Anatomical and physiological diagnostic discrepancies in fetuses with single-ventricle congenital heart disease in a contemporary cohort.

OBJECTIVE: Image quality of fetal echocardiography (FE) has improved in the recent era, but few recent studies have reported the accuracy of FE, specifically in single ventricle (SV) congenital heart disease (CHD). This study aimed to assess the ability of FE to correctly predict SV-CHD postnatal anatomy and physiology in a contemporary cohort. METHODS: The contemporary clinical reports of patients with SV-CHD, in which FE was performed between July 2017 and July 2021, were compared with postnatal echocardiograms from a formal quality assurance program. SV fetuses were grouped by anatomical subtype. Diagnostic errors were designated as major if the error would have caused significant alteration in parental counseling or postnatal management. The remaining errors were classified as minor. Physiological discrepancies, including prostaglandin-E (PGE) dependency, atrioventricular valve regurgitation (AVVR), pulmonary venous obstruction and restrictive atrial septum (RAS), were assessed by chart review of the postnatal course. RESULTS: A total of 119 subjects were analyzed. SV subtypes in the cohort included hypoplastic left heart syndrome (HLHS) (n = 68), tricuspid atresia (n = 16), double-inlet left ventricle (n = 12), unbalanced atrioventricular canal (UAVC) (n = 11), heterotaxy (n = 9) and other (n = 3). The rate of major anatomical and physiological errors was low (n = 6 (5.0%)). A higher proportion of minor errors was noted in HLHS and tricuspid atresia, but the differences were not statistically significant. Physiological discrepancies were uncommon, with three major discrepancies, including underestimation of the degree of venous obstruction in one non-HLHS fetus with total anomalous pulmonary venous return, overestimation of RAS in one HLHS fetus and incorrect prediction of PGE dependency in one case false-negative for pulmonary blood flow. No discrepancy in degree of AVVR or RAS affected postnatal care. Minor physiological discrepancies included two false-positive predictions of PGE dependency with one false-positive for ductal-dependent systemic flow and one false-positive for pulmonary blood flow. CONCLUSIONS: In this contemporary review of FE at our center, there was high accuracy in describing anatomical and physiological findings in SV-CHD. Major physiological discrepancies were uncommon but included important cases of false-negative prediction of PGE dependency and underestimation of obstruction of total anomalous pulmonary venous return. These data can inform more accurate counseling of families with SV-CHD fetuses and guide diagnostic improvement efforts. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.

The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?

Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.

Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.

Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression.

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.

Drug-induced Stevens-Johnson syndrome in Indian population: A multicentric retrospective analysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening hypersensitivity reactions mainly caused by drugs. Data on incubation period, hospital stay, and outcome for HIV-positive patients are sparse. Role of corticosteroids in their management is still controversial. METHODS: Indoor cases of SJS, SJS-TEN overlap, and TEN were analyzed for causative drugs, incubation period, a severity-of-illness score for toxic epidermal necrolysis (SCORTEN) score, HIV status, treatment, and outcome. Comparison of parameters between HIV and non-HIV cases was done. Utilization pattern of corticosteroids and their role in outcome were evaluated. RESULTS: Four SJS, 15 SJS-TEN overlap, and 21 TEN cases were evaluated. Antimicrobials (27.1%), antiviral (23%), antiseizure drugs (8.4%), and analgesics (8.4%) were commonly associated drugs. Among 12 (30%) HIV-reactive cases, nevirapine (97.6%) and cotrimoxazole (41.6%) were common causative drugs. Males (75%) were affected more than females (25%) among HIV-positive individuals. Incubation period was significantly higher in HIV-reactive patients. Total 30 (75%) patients were treated with corticosteroids. Dexamethasone (90%) and prednisolone (26.6%) were most commonly used. No significant difference was found among cases treated with or without corticosteroids. CONCLUSIONS: Antimicrobial drugs are common to cause SJS/TEN. Among HIV-reactive patients, male have more risk, incubation period is more and severity of reaction is less. Effectiveness of corticosteroids for treatment of SJS/TEN is inconclusive.

Quality assurance in cardiovascular CT: a practical guide.

Cardiovascular computed tomography (CCT) is a cutting-edge imaging technique providing important, non-invasive, diagnostic information. Concerns exist regarding radiation exposure to patient populations, but achieving optimal image quality at the lowest doses can be challenging. This guide provides practical advice about how quality can be assured in any CCT unit or radiology department. Illustrated by real-world vignettes and data analysis from our own experience, we highlight a multidisciplinary team approach to each stage of the patient journey, the effectiveness of regular dose audit overseen by a CT optimisation group, and the importance of underused systolic scanning techniques, in order to drive significant dose reduction without loss of image quality or clinical confidence.

