Differential effects of high-fat diet on endocrine, metabolic and depressive-like behaviors in male and female rats.

The complications of obesity extend beyond the periphery to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. Preclinical studies support this concept, including studies that have examined the effects of a high-fat diet (HFD) on depressive-like behaviors. Although women are approximately two-fold more likely to develop depressive illness compared to men, most preclinical studies have focused on the effects of HFD in male rodents. Accordingly, the goal of this study was to examine depressive-like behaviors in male and female rats provided access to a HFD. In agreement with prior studies, male and female rats provided a HFD segregate into an obesity phenotype (i.e., diet-induced obesity; DIO) or a diet resistant (DR) phenotype. Upon confirmation of the DR and DIO phenotypes, behavioral assays were performed in control chow, DR, and DIO rats. In the sucrose preference test, male DIO rats exhibited significant decreases in sucrose consumption (i.e., anhedonia) compared to male DR and male control rats. In the forced swim test (FST), male DIO rats exhibited increases in immobility and decreases in climbing behaviors in the pre-test sessions. Interestingly, male DR rats exhibited these same changes in both the pre-test and test sessions of the FST, suggesting that consumption of a HFD, even in the absence of the development of an obesity phenotype, has behavioral consequences. Female rats did not exhibit differences in sucrose preference, but female DIO rats exhibited increases in immobility exclusively in the test session of the FST, behavioral changes that were not affected by the stage of the estrous cycle. Collectively, these studies demonstrate that access to a HFD elicits different behavioral outcomes in male and female rats.

Post-acute COVID-19 complications in UK doctors: results of a cross-sectional survey.

BACKGROUND: As a consequence of their occupation, doctors and other healthcare workers were at higher risk of contracting coronavirus disease 2019 (COVID-19), and more likely to experience severe disease compared to the general population. However, systematic information on post-acute COVID complications in doctors is very limited. AIMS: This study aimed to determine the symptoms, perceived determinants, health and occupational impact, and consequent needs relating to post-acute COVID complications in UK doctors. METHODS: An online cross-sectional survey was distributed to UK doctors self-identifying as having Long COVID or other post-acute COVID complications. RESULTS: Of 795 responses, 603 fulfilled the inclusion criteria of being a UK-based medical doctor experiencing one or more post-acute COVID complications. Twenty-eight per cent reported a lack of adequate Respiratory Protective Equipment at the time of contracting COVID-19. Eighteen per cent of eligible respondents reported that they had been unable to return to work since acquiring COVID. CONCLUSIONS: Post-acute COVID (Long COVID) in UK doctors is a substantial burden for respondents to our questionnaire. The results indicated that insufficient respiratory protection could have contributed to occupational disease, with COVID-19 being contracted in the workplace, and resultant post-COVID complications. Although it may be too late to address the perceived determinants of inadequate protection for those already suffering with Long COVID, more investment is needed in rehabilitation and support of those afflicted.

Brain and Behavioral Evidence for Reweighting of Vestibular Inputs with Long-Duration Spaceflight.

Microgravity alters vestibular signaling. In-flight adaptation to altered vestibular afferents is reflected in post-spaceflight aftereffects, evidenced by declines in vestibularly mediated behaviors (e.g., walking/standing balance), until readaptation to Earth's 1G environment occurs. Here we examine how spaceflight affects neural processing of applied vestibular stimulation. We used fMRI to measure brain activity in response to vestibular stimulation in 15 astronauts pre- and post-spaceflight. We also measured vestibularly-mediated behaviors, including balance, mobility, and rod-and-frame test performance. Data were collected twice preflight and four times postflight. As expected, vestibular stimulation at the preflight sessions elicited activation of the parietal opercular area ("vestibular cortex") and deactivation of somatosensory and visual cortices. Pre- to postflight, we found widespread reductions in this somatosensory and visual cortical deactivation, supporting sensory compensation and reweighting with spaceflight. These pre- to postflight changes in brain activity correlated with changes in eyes closed standing balance, and greater pre- to postflight reductions in deactivation of the visual cortices associated with less postflight balance decline. The observed brain changes recovered to baseline values by 3 months postflight. Together, these findings provide evidence for sensory reweighting and adaptive cortical neuroplasticity with spaceflight. These results have implications for better understanding compensation and adaptation to vestibular functional disruption.

