Variables associated with antibiotic treatment tolerance in patients with Mycobacterium avium complex pulmonary disease.

BACKGROUND: Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) involves prolonged courses of multiple antibiotics that are variably tolerated and commonly cause adverse drug reactions (ADR). The purpose of this retrospective, single-center study was to identify demographic and disease-related variables associated with significant ADRs among patients treated with antibiotics against MAC-PD. METHODS: We reviewed all patients treated with antibiotic therapy for MAC-PD at a single center from 2000 to 2021. Patients were included if they met diagnostic criteria for MAC-PD, were prescribed targeted antibiotic therapy for any length of time and had their treatment course documented in their health record. We compared patients who completed antibiotics as originally prescribed (tolerant) with those whose antibiotic treatment course was modified or terminated secondary to an ADR (intolerant). RESULTS: Over the study period, 235 patients were prescribed antibiotic treatment with their clinical course documented in our center's electronic health record, and 246 treatment courses were analyzed. One hundred forty-three (57%) tolerated therapy versus 108 (43%) experienced ADRs. Among the 108 intolerant courses, 67 (63%) required treatment modification and 49 (46%) required premature treatment termination. Treatment intolerance was associated more frequently with smear positive sputum cultures (34% vs. 20%, p = 0.009), a higher Charlson Comorbidity Index (CCI) (4 vs. 6, p = 0.007), and existing liver disease (7% vs. 1%, p = 0.03). There was no between-group difference in BMI (21 vs. 22), fibrocavitary disease (24 vs. 19%), or macrolide sensitivity (94 vs. 80%). The use of daily therapy was not associated with intolerance (77 vs. 79%). Intolerant patients were more likely to be culture positive after 6 months of treatment (44 vs. 25%). CONCLUSIONS: Patients prescribed antibiotic therapy for MAC-PD are more likely to experience ADRs if they have smear positive sputum cultures at diagnosis, a higher CCI, or existing liver disease. Our study's rate of early treatment cessation due to ADR's was similar to that of other studies (20%) but is the first of its kind to evaluate patient and disease factors associated with ADR's. A systematic approach to classifying and addressing ADRs for patients undergoing treatment for MAC-PD is an area for further investigation.

Ubc13-Mms2 cooperates with a family of RING E3 proteins in budding yeast membrane protein sorting.

Polyubiquitin chains linked via lysine (K) 63 play an important role in endocytosis and membrane trafficking. Their primary source is the ubiquitin protein ligase (E3) Rsp5/NEDD4, which acts as a key regulator of membrane protein sorting. The heterodimeric ubiquitin-conjugating enzyme (E2), Ubc13-Mms2, catalyses K63-specific polyubiquitylation in genome maintenance and inflammatory signalling. In budding yeast, the only E3 proteins known to cooperate with Ubc13-Mms2 so far is a nuclear RING finger protein, Rad5, involved in the replication of damaged DNA. Here, we report a contribution of Ubc13-Mms2 to the sorting of membrane proteins to the yeast vacuole via the multivesicular body (MVB) pathway. In this context, Ubc13-Mms2 cooperates with Pib1, a FYVE-RING finger protein associated with internal membranes. Moreover, we identified a family of membrane-associated FYVE-(type)-RING finger proteins as cognate E3 proteins for Ubc13-Mms2 in several species, and genetic analysis indicates that the contribution of Ubc13-Mms2 to membrane trafficking in budding yeast goes beyond its cooperation with Pib1. Thus, our results widely implicate Ubc13-Mms2 as an Rsp5-independent source of K63-linked polyubiquitin chains in the regulation of membrane protein sorting.This article has an associated First Person interview with the first author of the paper.

Feasibility and acceptability of targeted salivary cytomegalovirus screening through universal newborn hearing screening.