Relating Nanoparticle Properties to Biological Outcomes in Exposure Escalation Experiments.

A fundamental goal in nano-toxicology is that of identifying particle physical and chemical properties, which are likely to explain biological hazard. The first line of screening for potentially adverse outcomes often consists of exposure escalation experiments, involving the exposure of micro-organisms or cell lines to a library of nanomaterials. We discuss a modeling strategy, that relates the outcome of an exposure escalation experiment to nanoparticle properties. Our approach makes use of a hierarchical decision process, where we jointly identify particles that initiate adverse biological outcomes and explain the probability of this event in terms of the particle physicochemical descriptors. The proposed inferential framework results in summaries that are easily interpretable as simple probability statements. We present the application of the proposed method to a data set on 24 metal oxides nanoparticles, characterized in relation to their electrical, crystal and dissolution properties.

Second Malignancy Probabilities in Patients With Breast Cancer Treated With Conventional Versus Hypofractionated External Beam Radiation Therapy in the Adjuvant Setting.

AIMS: For women with breast cancer, seminal studies have shown that adjuvant hypofractionated external beam radiation therapy (hEBRT) maintains similar outcomes and may reduce overall costs compared with conventionally fractionated external beam radiation therapy (cEBRT). However, it is unclear whether hEBRT may be associated with differential risk of development of radiation-induced second malignancies compared with cEBRT. Because the occurrence of second malignancies is small, large databases may improve our understanding of the relative risk of second malignancies between hEBRT and cEBRT. MATERIALS AND METHODS: Using the National Cancer Database, we carried out a retrospective cohort analysis of women diagnosed with non-metastatic, stage 0-III breast cancer from 2004 to 2017. All patients had a lumpectomy or mastectomy and a follow-up time of at least 60 months after diagnosis. The probability of second malignancies in women receiving adjuvant cEBRT or hEBRT was compared using multivariable logistic regression adjusting for sociodemographic, geographical, clinical and treatment factors, allowing for relative (but not absolute) comparison of second malignancy risk. Temporal sensitivity analyses stratified by year of diagnosis and length of follow-up time were also conducted. RESULTS: Of the 125 228 women in our study, 115 576 (92.3%) received cEBRT and 9652 (7.71%) received hEBRT. The median age of the cohort was 60 (interquartile range 51-68) years at diagnosis and the median follow-up time was 99.61 (interquartile range 77.5-128.49) months. Upon adjusting for sociodemographic and clinical factors, patients who received hEBRT had no difference in relative risk than patients who received cEBRT (odds ratio 0.937, 95% confidence interval 0.869-1.010, P = 0.091). In analyses stratified by year of diagnosis, and stratified by length of follow-up, there was no difference in second malignancy probability between patients who completed hEBRT and patients who completed cEBRT. CONCLUSIONS: In this analysis of over 120 000 women with non-metastatic breast cancer, hEBRT was not associated with different odds of developing second malignancies compared with cEBRT. Our findings may inform patient counselling in the choice of radiation regimens for breast cancer and further support the safety of hypofractionated regimens for breast cancer.

How we do it: using the nasion as a landmark for identifying the anterior ethmoidal artery.

BACKGROUND: In severe refractory epistaxis, the anterior ethmoidal artery may need to be ligated. Previously described endonasal or transorbital approaches are not always effective, or they have suboptimal aesthetic outcomes. This paper describes a safe and effective surgical technique, with a consistent landmark allowing quick identification. TECHNICAL DESCRIPTION: A transcaruncular incision is made, oriented medially in the direction of the medial orbital wall towards the level of the nasion. Once onto bone, a subperiosteal plane is developed and an endoscope is used to dissect posteriorly at the level of the nasion, until the anterior ethmoidal artery is identified, and subsequently ligated. CONCLUSION: The nasion is an easy, constant landmark to use for ligation of the anterior ethmoidal artery in refractory epistaxis. The traditional method of identifying the anterior ethmoidal artery is not applicable or constant enough for use during the transorbital approach. The described technique avoids injury to surrounding structures and has a satisfactory aesthetic outcome.

Tips and tricks for maximising access to the middle cranial fossa using the superior lateral orbital portal.

