IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for one week. The fetus underwent a metabolic study immediately prior to infusion start and after one week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P=0.0081) and had heavier hearts, livers, and adrenal glands than IGF and CON (P<0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P<0.0001) and lower final amino acid concentrations than CON (P=0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P<0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P<0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Local Anesthetic Systemic Toxicity: Ensuring Sustained Nursing Knowledge in a High-Volume Outpatient Surgery Center.

PURPOSE: Local anesthetic systemic toxicity (LAST) is a low-frequency, high-risk event that can occur within minutes of a patient receiving a local anesthetic. The goals of this project were to standardize LAST care management across an academic medical center and sustain an improvement in nurses' knowledge of how to recognize signs and symptoms of LAST and how to competently manage a LAST scenario. DESIGN: We used a quantitative design to accomplish the goals of the project. METHODS: Our interdisciplinary team developed a clinical practice guideline based on the LAST Checklist published by the American Society of Regional Anesthesia and Pain Medicine, and used a simulation scaffolded by multimodal education and system changes to ensure sustained knowledge. We measured improvement using a graded knowledge assessment as well as qualitative feedback. FINDINGS: Scores on the assessment increased from 4.76 to 6.34 (out of seven points) following the intervention and remained significantly higher than the baseline 9 months after the educational intervention (9-month score = 6.19, t = 2.99, P = .004). Nurses reported feeling more confident and knowledgeable following the intervention and requested to have regular sessions of the simulation. To sustain improvements, we developed a computer-based learning module. The module and simulation were integrated into nursing orientation and an annual competency. CONCLUSIONS: While standardizing LAST care in accordance with evidence-based guidance is critical to patient safety due to its infrequent occurrence, nurses should consider implementing simulation supplemented with multimodal education and system changes to ensure sustained knowledge.

Prioritisation processes for programme implementation and evaluation in public health: A scoping review.

Background: Programme evaluation is an essential and systematic activity for improving public health programmes through useful, feasible, ethical, and accurate methods. Finite budgets require prioritisation of which programmes can be funded, first, for implementation, and second, evaluation. While criteria for programme funding have been discussed in the literature, a similar discussion around criteria for which programmes are to be evaluated is limited. We reviewed the criteria and frameworks used for prioritisation in public health more broadly, and those used in the prioritisation of programmes for evaluation. We also report on stakeholder involvement in prioritisation processes, and evidence on the use and utility of the frameworks or sets of criteria identified. Our review aims to inform discussion around which criteria and domains are best suited for the prioritisation of public health programmes for evaluation. Methods: We reviewed the peer-reviewed literature through OVID MEDLINE (PubMed) on 11 March 2022. We also searched the grey literature through Google and across key websites including World Health Organization (WHO), US Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), and the International Association of National Public Health Institutes (IANPHI) (14 March 2022). Articles were limited to those published between 2002 and March 2022, in English, French or German. Results: We extracted over 300 unique criteria from 40 studies included in the analysis. These criteria were categorised into 16 high-level conceptual domains to allow synthesis of the findings. The domains most frequently considered in the studies were "burden of disease" (33 studies), "social considerations" (30 studies) and "health impacts of the intervention" (28 studies). We only identified one paper which proposed criteria for use in the prioritisation of public health programmes for evaluation. Few prioritisation frameworks had evidence of use outside of the setting in which they were developed, and there was limited assessment of their utility. The existing evidence suggested that prioritisation frameworks can be used successfully in budget allocation, and have been reported to make prioritisation more robust, systematic, transparent, and collaborative. Conclusion: Our findings reflect the complexity of prioritisation in public health. Development of a framework for the prioritisation of programmes to be evaluated would fill an evidence gap, as would formal assessment of its utility. The process itself should be formal and transparent, with the aim of engaging a diverse group of stakeholders including patient/public representatives.

Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets.