Commercial weight management programmes for patients living with overweight or obesity prior to elective orthopaedic surgery: an evidence review.

BACKGROUND: Increased body mass index is associated with increased operative risk during elective joint replacement surgery. Commercial weight management programmes are designed to achieve weight loss. It is not known whether commercial weight management programmes are effective at achieving weight loss in patients awaiting planned hip or knee replacement surgery, or whether achieving significant planned weight loss prior to surgery is associated with changes in surgical outcome. METHODS: A systematic literature search of seven databases was conducted. Reference lists and grey literature were searched, including commercial weight management programme and medical association websites. Four relevant primary interventional studies were identified. RESULTS: There is weak, low-quality evidence from four small studies, of which three demonstrated that commercial weight management programmes initiated between 3 and 6 months prior to elective joint replacement surgery are associated with a statistically significant weight loss and body mass index reduction. There is a weak evidence from two studies that peri- and post-operative complications are similar between control and commercial weight management programme groups. CONCLUSION: There is a paucity of studies investigating commercial weight management programmes aiming to reduce weight in patients living with overweight or obesity awaiting total joint replacement. Further, high-quality research is urgently needed.

Trends in sexually transmitted infection screening during COVID-19 and missed cases among adolescents.

OBJECTIVE: The COVID-19 pandemic disrupted sexual health services for young people, with potential consequences of decreasing preventive screening and increasing undiagnosed sexually transmitted infections (STIs). This study aimed to assess trends in asymptomatic screening among patients receiving STI testing and to estimate the number of STI cases that were missed during the early months of the pandemic. STUDY DESIGN: A cross-sectional study of electronic health records for chlamydia, gonorrhea, and trichomonas testing encounters from six pediatric primary care clinics in Philadelphia, July 2014 to November 2020. METHODS: A total of 35,548 testing encounters were analyzed, including 2958 during the pandemic. We assessed whether testing at each encounter was performed as asymptomatic screening, risk-based testing, or symptomatic testing. We evaluated screening trends over time and estimated the number of missed STI cases during the pandemic. RESULTS: The mean monthly testing encounters decreased from 479 per month prepandemic to 329 per month during the pandemic. The percent of tests performed as asymptomatic screening dropped from 72.5% prepandemic to a nadir of 54.5% in April 2020. We estimate that this decrease in asymptomatic screening would represent 159 missed cases (23.8% of expected cases) based on patient volume from the previous year. CONCLUSIONS: During the pandemic, the total volume of STI testing encounters and the proportion of tests performed as asymptomatic screening decreased, potentially resulting in missed diagnoses. Undiagnosed STIs can result in severe sequelae and contribute to community transmission of STIs. Efforts are needed to re-establish and sustain access to STI services for adolescents in response to disruptions caused by the pandemic.

Quantifying changes in ultrasound tongue-shape pre- and post-intervention in speakers with submucous cleft palate: an illustrative case study.

Ultrasound Tongue Imaging is increasingly used during assessment and treatment of speech sound disorders. Recent literature has shown that ultrasound is also useful for the quantitative analysis of a wide range of speech errors. So far, the compensatory articulations of speakers with cleft palate have only been analysed qualitatively. This study provides a pilot quantitative ultrasound analysis, drawing on longitudinal intervention data from a child with submucous cleft palate. Two key ultrasound metrics were used: 1. articulatory t-tests were used to compare tongue-shapes for perceptually collapsed phonemes on a radial measurement grid and 2. the Mean Radial Difference was reported to quantify the extent to which the two tongue shapes differ, overall. This articulatory analysis supplemented impressionistic phonetic transcriptions and identified covert contrasts. Articulatory errors identified in this study using ultrasound were in line with errors identified in the speech of children with cleft palate in previous literature. While compensatory error patterns commonly found in speakers with cleft palate have been argued to facilitate functional phonological development, the nature of our findings suggest that the compensatory articulations uncovered are articulatory in nature.