BACKGROUND: Transorbital endoscopic approaches are becoming increasingly popular for skull base pathologies; the superior lateral orbital portal is one such approach to the middle cranial fossa. This paper provides a technical description that maximises the surgical portal and minimises morbidity. TECHNICAL DESCRIPTION: A superior lid crease incision is made extending laterally and the orbital rim is exposed. A subperiosteal dissection of the lateral and superior orbit is performed, with elevation of periosteum off Whitnall's tubercle, ligation of the recurrent branch of the middle meningeal artery, and identification of the superior orbital fissure. The lacrimal keyhole is then drilled away. The middle cranial fossa is accessed by drilling posterior to the orbital rim to expose: the temporalis muscle anterior-laterally, the dura of the temporal lobe posterior-laterally, the anterior cranial fossa superiorly and the periorbita medially. CONCLUSION: These surgical steps can maximise the surgical portal and minimise morbidity, with avoidance of injury to surrounding structures.

Evaluating the effect of child home safety training upon three family support practitioner groups: a mixed-methods study.

AIMS: Unintentional injuries in the home contribute substantially to preschool child morbidity and mortality. Practitioners such as health visitors, family mentors and children's centre staff are well-positioned to facilitate child injury prevention by providing home safety advice to families, and training may enhance their ability to do so. We aimed to assess the impact of child home safety training for these practitioners. METHODS: An explanatory mixed-methods design was used. Practitioners completed questionnaires before, and up to 7 months after, receiving child home safety training and took part in interviews. Seventy-eight health visitors, 72 family mentors and 11 children's centre staff members completed questionnaires. Items were used to calculate scores on home safety knowledge, confidence to provide home safety advice and belief that child home safety promotion is important. Thematic analysis of interviews with seven health visitors and nine family mentors, open-ended responses to the questionnaires and an additional evaluation form was conducted to explore attendees' perceptions of the training and its impact. In addition, seven health visitors and six children's centre staff who had received no training were interviewed. RESULTS: Knowledge was greater post-training than pre-training across all participants (p < .001). When practitioner groups were analysed separately, there were significant increases in family mentors' knowledge (p < .001) and belief (p = .016), and health visitors' confidence (p = .0036). Qualitative findings indicated that most training session attendees valued the training, believed their practice relating to child home safety had improved as a result, and felt further similar training sessions would be beneficial. Those who had not attended the sessions described a need for more child home safety training. CONCLUSIONS: Delivering training to practitioners providing child home safety promotion to families with preschool children can enhance injury prevention knowledge, beliefs and confidence and positively impact on home safety promotion by practitioners.

Transesophageal Echocardiogram Before Cardioversion in Atrial Fibrillation Patients.

Transesophageal echocardiography (TEE) offers an invaluable, non-invasive avenue for diagnosing and managing various cardiac conditions, including atrial fibrillation (AF). As the most common cardiac arrhythmia, AF affects millions and can lead to severe complications. Cardioversion, a procedure to restore the heart's normal rhythm, is frequently conducted on AF patients resistant to medication. Due to inconclusive data, TEE's utility prior to cardioversion in AF patients remains ambiguous. Understanding TEE's potential benefits and limitations in this population could significantly influence clinical practice. This review aims to scrutinize the current literature on the use of TEE before cardioversion in AF patients. The principal objective is to understand TEE's potential benefits and limitations comprehensively. The study seeks to offer a clear understanding and practical recommendations for clinical practice, thereby improving the management of AF patients before cardioversion using TEE. A literature search of databases was conducted using the keywords "Atrial Fibrillation," "Cardioversion" and "Transesophageal echocardiography," resulting in 640 articles. These were narrowed to 103 following title and abstract reviews. After applying exclusion and inclusion criteria with a quality assessment, 20 papers were included: seven retrospective studies, 12 prospective observational studies, and one randomized controlled trial (RCT). Stroke risk associated with direct-current cardioversion (DCC) potentially results from post-cardioversion atrial stunning. Thromboembolic events occur post cardioversion, with or without prior atrial thrombus or cardioversion complications. Generally, cardiac thrombus localizes in the left atrial appendage (LAA), a clear contraindication to cardioversion. Atrial sludge without LAA thrombus in TEE is a relative contraindication. TEE before electrical cardioversion (ECV) in anticoagulated AF individuals is uncommon. In AF patients planned for cardioversion, contrast enhancement facilitates thrombus exclusion in TEE images, reducing embolic events. Left atrial thrombus (LAT) frequently occurs in AF patients, necessitating TEE examination. Despite the increased use of pre-cardioversion TEE, thromboembolic events persist. Notably, patients with post-DCC thromboembolic events had no LA thrombus or LAA sludge. The use of TEE-guided DCC has grown due to its ability to detect atrial thrombi pre-cardioversion, aiding risk stratification. Thrombus in the left atrium also signals an elevated risk of future thromboembolic events in AF patients. While atrial stunning post cardioversion detected by TEE is a significant risk factor for future thromboembolic events, further evidence is required. Therapeutic anticoagulation is essential during and post cardioversion, even if no atrial thrombus is detected. Current data recommends cardioversion guided by TEE, particularly in outpatient settings.