Insulin-like growth factor-1 (IGF-1) is a critical fetal growth hormone that has been proposed as a therapy for intrauterine growth restriction. We previously demonstrated that a 1-week IGF-1 LR3 infusion into fetal sheep reduces in vivo and in vitro insulin secretion suggesting an intrinsic islet defect. Our objective herein was to determine whether this intrinsic islet defect was related to chronicity of exposure. We therefore tested the effects of a 90-min IGF-1 LR3 infusion on fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion from isolated fetal islets. We first infused late gestation fetal sheep (n = 10) with either IGF-1 LR3 (IGF-1) or vehicle control (CON) and measured basal insulin secretion and in vivo GSIS utilizing a hyperglycemic clamp. We then isolated fetal islets immediately following a 90-min IGF-1 or CON in vivo infusion and exposed them to glucose or potassium chloride to measure in vitro insulin secretion (IGF-1, n = 6; CON, n = 6). Fetal plasma insulin concentrations decreased with IGF-1 LR3 infusion (P < 0.05), and insulin concentrations during the hyperglycemic clamp were 66% lower with IGF-1 LR3 infusion compared to CON (P < 0.0001). Insulin secretion in isolated fetal islets was not different based on infusion at the time of islet collection. Therefore, we speculate that while acute IGF-1 LR3 infusion may directly suppress insulin secretion, the fetal ß-cell in vitro retains the ability to recover GSIS. This may have important implications when considering the long-term effects of treatment modalities for fetal growth restriction.

Results and patient satisfaction from an early access infant hearing detection clinic.

INTRODUCTION: National recommendations in the United States specify that all infants with hearing impairment should be identified by 3 months of age. Infants who fail universal newborn hearing screening (UNHS) require follow up testing after hospital discharge. Follow up testing may be difficult to obtain in some communities within the ideal time frame. A rapid access multidisciplinary clinic was established for failed UNHS. The objective of this study is to report outcomes and patient satisfaction from an early access hearing detection clinic. METHODS: Infants that failed UNHS were seen in the multidisciplinary clinic between 1/1/19 and 2/28/22. Patients underwent automated auditory brainstem response (ABR) and distortion product otoacoustic emissions testing and consulted with an otolaryngology nurse practitioner. Failed results were followed by diagnostic ABR. Surveys were administered at the beginning and end of the appointment. RESULTS: In total, 169 infants were seen at a mean age of 8.4 weeks (95%CI 7.5, 9.4). Repeat testing was abnormal in 38 (22.4%). Diagnostic ABR was performed at an average age of 13.7 weeks (n = 34, 95% CI: 10.8, 16.6) and led to a diagnosis of hearing loss in 18 infants. Twenty-seven parents completed surveys at the initial visit. Anxiety level among patients with normal repeat testing (n = 20) decreased from 1.9 to 1.2 (p = .002), while anxiety level among those with abnormal repeat testing (n = 7) was not statistically different before and after (2.1 vs 2.7, p = .2). Satisfaction level was 3.7 ± 0.7 (scored 1-4). All parents reported having a better understanding of their child's hearing problem after the visit. DISCUSSION: This novel nurse practitioner-led early hearing detection clinic enabled timely diagnosis of hearing loss and reassurance to families without hearing loss. Age at hearing loss diagnosis compares favorably to published cohorts.

Economic impact of a rapid, on-demand ADAMTS-13 activity assay for the diagnosis of thrombotic thrombocytopenic purpura.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA), characterized by ADAMTS-13 activity <10%. ADAMTS-13 activity assays are typically performed in reference laboratories with a turnaround time of several days. First-line treatment for TTP, therapeutic plasma exchange (TPE), typically starts while results are pending. The automated, on-demand HemosIL AcuStar ADAMTS-13 Activity assay provides results in under an hour, which could reduce unnecessary TPE use and associated costs. Objectives: To estimate the hospital budget impact in the United States, United Kingdom, and France of using a rapid ADAMTS-13 activity assay. Methods: We compared routine use of a rapid assay in adults with TMA with a scenario in which results take 3 days. Model structure and variables were based on published literature, plus survey and interviews of five clinicians from the three countries. Costs for the ADAMTS-13 activity assays and TPE were included. Results: Model results suggest that if an on-demand, rapid ADAMTS-13 activity assay is used, US, UK, and French hospitals could save $18 million, £1.2 million, and €1.6 million annually, respectively. This equates to $10 788, £3497, and €4700 saved per patient with TMA in the United States, United Kingdom, and France. The model is most sensitive to the exact split of diagnoses of TMA cases, as savings accrue from non-TTP diagnoses. Conclusions: In patients with TMA, use of a rapid, on-demand ADAMTS-13 activity assay such as the HemosIL AcuStar ADAMTS-13 Activity assay has the potential to be cost saving for hospitals.