An agenda for research and action toward diverse and just futures for life on Earth.

Decades of research and policy interventions on biodiversity have insufficiently addressed the dual issues of biodiversity degradation and social justice. New approaches are therefore needed. We devised a research and action agenda that calls for a collective task of revisiting biodiversity toward the goal of sustaining diverse and just futures for life on Earth. Revisiting biodiversity involves critically reflecting on past and present research, policy, and practice concerning biodiversity to inspire creative thinking about the future. The agenda was developed through a 2-year dialogue process that involved close to 300 experts from diverse disciplines and locations. This process was informed by social science insights that show biodiversity research and action is underpinned by choices about how problems are conceptualized. Recognizing knowledge, action, and ethics as inseparable, we synthesized a set of principles that help navigate the task of revisiting biodiversity. The agenda articulates 4 thematic areas for future research. First, researchers need to revisit biodiversity narratives by challenging conceptualizations that exclude diversity and entrench the separation of humans, cultures, economies, and societies from nature. Second, researchers should focus on the relationships between the Anthropocene, biodiversity, and culture by considering humanity and biodiversity as tied together in specific contexts. Third, researchers should focus on nature and economies by better accounting for the interacting structures of economic and financial systems as core drivers of biodiversity loss. Finally, researchers should enable transformative biodiversity research and action by reconfiguring relationships between human and nonhuman communities in and through science, policy, and practice. Revisiting biodiversity necessitates a renewed focus on dialogue among biodiversity communities and beyond that critically reflects on the past to channel research and action toward fostering just and diverse futures for human and nonhuman life on Earth.

Una Agenda para la Investigación y la Acción hacia un Futuro Diverso y Justo para la Vida sobre la Tierra Resumen Las décadas de investigación e intervenciones políticas sobre la biodiversidad han tratado significativamente los temas de la degradación de la biodiversidad y la justicia social. Debido a esto, se requieren nuevas estrategias. Diseñamos una agenda de investigación y acción que llama a la labor colectiva de revisar la biodiversidad hacia el objetivo de sustentar un futuro diverso y justo para la vida sobre la Tierra. Cuando se revisa la biodiversidad, se requiere de una reflexión crítica sobre las investigaciones, políticas y prácticas presentes y pasadas sobre la biodiversidad para inspirar un pensamiento creativo acerca del futuro. Desarrollamos la agenda por medio de un proceso de diálogo de dos años que involucró a casi 300 expertos de diversas disciplinas y localidades. Este proceso estuvo orientado por el conocimiento de las ciencias sociales que muestra cómo la investigación y la acción para la biodiversidad están sostenidas por las opciones de cómo están conceptualizados los problemas. Reconocimos al conocimiento, la acción y la ética como inseparables y sintetizamos un conjunto de principios que ayuda a navegar la labor de revisar la biodiversidad. La agenda articula cuatro áreas temáticas para la investigación en el futuro. Primero, los investigadores necesitan revisar las narrativas de la biodiversidad mediante el cuestionamiento de las conceptualizaciones que excluyen a la diversidad y consolidan la separación entre humanos, culturas, economías y sociedades y la naturaleza. Segundo, los investigadores deberían enfocarse en las relaciones entre el antropoceno, la biodiversidad y la cultura al considerar a la humanidad y la biodiversidad como interconectadas en contextos específicos. Tercero, los investigadores deberían enfocarse en la naturaleza y las economías al tener en mejor cuenta la interacción de las estructuras de los sistemas económico y financiero como conductores nucleares de la pérdida de la biodiversidad. Finalmente, los investigadores deberían permitir la investigación y acción transformadoras de la biodiversidad al reconfigurar las relaciones entre las comunidades humanas y no humanas dentro y a través de la ciencia, la política y la práctica. La revisión de la biodiversidad necesita de un enfoque renovado sobre el diálogo entre las comunidades de la biodiversidad y más allá, que reflexione críticamente sobre el pasado para canalizar a la investigación y acción hacia el fomento del futuro justo y diverso para la vida humana y no humana sobre la Tierra.