Sensory thresholds obtained from MEG data: cortical psychometric functions.

Sensory sensitivity is typically measured using behavioural techniques (psychophysics), which rely on observers responding to very large numbers of stimulus presentations. Psychophysics can be problematic when working with special populations, such as children or clinical patients who may lack the compliance or cognitive skills to perform the behavioural tasks. We used an auditory gap-detection paradigm to develop an accurate measure of sensory threshold derived from passively-recorded magnetoencephalographic (MEG) data. Auditory evoked responses were elicited by silent gaps of varying durations in an on-going noise stimulus. Source modelling was used to spatially filter the MEG data and sigmoidal 'cortical psychometric functions' relating response amplitude to gap duration were obtained for each individual participant. Fitting the functions with a curve and estimating the gap duration at which the amplitude of the evoked response exceeded one standard deviation of the prestimulus brain activity provided an excellent prediction of psychophysical threshold. Accurate sensory thresholds can therefore be reliably extracted from MEG data recorded while participants listen passively to a stimulus. Because our paradigm required no behavioural task, the method is suitable for studies of populations where variations in cognitive skills or vigilance make traditional psychophysics unsuitable.

Does fasting during Ramadan affect the use of topical dermatological treatment by Muslim patients in the UK?

BACKGROUND: Ritual fasting during the Muslim religious festival of Ramadan is one of the 'Five Pillars' of Islam, and is widely observed by Muslims. Previous studies have highlighted compliance issues in patients prescribed oral medications during this period. Aim. To assess whether fasting during Ramadan influence the use of topical treatments for skin disease in Muslim patients. METHODS: This was a prospective, anonymous, questionnaire survey undertaken in a dermatology centre in a tertiary hospital in the UK. Patients were asked if they would use topical treatment while fasting, and whether they would consider this a breach of their fast. RESULTS: We found that more than one-third of the people interviewed would not use topical treatment while fasting, and around the same number (> 30%) would also consider this a breach of their fast. Although the majority of these patients thought that using steroid-based topical products was not acceptable, a significant proportion extended this opinion to use of any cream or emollient, and even to light therapy. Gender, age, or educational level were not useful predictors of patient opinion, but there was a significant association with birthplace and likelihood of using topical treatment during Ramadan; patients born outside the UK were significantly (P < 0.01) less likely than those born in the UK to use topical treatment in the fasting period. CONCLUSIONS: Our study indicates that fasting may be a significant and a hitherto unrecognised cause of non-compliance with topical treatment in Muslim patients in the UK, with potential health, quality and cost implications. Ritual fasting during Ramadan is widely observed by Muslims. Previous studies have highlighted compliance issues in patients prescribed oral medications during this period, and it seems this extends to use of topical treatments for skin disease.

Symptoms in heart failure correlate poorly with objective haemodynamic parameters.

INTRODUCTION: Even though heart failure (HF) is a very common condition, surprisingly little is known regarding association between patient's symptoms and objective data. The purpose of this study was to evaluate for any correlations between haemodynamic, echocardiographic and laboratory data of presenting symptoms in HF patients. METHODS: This study is a retrospective analysis of the limited access dataset from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial provided by the National Heart, Lung and Blood Institute. Symptoms including dyspnoea, orthopnoea, fatigue and gastrointestinal (GI) discomfort were graded by their severity from minimal (0) to maximal (3) on admission, at discharge, at 3 months and at 6 months from the admission. Results of Minnesota Living with Heart Failure (MLHF) score and assigned New York Heart Association (NYHA) functional class were available at the same time points. RESULTS: A total of 433 patients with decompensated HF and decreased systolic function (ejection fraction < 30%) were included in this trial. Orthopnoea, dyspnoea and fatigue had weak correlation with invasive pulmonary artery systolic and diastolic pressure and negative correlation with serum creatinine, albumin, sodium, total bilirubin, haemoglobin and haematocrit; fatigue showed positive correlation to pulmonary artery pressures. Abdominal discomfort had no correlation to symptoms. There was no correlation of symptoms, NYHA class, or MLHF scores with age, gender, peak VO(2) on cardiopulmonary stress test, body mass index, either right or left ventricular systolic function, B-type natriuretic peptide, cardiac output or cardiac index, troponin level, velocity of tricuspid regurgitation and multiple other factors predicting morbidity and mortality in HF. CONCLUSION: Overall, the correlation between symptoms and objective parameters was weak. Because of low magnitude of relationship between symptoms to objective parameters, it was concluded that there are likely other factors determining the perception of symptoms in HF patients.