Fetal Sex Does Not Impact Placental Blood Flow or Placental Amino Acid Transfer in Late Gestation Pregnant Sheep With or Without Placental Insufficiency.

Pregnant sheep have been used to model complications of human pregnancies including placental insufficiency and intrauterine growth restriction. Some of the hallmarks of placental insufficiency are slower uterine and umbilical blood flow rates, impaired placental transport of oxygen and amino acids, and lower fetal arterial concentrations of anabolic growth factors. An impact of fetal sex on these outcomes has not been identified in either human or sheep pregnancies. This is likely because most studies measuring these outcomes have used small numbers of subjects or animals. We undertook a secondary analysis of previously published data generated by our laboratory in late-gestation (gestational age of 133 ± 0 days gestational age) control sheep (n = 29 male fetuses; n = 26 female fetuses; n = 3 sex not recorded) and sheep exposed to elevated ambient temperatures to cause experimental placental insufficiency (n = 23 male fetuses; n = 17 female fetuses; n = 1 sex not recorded). The primary goal was to determine how fetal sex modifies the effect of the experimental insult on outcomes related to placental blood flow, amino acid and oxygen transport, and fetal hormones. Of the 112 outcomes measured, we only found an interaction between fetal sex and experimental insult for the uterine uptake rates of isoleucine, phenylalanine, and arginine. Additionally, most outcomes measured did not show a difference based on fetal sex when adjusting for the impact of placental insufficiency. Exceptions included fetal norepinephrine and cortisol concentrations, which were higher in female compared to male fetuses. For the parameters measured in the current analysis, the impact of fetal sex was not widespread.

The Oldest Co-opted gag Gene of a Human Endogenous Retrovirus Shows Placenta-Specific Expression and Is Upregulated in Diffuse Large B-Cell Lymphomas.

Vertebrate genomes contain endogenous retroviruses (ERVs) that represent remnants of past germline infections by ancient retroviruses. Despite comprising 8% of the human genome, the human ERVs (HERVs) do not encode a replication competent retrovirus. However, some HERV genes have been co-opted to serve host functions, most notably the viral envelope-derived syncytins involved in placentation. Here, we identify the oldest HERV intact gag gene with an open reading frame, gagV1. Its provirus contains an intact env, envV1, and the first open reading frame found in an HERV gag leader, pre-gagV1, which encodes a novel protein. This HERV is linked to a related gag gene, gagV3, and these three genes all show patterns of evolutionary conservation in primates. gagV1 and pre-gagV1 orthologs are present in all simian primate lineages indicating that this HERV entered the germline of the common simian primate ancestor at least 43 Ma, whereas gagV3 is found in Old and New World monkeys. gagV1 and gagV3 have undergone recurrent gene conversion events and positive selection. Expression of gagV1, gagV3, and pre-gagV1 is restricted to the placenta in humans and macaques suggesting co-option for placenta-specific host functions. Transcriptomic analysis of human tumors also found upregulated levels of gagV1 transcripts in diffuse large B-cell lymphomas. These findings suggest that these HERV-V genes may be useful markers for the most common type of non-Hodgkin's lymphoma and that they may have contributed to the successive domestications of env and gag genes in eutherians involved in the ongoing ERV-driven evolution of the placenta.

Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in ß-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.NEW & NOTEWORTHY After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.

