infection risk and lack of published data to guide community management. The REDUCe 2 trial will clarify if these concerns are real and provide conclusive evidence on role, if any, of palliative LTADs in this vulnerable and under researched cohort with ESLD.

Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review.

BACKGROUND: Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM: To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS: This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS: Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION: Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

A conceptual model for chronic hepatitis B and content validity of the Hepatitis B Quality of Life (HBQOL) instrument.

BACKGROUND: There is increased emphasis on incorporating patient perspectives and patient-relevant endpoints in drug development. We developed a conceptual model of the impact of chronic hepatitis B (CHB) on patients' lives and evaluated the content validity of the Hepatitis B Quality of Life (HBQOL) instrument, a patient-reported outcome tool for use in clinical studies, as a patient-relevant endpoint to measure health-related quality of life in patients with CHB. METHODS: A literature review of qualitative studies of patient experience with CHB and concept elicitation telephone interviews with patients with CHB in the United Kingdom were used to develop a conceptual model of the experience and impact of living with CHB. The content validity of the HBQOL was evaluated using cognitive debriefing techniques. RESULTS: The qualitative literature review (N = 43 publications) showed that patients with CHB experience emotional/psychological impacts. During concept elicitation interviews (N = 24), fatigue was the most commonly reported symptom, and most participants were worried/anxious about virus transmission and disease progression/death. A conceptual model of patients' experiences with CHB was developed. The conceptual relevance and comprehensibility of the HBQOL were supported, though limitations, including the lack of a self-stigma item and recall period, were noted for future improvement. CONCLUSIONS: The conceptual model shows that patients with CHB experience emotional/psychological impacts that affect their lifestyles, relationships, and work/schooling. The cognitive debriefing interviews support the content validity of the HBQOL as a conceptually relevant patient-reported outcome measure of health-related quality of life.

Measures of satisfaction with care during labour and birth: a comparative review.

BACKGROUND: Satisfaction is the one of the most frequently reported outcome measures for quality of care. Assessment of satisfaction with maternity services is crucial, and psychometrically sound measures are needed if this is to inform health practices. This paper comparatively reviews current measures of satisfaction with care during labour and birth. METHODS: A review of the literature was conducted. Studies were located through computerised databases and hand searching references of identified articles and reviews. Inclusion criteria were that the questionnaire was a multi-item scale of satisfaction with care during labour and birth, and some form of psychometric information (either information about questionnaire construction, or reliability, or validity) had to be reported. RESULTS: Nine questionnaires of satisfaction with care during labour and birth were identified. Instruments varied in psychometric properties and dimensions. Most described questionnaire construction and tested some form of reliability and validity. Measures were generally not based on the main theoretical models of satisfaction and varied in scope and application to different types of samples (e.g. satisfaction following caesarean section). For an in-depth measure of satisfaction with intrapartum care, the Intrapartal-Specific Quality from the Patient's Perspective questionnaire (QPP-I) is recommended. Brief measures with good reliability and validity are provided by the Six Simple Questions (SSQ) or Perceptions of Care Adjective Checklist (PCACL-R). CONCLUSIONS: Despite the interest in measures of satisfaction there are only a small number of validated measures of satisfaction with care during labour and birth. It is important that brief, reliable and valid measures are available for use in general and specific populations in order to assist research and inform practice.

Differential immunogenicity of homologous versus heterologous boost in Ad26.COV2.S vaccine recipients.

BACKGROUND: Protection offered by coronavirus disease 2019 (COVID-19) vaccines wanes over time, requiring an evaluation of different boosting strategies to revert such a trend and enhance the quantity and quality of Spike-specific humoral and cellular immune responses. These immunological parameters in homologous or heterologous vaccination boosts have thus far been studied for mRNA and ChAdOx1 nCoV-19 vaccines, but knowledge on individuals who received a single dose of Ad26.COV2.S is lacking. METHODS: We studied Spike-specific humoral and cellular immunity in Ad26.COV2.S-vaccinated individuals (n = 55) who were either primed with Ad26.COV2.S only (n = 13) or were boosted with a homologous (Ad26.COV2.S, n = 28) or heterologous (BNT162b2, n = 14) second dose. We compared our findings with the results found in individuals vaccinated with a single (n = 16) or double (n = 44) dose of BNT162b2. FINDINGS: We observed that a strategy of heterologous vaccination enhanced the quantity and breadth of both Spike-specific humoral and cellular immunity in Ad26.COV2.S-vaccinated individuals. In contrast, the impact of the homologous boost was quantitatively minimal in Ad26.COV2.S-vaccinated individuals, and Spike-specific antibodies and T cells were narrowly focused to the S1 region. CONCLUSIONS: Despite the small sample size of the study and the lack of well-defined correlates of protection against COVID-19, the immunological features detected support the utilization of a heterologous vaccine boost in individuals who received Ad26.COV2.S vaccination. FUNDING: This study is partially supported by the Singapore Ministry of Health's National Medical Research Council under its COVID-19 Research Fund (COVID19RF3-0060, COVID19RF-001, and COVID19RF-008), The Medical College St. Bartholomew's Hospital Trustees - Pump Priming Fund for SMD COVID-19 Research.