Risk of recurrent stillbirth: a cohort study.

OBJECTIVES: To evaluate the recurrence risk of stillbirth. DESIGN: Retrospective cohort study. SETTING AND POPULATION: All births 1992-2017, Alberta, Canada. METHODS: Retrospective cohort study. MAIN OUTCOME MEASURES: Stillbirth was defined as the death in utero of a fetus with gestational age ≥20 weeks or weighing ≥500 g. Stillbirths were further subdivided into those occurring before labour and those in labour. RESULTS: We identified 744 897 births from 308 478 women. Of these, 3698 women experienced a stillbirth and, of these, 97.7%, experienced only one. For women with a small-for-gestational- age stillbirth in the first birth, their risk of a subsequent antepartum stillbirth was increased substantially: 4.09%, relative risk (RR) 10.39, 95% CI 5.81-18.59. For women with a first birth appropriate-for-gestational-age stillbirth with no risk factors such as pregnancy induced hypertension, the risk with pre-existing diabetes mellitus or hypertension was also increased but to a much lesser degree (RR 2.46, 95% CI 1.23-4.91). For women who had experienced a first birth intrapartum stillbirth, the risk of another intrapartum stillbirth was very high (3.59%, RR 36.50, 95% CI 20.17-66.05). Most of these births also occurred prior to 24 weeks' gestation: 83% (10/12). CONCLUSIONS: The risk of recurrent antepartum stillbirth is low. The increase in risk in instances where the antepartum stillbirth was not growth-restricted is not clinically meaningful. Given the very low risk in any given gestational week, fetal surveillance is unlikely to be effective and may lead to unnecessary interventions. Intrapartum stillbirth has a very high recurrence risk but may not be preventable. TWEETABLE ABSTRACT: Stillbirth recurrence is rare.

Severe neonatal hypoglycaemia and intrapartum glycaemic control in pregnancies complicated by type 1, type 2 and gestational diabetes.

AIMS: To determine if in-target intrapartum glucose control is associated with neonatal hypoglycaemia in women with type 1, type 2 or gestational diabetes. METHODS: This was a retrospective cohort study of pregnant women with diabetes and their neonates. The primary exposure was in-target glucose control, defined as all capillary glucose values within the range 3.5-6.5 mmol/l during the intrapartum period. The primary outcome, neonatal hypoglycaemia, was defined as treatment with intravenous dextrose therapy. Multiple logistic regression was used to examine the association between maternal intrapartum glycaemic control and neonatal hypoglycaemia, adjusting for covariates. RESULTS: Intrapartum glucose testing was available for 157 (86.3%), 267 (76.3%) and 3256 (52.4%) women with type 1, type 2 and gestational diabetes, respectively. In the univariate analysis, in-target glycaemic control was significantly associated with neonatal hypoglycaemia in women with gestational diabetes, but not in women with type 1 or 2 diabetes. However, after adjustment for important neonatal factors (large for gestational age, preterm delivery and infant sex), intrapartum in-target glycaemic control was not significantly associated with neonatal hypoglycaemia in women regardless of diabetes type [adjusted odds ratios 0.4 (95% CI 0.1, 1.4), 0.7 (95% CI 0.3, 1.3) and 0.7 (95% CI 0.5, 1.0) for women with type 1, type 2 and gestational diabetes, respectively]. CONCLUSIONS: There was no significant association between in-target glycaemic control and neonatal hypoglycaemia after adjustment for neonatal factors. Given the high risk of maternal hypoglycaemia and the resources required, future trials should consider whether more relaxed intrapartum glycaemic targets may be safer and yield similar neonatal outcomes.

Pharmacological treatment initiation for type 2 diabetes in Australia: are the guidelines being followed?