IGF-1 infusion to fetal sheep increases organ growth but not by stimulating nutrient transfer to the fetus.

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher (P < 0.05), and insulin was lower in LR3 IGF-1 (P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 (P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation (P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus.NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.

Immunotherapy during the acute SHIV infection of macaques confers long-term suppression of viremia.

We report that combination bNAb immunotherapy initiated on day 3 post-infection (PI) maintained durable CD8+ T cell-mediated suppression of SHIVAD8 viremia and preinoculation levels of CD4+ T cells in 9 of 13 treated monkeys during nearly 6 yr of observation, as assessed by successive CD8+ T cell-depletion experiments. In an extension of that study, two treatment interventions (bNAbs alone or cART plus bNAbs) beginning on week 2 PI were conducted and conferred controller status to 7 of 12 monkeys that was also dependent on control mediated by CD8+ cells. However, the median time to suppression of plasma viremia following intervention on week 2 was markedly delayed (85 wk) compared with combination bNAb immunotherapy initiated on day 3 (39 wk). In both cases, the principal correlate of virus control was the induction of CD8+ T cellular immunity.

Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms.

CDKL5 deficiency disorder (CDD) is a devastating neurodevelopmental disorder characterized by early-onset epilepsy, severe intellectual disability, cortical visual impairment and motor disabilities. Epilepsy is a central feature of CDD, with most patients having intractable seizures, but seizure frequency and severity can vary. Clinical reports demonstrate a diversity in seizure semiology and electrographic features, with no pattern diagnostic of CDD. Although animal models of CDD have shown evidence of hyperexcitability, spontaneous seizures have not been previously reported. Here, we present the first systematic study of spontaneous seizures in mouse models of CDD. Epileptic spasms, the most frequent and persistent seizure type in CDD patients, were recapitulated in two mouse models of CDD carrying heterozygous mutations, Cdkl5R59X and Cdkl5KO. Spasm-like events were present in a significant proportion of aged heterozygous female mice carrying either of the two Cdkl5 mutations with significant variability in seizure burden. Electrographically, spasms were most frequently associated with generalized slow-wave activity and tended to occur in clusters during sleep. CDD mice also showed interictal and background abnormalities, characterized by high-amplitude spiking and altered power in multiple frequency bands. These data demonstrate that aged female heterozygous Cdkl5 mice recapitulate multiple features of epilepsy in CDD and can serve to complement existing models of epileptic spasms in future mechanistic and translational studies.

Neonates Hospitalized with Community-Acquired SARS-CoV-2 in a Colorado Neonatal Intensive Care Unit.

IMPORTANCE: The novel coronavirus 2019 (SARS-CoV-2) has been well described in adults. Further, the impact on older children and during the perinatal time is becoming better studied. As community spread increases, it is important to recognize that neonates are vulnerable to community spread as well. The impact that community-acquired SARS-CoV-2 has in the neonatal time period is unclear, as this population has unique immunity considerations. OBJECTIVE: To report on a case series of SARS-CoV-2 in neonates through community acquisition in the USA. DESIGN: This is an early retrospective study of patients admitted to the Neonatal Intensive Care Unit (NICU) identified as having SAR-CoV-2 through positive real-time polymerase chain reaction assay of nasopharyngeal swabs. FINDINGS: Three patients who required admission to the NICU between the ages of 17 and 33 days old were identified. All 3 had ill contacts in the home or had been to the pediatrician and presented with mild to moderate symptoms including fever, rhinorrhea, and hypoxia, requiring supplemental oxygen during their hospital stay. One patient was admitted with neutropenia, and the other 2 patients became neutropenic during hospitalization. None of the patients had meningitis or multiorgan failure. CONCLUSIONS AND RELEVANCE: Infants with community-acquired SARS-CoV-2 may require hospitalization due to rule-out sepsis guidelines if found to have fever and/or hypoxia. Caregivers of neonates should exercise recommended guidelines before contact with neonates to limit community spread of SARS-CoV-2 to this potentially vulnerable population, including isolation, particularly as asymptomatic cases become prevalent.