AIM: This study aimed to determine the feasibility and parental acceptability of screening for congenital cytomegalovirus (cCMV) through saliva polymerase chain reaction in infants who did not pass their newborn hearing screening. Additionally, the utility (i.e. time to diagnosis and treatment) of this enhanced clinical pathway was evaluated. METHODS: The study was conducted through the Victorian Infant Hearing Screening Programme (VIHSP) across four maternity hospitals in Melbourne, Australia, during June 2019-March 2020. Parents were approached by VIHSP staff about obtaining a test for cytomegalovirus (CMV) at the time of their baby's second positive ('refer') result on the VIHSP screen. Participating parents collected a saliva swab for CMV polymerase chain reaction from their infants. Feasibility was determined by the proportion of 'referred' infants whose parents completed the salivary CMV screening test ≤21 days of life. Acceptability was measured through parent survey. RESULTS: Of 126 eligible families, 96 (76.0%) had salivary screening swabs taken ≤21 days of life. Most families (>92.0%) indicated that screening was acceptable, straightforward and thought testing their baby for cCMV was a good idea. One infant screened positive on day 30, was diagnosed with cCMV via confirmatory testing by day 31 and commenced valganciclovir on day 32. CONCLUSIONS: Obtaining a saliva sample to screen for cCMV in infants who do not pass their newborn hearing screen is feasible and appears acceptable to parents. This targeted cCMV screening method could be an option where mothers are rapidly discharged from hospital, especially in the context of the COVID-19 pandemic.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Home Oxygen Therapy for Adults with Chronic Lung Disease. An Official American Thoracic Society Clinical Practice Guideline.

Background: Evidence-based guidelines are needed for effective delivery of home oxygen therapy to appropriate patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD).Methods: The multidisciplinary panel created six research questions using a modified Delphi approach. A systematic review of the literature was completed, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to formulate clinical recommendations.Recommendations: The panel found varying quality and availability of evidence and made the following judgments: 1) strong recommendations for long-term oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe chronic resting hypoxemia, 2) a conditional recommendation against long-term oxygen use in patients with COPD with moderate chronic resting hypoxemia, 3) conditional recommendations for ambulatory oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe exertional hypoxemia, 4) a conditional recommendation for ambulatory liquid-oxygen use in patients who are mobile outside the home and require >3 L/min of continuous-flow oxygen during exertion (very-low-quality evidence), and 5) a recommendation that patients and their caregivers receive education on oxygen equipment and safety (best-practice statement).Conclusions: These guidelines provide the basis for evidence-based use of home oxygen therapy in adults with COPD or ILD but also highlight the need for additional research to guide clinical practice.

Postnatal probiotics and allergic disease in very preterm infants: Sub-study to the ProPrems randomized trial.

BACKGROUND: Probiotic supplementation to mothers and/or their term-born infants has been suggested to prevent allergic disease, in particular eczema; however, no studies have investigated probiotics for prevention of allergic diseases in very preterm infants. We evaluated the effect of a postnatal probiotic combination on development of allergic diseases in very preterm infants. METHODS: This sub-study was an a priori secondary outcome of the ProPrems multi-center, double-blind, placebo-controlled randomized trial (ANZCTR:12607000144415). ProPrems randomized 1099 very preterm infants to receive a probiotic combination or placebo from soon after birth until discharge from hospital or term corrected age (CA), whichever was earlier. Allergic disease (eczema, atopic eczema, food allergy, wheeze, atopic sensitization) was assessed in a subgroup of ProPrems infants (n = 281) as close to 12 months CA as possible by questionnaire, clinical examination, and skin prick tests to common allergens. RESULTS: There was no difference in eczema incidence between the probiotic and placebo groups (35[30%] of 118 infants vs 37[27%] of 137 infants, respectively, absolute difference 2.65%, 95% CI -8.45 to 13.75). Similarly, the incidence of atopic eczema (6[5%] of 118 vs 3[2%] of 137), food allergy (4[3%] of 124 vs 2[1%] of 154), wheeze (39[31%] of 127 vs 45[29%] of 154), and atopic sensitization (14[13%] of 106 vs 13[11%] of 123) were similar between the probiotic and placebo groups. CONCLUSION: This study found no effect of postnatal administration of a probiotic combination on the incidence of allergic diseases or atopic sensitization in the first 2 years of life in children born very preterm. Evidence that probiotics are effective for prevention of allergic disease in premature infants remains lacking; adequately powered randomized controlled trials evaluating probiotic supplementation for allergy prevention in very preterm infants are needed.