AIM: To determine the patterns and predictors of pharmacological treatment initiation for type 2 diabetes and whether treatment initiation is consistent with Australian clinical practice guidelines that recommend metformin monotherapy. METHODS: Individuals aged 40-99 years initiating a non-insulin type 2 diabetes medication between July 2013 and February 2018 were identified from a 10% random national sample of pharmacy dispensing data. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the predictors of initiating sulfonylurea monotherapy, non-guideline monotherapy and combination therapy compared with metformin monotherapy. Predictors included age, sex, initiation year and comorbidities determined using the Rx-Risk comorbidity index. RESULTS: Of the 47 860 initiators, [47% women, mean age 60.7 (sd 12.1) years], 85.8%, 4.6%, 1.9% and 7.7% received metformin monotherapy, sulfonylurea monotherapy, non-guideline monotherapy and combination therapy, respectively. Increasing age was associated with increasing odds of initiating sulfonylurea monotherapy and non-guideline monotherapy. Combination therapy initiation was less likely in women (OR 0.74, 95% CI 0.69-0.79) and people with more comorbidities (e.g. OR 0.36, 95% CI 0.29-0.44 for seven or more comorbidities vs. no comorbidities) but more likely in congestive heart failure (OR 1.42, 95% CI 1.22-1.65), cerebrovascular disease (OR 1.50, 95% CI 1.32-1.69) and dyslipidaemia (OR 1.29, 95% CI 1.19-1.40). CONCLUSION: Treatment initiation in Australia is largely consistent with clinical practice guidelines, with 86% of individuals initiating metformin monotherapy. Initiation on combination therapy was more common in men and in those with fewer comorbidities.

The Effect of Intramuscular 17α-Hydroxyprogesterone in Women Screened for Shortened Cervical Length.

OBJECTIVE: This article assesses the effect of weekly intramuscular 17α-hydroxyprogesterone caproate (17P) on midtrimester cervical length (CL) in patients with prior spontaneous preterm birth. STUDY DESIGN: Retrospective cohort study of all singletons that underwent CL screening at a single institution from 2011 to 2016. The timing of 17P exposure was assessed. The primary outcome was shortest midtrimester CL. Secondary outcomes included gestational age at delivery, rate of short cervix, cerclage, preterm labor admission, and preterm premature rupture of the membranes (PROM). Multivariable regression analysis was used to model the relationship between 17P exposure and shortest CL, controlling for selected covariates. RESULTS: Of 409 women who underwent screening, 211 received and 198 did not receive 17P prior to the last CL. Rates of short cervix and cerclage were similar between groups. After adjusting for covariates, the shortest CL was significantly shorter in the 17P group. In a secondary analysis, those who received any 17P (n = 293) versus those who did not (n = 116) had higher rates of preterm PROM, preterm labor admission, and cerclage. After controlling for covariates, gestational age at delivery was significantly lower in those receiving 17P. CONCLUSION: In high-risk patients undergoing CL screening for ultrasound-indicated cerclage, 17P did not prevent midtrimester cervical shortening or prolong gestation.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Understanding the core principles of a 'modified ketogenic diet': a UK and Ireland perspective.

BACKGROUND: Many centres across the UK and Ireland anecdotally report using a 'modified ketogenic diet' (MKD) as a treatment for refractory epilepsy. Although a MKD is within the spectrum of ketogenic diets (KDs), there is little literature reporting upon its definition, use or clinical effectiveness. We aimed to understand the core principles of MKD practice and to assess whether and how the MKD differs from other KD protocols. METHODS: An online survey, designed by a consensus group of ketogenic dietitians, was circulated to 39 KD centres across the UK and Ireland. It consisted of 35 questions regarding dietetic practice when providing MKD. RESULTS: Eighteen centres completed the questionnaire: 13 paediatric, three adult and two combined centres. All dietitians based MKD 'prescriptions' on estimated total energy requirements. The average macronutrient profile was 75% fat and 5% carbohydrate, with protein ad libitum. Carbohydrate and fat targets were implemented via weighed portions (carbohydrate lists n = 18; fat lists n = 13) and 'household measures' (carbohydrate lists n = 2; fat lists n = 3). Of the centres, 94% (n = 17) adjusted macronutrients over time; these decisions were based on ketone levels and seizures in most cases (83%; n = 14). Ketogenic nutritional products available on prescription were used by 10 centres (56%) when initiating and by all centres when 'fine-tuning' the MKD. CONCLUSIONS: A modified ketogenic diet in the UK and Ireland is a hybrid KD, adopting principles from other established KD protocols and defining new elements unique to the MKD. Further research into the clinical and cost-effectiveness of MKD would be of benefit.