Online patient feedback is positive, but not used effectively.

The studyPowell J, Atherton H, Williams V, et al. Using online patient feedback to improve NHS services: the INQUIRE multimethod study. Health Serv Deliv Res 2019;7:38.This project was funded by the NIHR Health Services and Delivery Research programme (project number HS&DR 14/04/48).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000861/online-patient-feedback-is-mostly-positive-but-is-not-being-used-effectively.

Clinicians prescribe antibiotics for childhood respiratory tract infection based on assessment, rather than parental expectation.

The studyCabral C, Horwood J, Symonds J, et al. Understanding the influence of parent-clinician communication on antibiotic prescribing for children with respiratory tract infections in primary care: a qualitative observational study using a conversation analysis approach. BMC Fam Pract 2019;20:102.This project was funded by the NIHR School for Primary Care Research Programme (project number SPCR204).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000829/gps-assessment-not-parental-expectation-drives-antibiotic-prescribing.

Identification of Potential Barriers to Timely Access to Pediatric Hearing Aids.

Importance: Despite various barriers identified to early pediatric access to cochlear implantation, barriers to timely access to pediatric hearing aids are not well characterized. Objective: To identify socioeconomic, demographic, and clinical factors that may be associated with pediatric access to hearing aids. Design, Setting, and Participants: This retrospective cohort study included 90 patients aged 1 to 15 years who were referred for auditory brainstem response (ABR) testing and evaluation for hearing aids at a single tertiary care academic medical center from March 2004 to July 2018. Children who did not receive both ABR testing and hearing aids at the same center were excluded from analysis. Main Outcomes and Measures: Associations of insurance type (private vs public), race/ethnicity (white vs other), primary language (English vs other), cause of hearing loss (complex vs not complex), zip code, hearing aid manufacturer, and severity of hearing loss (in decibels) with the duration of intervals from newborn hearing screening to ABR testing, from ABR testing to ordering of hearing aids, and from ABR testing to dispensing of hearing aids. Results: Of the 90 patients, mean (SD) age was 5.6 (3.7) years, 56% were female, and 77 (86%) were non-Hispanic. Results of χ2 tests indicated significant assocations existed between public insurance and race/ethnicity and between public insurance and primary language other than English. Variables associated with the interval from newborn hearing screening to ABR testing included insurance type (mean difference, 7.4 months; 95% CI, 2.6-12.2 months) and race/ethnicity (mean difference, 6.9 months; 95% CI, 2.7-11.1 months). Increased delays between birth and a child's first ABR test were associated with public insurance (mean difference, 6.0 months; 95% CI, 1.8-10.2 months) and race/ethnicity other than white (mean difference, 6.0 months; 95% CI, 2.3-9.7 months). The mean time from birth to initial ABR testing was a mean of 6 months longer for patients from non-English-speaking families than for those from English-speaking families (mean [SD] interval, 14.9 [16.3] months vs 9.0 [8.5] months), although the difference was not statistically significant. Severity of hearing loss was associated with a decrease in the interval from ABR testing to ordering of hearing aids after accounting for other potential barriers (odds ratio, 0.6; 95% CI, 0.4-0.9). Zip code and complexity of the child's medical condition did not appear to be associated with timely access to pediatric hearing aids. Conclusions and Relevance: This study's findings suggest that insurance type, race/ethnicity, and primary language may be barriers associated with pediatric access to hearing aids, with the greatest difference observed in time to initial ABR testing. Clinical severity of hearing loss appeared to be associated with a significant decrease in time from ABR testing to ordering of hearing aids. Greater efforts to assist parents with ABR testing and coordination of follow-up may help improve access for other at-risk children.

Evolution of the rodent Trim5 cluster is marked by divergent paralogous expansions and independent acquisitions of TrimCyp fusions.