Recruitment of US Adolescents and Young Adults (AYA) into Human Immunodeficiency Virus (HIV)-Related Behavioral Research Studies: A Scoping Review.

PURPOSE OF REVIEW: The objective of this scoping review was to examine the range of published evidence on recruitment approaches and outcomes of US adolescents and young adults (AYA) ages (18-29 years) into human immunodeficiency virus (HIV)-related behavioral research studies during the past 10 years. RECENT FINDINGS: Implementation of effective behavioral research strategies among HIV at-risk and infected AYA is key to ending the HIV epidemic and necessitates successful recruitment strategies. A comprehensive search was executed across four electronic databases. Of the 1697 identified studies, seven met inclusion criteria with six of these seven directed to HIV prevention. Most studies used online recruitment as part of a hybrid strategy, and combined field-based/in-person and online methods. Recruitment strategies and outcomes, resources and compensation, procedures for consent, and timelines varied among all seven studies. Our results highlight the need for development of recruitment models in alignment with behavioral strategies aimed to treat and prevent HIV among US AYA.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Towards evidence-based resuscitation of the newborn infant.

Effective resuscitation of the newborn infant has the potential to save many lives around the world and reduce disabilities in children who survive peripartum asphyxia. In this Series paper, we highlight some of the important advances in the understanding of how best to resuscitate newborn infants, which includes monitoring techniques to guide resuscitative efforts, increasing awareness of the adverse effects of hyperoxia, delayed umbilical cord clamping, the avoidance of routine endotracheal intubation for extremely preterm infants, and therapeutic hypothermia for hypoxic-ischaemic encephalopathy. Despite the challenges of performing high-quality clinical research in the delivery room, researchers continue to refine and advance our knowledge of effective resuscitation of newborn infants through scientific experiments and clinical trials.

Advising women with diabetes in pregnancy to express breastmilk in late pregnancy (Diabetes and Antenatal Milk Expressing [DAME]): a multicentre, unblinded, randomised controlled trial.

BACKGROUND: Infants of women with diabetes in pregnancy are at increased risk of hypoglycaemia, admission to a neonatal intensive care unit (NICU), and not being exclusively breastfed. Many clinicians encourage women with diabetes in pregnancy to express and store breastmilk in late pregnancy, yet no evidence exists for this practice. We aimed to determine the safety and efficacy of antenatal expressing in women with diabetes in pregnancy. METHODS: We did a multicentre, two-group, unblinded, randomised controlled trial in six hospitals in Victoria, Australia. We recruited women with pre-existing or gestational diabetes in a singleton pregnancy from 34 to 37 weeks' gestation and randomly assigned them (1:1) to either expressing breastmilk twice per day from 36 weeks' gestation (antenatal expressing) or standard care (usual midwifery and obstetric care, supplemented by support from a diabetes educator). Randomisation was done with a computerised random number generator in blocks of size two and four, and was stratified by site, parity, and diabetes type. Investigators were masked to block size but masking of caregivers was not possible. The primary outcome was the proportion of infants admitted to the NICU. We did the analyses by intention to treat; the data were obtained and analysed masked to group allocation. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000217909. FINDINGS: Between June 6, 2011, and Oct 29, 2015, we recruited and randomly assigned 635 women: 319 to antenatal expressing and 316 to standard care. Three were not included in the primary analysis (one withdrawal from the standard care group, and one post-randomisation exclusion and one withdrawal from the antenatal expressing group). The proportion of infants admitted to the NICU did not differ between groups (46 [15%] of 317 assigned to antenatal expressing vs 44 [14%] of 315 assigned to standard care; adjusted relative risk 1·06, 95% CI 0·66 to 1·46). In the antenatal expressing group, the most common serious adverse event for infants was admission to the NICU for respiratory support (for three [<1%] of 317. In the standard care group, the most common serious adverse event for infants was moderate to severe encephalopathy with or without seizures (for three [<1%] of 315). INTERPRETATION: There is no harm in advising women with diabetes in pregnancy at low risk of complications to express breastmilk from 36 weeks' gestation. FUNDING: Australian National Health and Medical Research Council.