Two speeds of increasing milk feeds for very preterm or very low-birthweight infants: the SIFT RCT.

BACKGROUND: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. OBJECTIVE: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. DESIGN: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. SETTING: The setting was 55 UK neonatal units, from May 2013 to June 2015. PARTICIPANTS: The participants were infants born at < 32 weeks' gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment. INTERVENTIONS: When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds. MAIN OUTCOME MEASURES: The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell's stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability. RESULTS: The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost-consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention. LIMITATIONS: The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered. CONCLUSIONS: No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76463425. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 18. See the NIHR Journals Library website for further project information.

Some infants who are born early need to be fed through a tube into their stomach. A small volume of milk is given to begin with, which is gradually increased. To determine whether infants do better if they are fed faster or slower, this study compared increasing the milk feeds by 30 ml/kg/day with increasing the milk feeds by 18 ml/kg/day, aiming to get to full feeds (when other fluids are not needed) in 5 or 9 days. We compared results from the two groups at discharge from hospital and at 24 months of age, after correcting for prematurity. We also assessed the economic impact of the two daily feed increments, interviewed parents about taking part in multiple studies and tested methods for improving questionnaire returns. The faster-fed group reached full milk feeds sooner and needed less intravenous nutrition, and the proportion of infants developing bowel inflammation or bloodstream infection were similar. At 24 months of age, we found an unexpected increase in the risk of moderate or severe motor impairment in the faster-fed group, which is difficult to explain. We also saw that other types of disability were more frequent in the faster group, although this was not significantly different mathematically. This means that no clear advantage of increasing feeds at faster or slower rates was identified and health professionals will need to carefully consider how to increase feeds. After accepting the increased risk of disability, an economic evaluation showed that increasing milk feed volumes at a faster rate was not a cost-effective strategy. Interviews with parents showed that they valued opportunities for their infant to take part in studies, but this interaction is complex and difficult to remember at a stressful and confusing time and made worse by considering multiple studies. More questionnaires were returned when vouchers were given before rather than after receiving them.

What's Age Got to do with it? A Review of Contemporary Revascularization in the Elderly.

Currently a quarter of all patients treated with percutanous coronary intervention (PCI) are aged >75 years, with this proportion steadily growing. This subset of patients have a number of unique characteristics, such as a greater number of cardiovascular risk factors and frequently a larger burden of coronary artery disease, when compared to younger patients, therefore potentially deriving increased benefit from revascularization. Nonetheless this population are also more likely to experience procedural complications, secondary to age-related physiological alterations, increased frailty and increased prevalence of other co-morbidities. This article reviews the various aspects and data available to clinicians pertaining to and guiding revascularization in the elderly, including the use of adjuvant pharmacotherapy, specific considerations when considering age-related physiology, and revascularization in acute coronary syndromes.

Parents' first moments with their very preterm babies: a qualitative study.

OBJECTIVES: To assess parents' first experiences of their very preterm babies and the neonatal intensive care unit (NICU). DESIGN: Qualitative study using semistructured interviews. PARTICIPANTS: 32 mothers and 7 fathers of very preterm babies (<32 weeks gestation). SETTING: Three neonatal units in tertiary care hospitals in South East England. RESULTS: Five themes were identified. The first describes parents' blurred recall of the birth. The second shows the anticipation of seeing and touching their baby for the first time was characterised by contrasting emotions, with some parents feeling scared and others excited about the event. The third theme describes parents' first sight and touch of their babies and their 'rollercoaster' of emotions during this time. It also highlights the importance of touch to trigger and strengthen the parent-baby bond. However, some parents were worried that touching or holding the baby might transmit infection or interfere with care. The fourth theme captures parents' impressions of NICU and how overwhelming this was particularly for parents who had not toured NICU beforehand or whose first sight of their baby was on NICU. The final theme captures unique experiences of fathers, in particular that many felt excluded and confused about their role. CONCLUSIONS: This study informs family-centred care by providing insight into the experiences of parents of very preterm infants at a time when they are most in need of support. Clinical implications include the importance of offering parents preparatory tours of the NICU and including fathers.

The use of routinely collected patient data for research: a critical review.

Over recent years in the UK there has been growing interest in the potential for routinely collected NHS (National Health Service) patient data to be used for secondary purposes, facilitated by the potential of increasingly sophisticated electronic databases. This article is based on a critically reflective literature review which analyses the key debates pertaining to this issue. The work arose in the context of a programme of research concerning routine patient data use in neonatal care. The article includes analysis of commentary (opinion and ethical inquiry) as well as empirically derived claims. It aims to deconstruct the knowledge assumptions on which relevant research studies have been based or are proposed and it also incorporates ontological position and moral argument. Results are presented according to three predominant debates: the prevailing claim that all health research benefits civic society; the varieties of informed consent and choices open to patients regarding secondary uses of their data; and the 'rights and responsibilities' of patients when it comes to their data being used for research purposes. It examines the relevance of these themes specifically to the neonatal context and the implications for our own research, concluding that employing an alternative ethical model to the traditional professional one might be useful in order to provide a further perspective on the issue.