Deterioration of visuospatial associative memory following a first psychotic episode: a long-term follow-up study.

BACKGROUND: Cognitive deficits are a core feature of schizophrenia, and impairments in most domains are thought to be stable over the course of the illness. However, cross-sectional evidence indicates that some areas of cognition, such as visuospatial associative memory, may be preserved in the early stages of psychosis, but become impaired in later established illness stages. This longitudinal study investigated change in visuospatial and verbal associative memory following psychosis onset. METHODS: In total 95 first-episode psychosis (FEP) patients and 63 healthy controls (HC) were assessed on neuropsychological tests at baseline, with 38 FEP and 22 HCs returning for follow-up assessment at 5-11 years. Visuospatial associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery Visuospatial Paired-Associate Learning task, and verbal associative memory was assessed using Verbal Paired Associates subtest of the Wechsler Memory Scale - Revised. RESULTS: Visuospatial and verbal associative memory at baseline did not differ significantly between FEP patients and HCs. However, over follow-up, visuospatial associative memory deteriorated significantly for the FEP group, relative to healthy individuals. Conversely, verbal associative memory improved to a similar degree observed in HCs. In the FEP cohort, visuospatial (but not verbal) associative memory ability at baseline was associated with functional outcome at follow-up. CONCLUSIONS: Areas of cognition that develop prior to psychosis onset, such as visuospatial and verbal associative memory, may be preserved early in the illness. Later deterioration in visuospatial memory ability may relate to progressive structural and functional brain abnormalities that occurs following psychosis onset.

Intrapartum glycaemic control and neonatal hypoglycaemia in pregnancies complicated by diabetes: a systematic review.

AIMS: To examine whether, in neonates of mothers with Type 1, Type 2 and gestational diabetes, in-target intrapartum glycaemic control was associated with a lower risk of neonatal hypoglycaemia compared with out-of-target glycaemic control. METHODS: We searched PubMed and EMBASE for all available publications, regardless of year, based on a published protocol (PROSPERO CRD42016052439). Studies were excluded if they did not report original data or were animal studies. Data were extracted from published reports in duplicate using a prespecified data extraction form. The main outcome of interest was the association between in-target intrapartum glycaemic control and neonatal hypoglycaemia. RESULTS: We screened 2846 records for potential study inclusion; 23 studies, including approximately 2835 women with diabetes, were included in the systematic review. Only two of those studies specifically examined in-target vs out-of-target intrapartum glycaemic control. Of the studies included, six showed a relationship between intrapartum glucose and neonatal hypoglycaemia, five others showed a relationship in at least one of the analyses performed and 12 did not find a significant relationship. Only one study was identified as having a low risk of bias. CONCLUSIONS: There is a paucity of high-quality data supporting the association of glucose during labour and delivery with neonatal hypoglycaemia in pregnancies complicated by diabetes. Further studies are required to examine the impact of tight glycaemic targets in labour.

Lithium suppression of tau induces brain iron accumulation and neurodegeneration.

Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer's disease), and may explain lithium-associated motor symptoms in susceptible patients.

The Utility of Repeat Midtrimester Anatomy Ultrasound for Anomaly Detection.

INTRODUCTION: Although guidelines recommend repeat ultrasound in the setting of an incomplete fetal anatomic survey, the clinical utility of this practice has not been established. As such, we aimed to assess the yield of repeat ultrasound for anomaly detection following an incomplete survey. MATERIALS AND METHODS: This is a retrospective cohort study of all singletons who underwent a midtrimester anatomic ultrasound at University of Alabama at Birmingham (UAB) from 2006 to 2014. Patients with an incomplete ultrasound underwent repeat examinations until completion. The population was divided into cohorts FIRST, SECOND, and THIRD, corresponding to the ultrasound at which the exam was deemed complete. Each detected anomaly was tallied. The number of ultrasounds needed to detect an anomaly was then assessed per group. RESULTS: Of 15,768 ultrasounds performed on 13,740 patients, 11,828 exams were completed on first attempt; 1,796 patients required a second, while 116 patients required a third scan or more. We detected 324 anomalies; 93.8% in FIRST, 5.9% in SECOND, and 0.3% in THIRD. The number of scans needed to detect an anomaly was 39, 189, and 348 for FIRST, SECOND, and THIRD, respectively. CONCLUSION: Over 90% of anomalies are detected on the initial fetal anatomic survey. The incremental diagnostic yield then decreases, requiring appreciably more repeat scans to detect one anomaly.