Gut microbiota of preterm infants supplemented with probiotics: sub-study of the ProPrems trial.

BACKGROUND: The ProPrems trial, a multi-center, double-blind, placebo-controlled randomized trial, previously reported a 54% reduction in necrotizing enterocolitis (NEC) of Bell stage 2 or more from 4.4 to 2.0% in 1099 infants born before 32 completed weeks' gestation and weighing < 1500 g, receiving probiotic supplementation (with Bifidobacterium longum subsp. infantis BB-02, Streptococcus thermophilus TH-4 and Bifidobacterium animalis subsp. lactis BB-12). This sub-study investigated the effect of probiotic supplementation on the gut microbiota in a cohort of very preterm infants in ProPrems. RESULTS: Bifidobacterium was found in higher abundance in infants who received the probiotics (AOR 17.22; 95% CI, 3.49-84.99, p < 0.001) as compared to the placebo group, and Enterococcus was reduced in infants receiving the probiotic during the supplementation period (AOR 0.27; 95% CI, 0.09-0.82, p = 0.02). CONCLUSION: Probiotic supplementation with BB-02, TH-4 and BB-12 from soon after birth increased the abundance of Bifidobacterium in the gut microbiota of very preterm infants. Increased abundance of Bifidobacterium soon after birth may be associated with reducing the risk of NEC in very preterm infants.

Health Technology-Enabled Interventions for Adherence Support and Retention in Care Among US HIV-Infected Adolescents and Young Adults: An Integrative Review.

The objective of this integrative review was to describe current US trends for health technology-enabled adherence interventions among behaviorally HIV-infected youth (ages 13-29 years), and present the feasibility and efficacy of identified interventions. A comprehensive search was executed across five electronic databases (January 2005-March 2016). Of the 1911 identified studies, nine met the inclusion criteria of quantitative or mixed methods design, technology-enabled adherence and or retention intervention for US HIV-infected youth. The majority were small pilots. Intervention dose varied between studies applying similar technology platforms with more than half not informed by a theoretical framework. Retention in care was not a reported outcome, and operationalization of adherence was heterogeneous across studies. Despite these limitations, synthesized findings from this review demonstrate feasibility of computer-based interventions, and initial efficacy of SMS texting for adherence support among HIV-infected youth. Moving forward, there is a pressing need for the expansion of this evidence base.

Frenotomy for tongue-tie in newborn infants.