Evolution of cellular innate immune genes in response to viral threats represents a rich area of study for understanding complex events that shape mammalian genomes. One of these genes, TRIM5, is a retroviral restriction factor that mediates a post-entry block to infection. Previous studies on the genomic cluster that contains TRIM5 identified different patterns of gene amplification and the independent birth of CypA gene fusions in various primate species. However, the evolution of Trim5 in the largest order of mammals, Rodentia, remains poorly characterized. Here, we present an expansive phylogenetic and genomic analysis of the Trim5 cluster in rodents. Our findings reveal substantial evolutionary changes including gene amplifications, rearrangements, loss and fusion. We describe the first independent evolution of TrimCyp fusion genes in rodents. We show that the TrimCyp gene found in some Peromyscus species was acquired about 2 million years ago. When ectopically expressed, the P. maniculatus TRIMCyp shows anti-retroviral activity that is reversed by cyclosporine, but it does not activate Nf-κB or AP-1 promoters, unlike the primate TRIMCyps. These results describe a complex pattern of differential gene amplification in the Trim5 cluster of rodents and identify the first functional TrimCyp fusion gene outside of primates and tree shrews.

Modelling the effect of the introduction of antenatal screening for group B Streptococcus (GBS) carriage in the UK.

OBJECTIVES: To estimate the potential impact of the addition of culture-based screening for group B streptococcus (GBS) carriage in pregnancy to a risk-based prevention policy in the UK. We aimed to establish agreement within a multidisciplinary group of key stakeholders on the model input parameters. DESIGN: Deterministic model using a consensus approach for the selection of input parameters. SETTING AND PARTICIPANTS: A theoretical annual cohort of 711 999 live births in the UK (excluding births by elective caesarean section). INTERVENTIONS: Culture-based screening for GBS at 35-37 weeks of pregnancy added to the recommended risk-based prevention policy in place on the date of modelling. OUTCOME MEASURES: Outcomes assessed included use of intrapartum antibiotic prophylaxis (IAP), early onset GBS (EOGBS), EOGBS mortality, severe EOGBS-related morbidity and maternal penicillin anaphylaxis. RESULTS: With no prophylaxis strategy, the model estimated that there would be 421 cases of culture positive EOGBS in a year (0.59/1000 live births). In the risk-based prophylaxis scenario, 30 666 women were estimated to receive IAP and 70 cases of EOGBS were prevented. Addition of screening resulted in a further 96 260 women receiving IAP and the prevention of an additional 52 to 57 cases of EOGBS. This resulted in the prevention of three EOGBS deaths and four cases of severe disability. With screening, an additional 1675 to 1854 women receive IAP to prevent one EOGBS case and 24 065 to 32 087 receive IAP to prevent one EOGBS death. CONCLUSIONS: The evidence base available for a broad range of model input parameters was limited, leading to uncertainty in the estimates produced by the model. Where data was limited, the model input parameters were agreed with the multidisciplinary stakeholder group, the first time this has been done to our knowledge. The main impact of screening is likely to be on the large group of low-risk women where the clinical impact of EOGBS tends to be less severe. This model suggests that the reduction in mortality and severe disability due to EOGBS with antenatal GBS screening is likely to be very limited, with a high rate of overdetection and overuse of antibiotics.

C reactive protein testing in general practice safely reduces antibiotic use for flare-ups of COPD.

The studyButler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med 2019;381:111-20.This research was funded by the NIHR Technology Assessment Programme (project number 12/33/12). The testing machines used in the study were loaned to researchers by the manufacturer, who also provided training on their use. The manufacturer had no other role in any part of the trial.To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000820/crp-testing-safely-reduces-antibiotic-use-for-copd-flare-ups.

Partial knee replacement could be first choice for some patients with osteoarthritis.

The studyBeard D, Davies L, Cook J, et al. The clinical and cost-effectiveness of total versus partial knee replacement in patients with medial compartment osteoarthritis (TOPKAT): 5-year outcomes of a randomised controlled trial. Lancet 2019;394:746-56.The study was funded by the NIHR Health Technology Assessment Programme (project number 08/14/08).To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000824/partial-knee-replacement-could-be-first-choice-in-some-patients.