Systemic inflammation in acute intermittent porphyria: a case-control study.

This study aimed to examine whether acute intermittent porphyria (AIP) is associated with systemic inflammation and whether the inflammation correlates with disease activity. A case-control study with 50 AIP cases and age-, sex- and place of residence-matched controls was performed. Plasma cytokines, insulin and C-peptide were analysed after an overnight fast using multiplex assay. Long pentraxin-3 (PTX3) and complement activation products (C3bc and TCC) were analysed using enzyme-linked immunosorbent assay (ELISA). Urine porphobilinogen ratio (U-PBG, µmol/mmol creatinine), haematological and biochemical tests were performed using routine methods. Questionnaires were used to register AIP symptoms, medication and other diseases. All 27 cytokines, chemokines and growth factors investigated were increased significantly in symptomatic AIP cases compared with controls (P < 0·0004). Hierarchical cluster analyses revealed a cluster with high visfatin levels and several highly expressed cytokines including interleukin (IL)-17, suggesting a T helper type 17 (Th17) inflammatory response in a group of AIP cases. C3bc (P = 0·002) and serum immunoglobulin (Ig)G levels (P = 0·03) were increased significantly in cases with AIP. The U-PBG ratio correlated positively with PTX3 (r = 0·38, P = 0·006), and with terminal complement complex (TCC) levels (r = 0·33, P = 0·02). PTX3 was a significant predictor of the biochemical disease activity marker U-PBG in AIP cases after adjustment for potential confounders in multiple linear regression analyses (P = 0·032). Prealbumin, C-peptide, insulin and kidney function were all decreased in the symptomatic AIP cases, but not in the asymptomatic cases. These results indicate that AIP is associated with systemic inflammation. Decreased C-peptide levels in symptomatic AIP cases indicate that reduced insulin release is associated with enhanced disease activity and reduced kidney function.

Cannabis-induced attenuated psychotic symptoms: implications for prognosis in young people at ultra-high risk for psychosis.

BACKGROUND: Cannabis use shows a robust dose-dependent relationship with psychosis risk among the general population. Despite this, it has been difficult to link cannabis use with risk for transitioning to a psychotic disorder among individuals at ultra-high risk (UHR) for psychosis. The present study examined UHR transition risk as a function of cannabis use characteristics which vary substantially between individuals including age of first use, cannabis abuse severity and a history of cannabis-induced attenuated psychotic symptoms (APS). METHOD: Participants were 190 UHR individuals (76 males) recruited at entry to treatment between 2000 and 2006. They completed a comprehensive baseline assessment including a survey of cannabis use characteristics during the period of heaviest use. Outcome was transition to a psychotic disorder, with mean time to follow-up of 5.0 years (range 2.4-8.7 years). RESULTS: A history of cannabis abuse was reported in 58% of the sample. Of these, 26% reported a history of cannabis-induced APS. These individuals were 4.90 (95% confidence interval 1.93-12.44) times more likely to transition to a psychotic disorder (p = 0.001). Greater severity of cannabis abuse also predicted transition to psychosis (p = 0.036). However, this effect was mediated by higher abuse severity among individuals with a history of cannabis-induced APS. CONCLUSIONS: Findings suggest that cannabis use poses risk in a subpopulation of UHR individuals who manifest cannabis-induced APS. Whether this reflects underlying genetic vulnerability requires further study. Nevertheless, findings reveal an important early marker of risk with potentially significant prognostic utility for UHR individuals.

Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA.

BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.