BACKGROUND: Tongue-tie, or ankyloglossia, is a condition whereby the lingual frenulum attaches near the tip of the tongue and may be short, tight and thick. Tongue-tie is present in 4% to 11% of newborns. Tongue-tie has been cited as a cause of poor breastfeeding and maternal nipple pain. Frenotomy, which is commonly performed, may correct the restriction to tongue movement and allow more effective breastfeeding with less maternal nipple pain. OBJECTIVES: To determine whether frenotomy is safe and effective in improving ability to feed orally among infants younger than three months of age with tongue-tie (and problems feeding).Also, to perform subgroup analysis to determine the following.• Severity of tongue-tie before frenotomy as measured by a validated tool (e.g. Hazelbaker Assessment Tool for Lingual Frenulum Function (ATLFF) scores < 11; scores ≥ 11) (Hazelbaker 1993).• Gestational age at birth (< 37 weeks' gestation; 37 weeks' gestation and above).• Method of feeding (breast or bottle).• Age at frenotomy (≤ 10 days of age; > 10 days to three months of age).• Severity of feeding difficulty (infants with feeding difficulty affecting weight gain (as assessed by infant's not regaining birth weight by day 14 or falling off centiles); infants with symptomatic feeding difficulty but thriving (greater than birth weight by day 14 and tracking centiles). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL up to January 2017, as well as previous reviews including cross-references, expert informants and journal handsearching. We searched clinical trials databases for ongoing and recently completed trials. We applied no language restrictions. SELECTION CRITERIA: Randomised, quasi-randomised controlled trials or cluster-randomised trials that compared frenotomy versus no frenotomy or frenotomy versus sham procedure in newborn infants. DATA COLLECTION AND ANALYSIS: Review authors extracted from the reports of clinical trials data regarding clinical outcomes including infant feeding, maternal nipple pain, duration of breastfeeding, cessation of breastfeeding, infant pain, excessive bleeding, infection at the site of frenotomy, ulceration at the site of frenotomy, damage to the tongue and/or submandibular ducts and recurrence of tongue-tie. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Five randomised trials met our inclusion criteria (n = 302). Three studies objectively measured infant breastfeeding using standardised assessment tools. Pooled analysis of two studies (n = 155) showed no change on a 10-point feeding scale following frenotomy (mean difference (MD) -0.1, 95% confidence interval (CI) -0.6 to 0.5 units on a 10-point feeding scale). A third study (n = 58) showed objective improvement on a 12-point feeding scale (MD 3.5, 95% CI 3.1 to 4.0 units of a 12-point feeding scale). Four studies objectively assessed maternal pain. Pooled analysis of three studies (n = 212) based on a 10-point pain scale showed a reduction in maternal pain scores following frenotomy (MD -0.7, 95% CI -1.4 to -0.1 units on a 10-point pain scale). A fourth study (n = 58) also showed a reduction in pain scores on a 50-point pain scale (MD -8.6, 95% CI -9.4 to -7.8 units on a 50-point pain scale). All studies reported no adverse effects following frenotomy. These studies had serious methodological shortcomings. They included small sample sizes, and only two studies blinded both mothers and assessors; one did not attempt blinding for mothers nor for assessors. All studies offered frenotomy to controls, and most controls underwent the procedure, suggesting lack of equipoise. No study was able to report whether frenotomy led to long-term successful breastfeeding. AUTHORS' CONCLUSIONS: Frenotomy reduced breastfeeding mothers' nipple pain in the short term. Investigators did not find a consistent positive effect on infant breastfeeding. Researchers reported no serious complications, but the total number of infants studied was small. The small number of trials along with methodological shortcomings limits the certainty of these findings. Further randomised controlled trials of high methodological quality are necessary to determine the effects of frenotomy.

Implementation of dextrose gel in the management of neonatal hypoglycaemia.

AIM: The aim of this study was to evaluate dextrose gel in the management of neonatal hypoglycaemia in the postnatal wards at an Australian tertiary level perinatal centre. METHODS: An audit was performed before and after implementation of dextrose gel. Pre-implementation, neonatal hypoglycaemia was managed with feed supplementation alone, and dextrose gel was used in addition to feed supplementation in the post-implementation phase. Outcomes included admission to neonatal intensive care unit (NICU) for management of hypoglycaemia, proportion of neonates who achieved normoglycaemia (defined as blood glucose ≥2.6 mmol/L, with no clinical signs after one or two treatment attempts) and proportion of neonates with hypoglycaemia recurrence after normoglycaemia and one or two treatment attempts. RESULTS: NICU admission for treatment of hypoglycaemia reduced significantly post-implementation of dextrose gel (29/100 (29%) vs. 14/100 (14%), P = 0.01). No significant difference was seen in the proportion of neonates achieving normoglycaemia (71/100 (71%) vs. 75/100 (75%), P = 0.52), but hypoglycaemia recurrence was higher in the post-implementation group (22/71 (31%) vs. 37/75 (49%), P = 0.02). CONCLUSIONS: Dextrose gel is effective in the management of neonatal hypoglycaemia in the postnatal ward setting, reducing admission to NICU and mother-infant separation.

Differential regulation of GABAB receptor trafficking by different modes of N-methyl-D-aspartate (NMDA) receptor signaling.

Inhibitory GABAB receptors (GABABRs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABABRs are heterodimers of GABAB1 and GABAB2 subunits and here we show that the trafficking and surface expression of GABABRs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABABR recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABABRs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABAB1 but decreases GABAB2 surface expression. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABABR trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival.

Stable rates of neonatal sepsis in a tertiary neonatal unit.

AIMS: To describe the rate of early- and late-onset sepsis in neonates admitted to the neonatal intensive care unit at the Royal Women's Hospital and to compare the rate of late-onset sepsis (LOS) with a published (2008) cohort from the same unit. The secondary aim was to examine clinicians' compliance with antibiotic guidelines. METHODS: Infants born <32 weeks' gestation or <1500 g admitted between 1 July 2011 and 31 December 2011 were included. Strict definitions of sepsis and compliance with antibiotic guidelines were applied. RESULTS: One hundred and seventy-two infants met the inclusion criteria, with 152 having blood culture evaluations for early-onset sepsis (EOS) and 58 having 109 evaluations for LOS. Definite EOS occurred in 1.3% with Escherichia coli isolated. The rate of definite LOS in 2011 of 22% was not significantly different than the 27% in 2008, with coagulase-negative staphylococcus the main isolate. Antibiotic continuation beyond 72 h in infants with negative blood cultures was the main reason for non-compliance with antibiotic guidelines. CONCLUSIONS: The rate of EOS is comparable with published reports and the rate of LOS has remained stable over a 3-year period. Discontinuation of antibiotics with negative septic markers and blood cultures at 48-72 h is encouraged.

Homeostatic synaptic scaling is regulated by protein SUMOylation.

Homeostatic scaling allows neurons to alter synaptic transmission to compensate for changes in network activity. Here, we show that suppression of network activity with tetrodotoxin, which increases surface expression of AMPA receptors (AMPARs), dramatically reduces levels of the deSUMOylating (where SUMO is small ubiquitin-like modifier) enzyme SENP1, leading to a consequent increase in protein SUMOylation. Overexpression of the catalytic domain of SENP1 prevents this scaling effect, and we identify Arc as a SUMO substrate involved in the tetrodotoxin-induced increase in AMPAR surface expression. Thus, protein SUMOylation plays an important and previously unsuspected role in synaptic trafficking of AMPARs that underlies homeostatic scaling.

Cooling for newborns with hypoxic ischaemic encephalopathy.

BACKGROUND: Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. OBJECTIVES: To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. SELECTION CRITERIA: We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. DATA COLLECTION AND ANALYSIS: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). MAIN RESULTS: We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. AUTHORS' CONCLUSIONS: There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

A randomised trial of two techniques for bottle feeding preterm infants.

AIM: Preterm infants begin the transition from gastric tube feeds to sucking feeds around 34 weeks' postmenstrual age. We compared physiological stability in two bottle feeding positions, cradle hold versus side lying in preterm infants. METHODS: Randomised crossover trial of infants <34 weeks' gestation at birth, ≥34 weeks' postmenstrual age at study and receiving at least two sucking feeds/day. Two feeds were studied on successive days. A pulse oximeter measured oxygen saturation (SpO2) and heart rate (HR) before, during and 30 min after feeds. Continuous data were compared using paired t-tests and proportions using chi squared. RESULTS: Twenty-five study infants were mean (standard deviation (SD)) 37 (2.4) weeks' post-menstrual age and 2740 (589) g at study. There was little difference in mean (SD) SpO2 during feeds between the cradle-hold and side-lying position 94 (6) % versus 95 (6) %, respectively (P = 0.55, confidence interval (CI) -1.4, 5.4). During feeds, 17/25 (68%) experienced a period of SpO2 <80% in the cradle-hold position compared with 14/25 (56) % in the side-lying position (P = 0.26, CI 0.68, 4.10). There were no significant differences in the mean HR or number of episodes of bradycardia HR <100 bpm. There was a trend towards infants consuming a smaller mean (SD) proportion of their feed in the cradle-hold position compared with the side-lying position, 82 (25) % versus 87 (20) % (P = 0.08, CI -0.64, 10.00). CONCLUSIONS: There was little difference in infants' physiological stability between the two bottle feeding positions. Both methods may be appropriate for the transition from gastric tube to sucking feeds in preterm infants.