HIV matters when diagnosing TB in young children: an ancillary analysis in children enrolled in the INPUT stepped wedge cluster randomized study.

BACKGROUND: Children under age five years, particularly those living with HIV (CLHIV), are at risk for rapid progression of tuberculosis (TB). We aimed to describe TB clinical presentations, diagnostic pathways and treatment outcomes in CLHIV compared to children without HIV in Cameroon and Kenya. METHODS: This sub-analysis of a cluster-randomized trial evaluating the integration of pediatric TB services from May 2019 to March 2021 enrolled children age < 5 years with TB. We estimated the HIV infection rate with 95% confidence interval (CI). We compared TB clinical presentations, diagnostic pathways and treatment outcomes in CLHIV and children without HIV. Finally, we investigated whether HIV infection was associated with a shorter time to TB diagnosis (≤ 3 months from symptoms onset) after adjusting for covariates. Univariable and multivariable logistic regression analysis were performed with adjusted odds ratios (AORs) presented as measures of the association of covariates with HIV status and with shorter time to TB diagnosis. RESULTS: We enrolled 157 children with TB (mean age was 1.5 years) and 22/157 (14.0% [9.0-20.4%]) were co-infected with HIV. CLHIV were more likely to initially present with acute malnutrition (AOR 3.16 [1.14-8.71], p = 0.027). Most TB diagnoses (140/157, 89%) were made clinically with pulmonary TB being the most common presentation; however, there was weak evidence of more frequent bacteriologic confirmation of TB in CLHIV, 18% vs. 9% (p = 0.067), due to the contribution of lateral-flow urine lipoarabinomannan to the diagnosis. HIV positivity (AOR: 6.10 [1.32-28.17], p = 0.021) was independently associated with a shorter time to TB diagnosis as well as fatigue (AOR: 6.58 [2.28-18.96], p = 0.0005), and existence of a household contact diagnosed with TB (AOR: 5.60 [1.58-19.83], p = 0.0075), whereas older age (AOR: 0.35 [0.15-0.85], p = 0.020 for age 2-5 years), night sweats (AOR: 0.24 [0.10-0.60], p = 0.0022) and acute malnutrition (AOR: 0.36 [0.14-0.92], p = 0.034) were associated with a delayed diagnosis. The case fatality rate was 9% (2/22) in CLHIV and 4% (6/135) in children without HIV, p = 0.31. CONCLUSIONS: These results altogether advocate for better integration of TB services into all pediatric entry points with a special focus on nutrition services, and illustrate the importance of non-sputum-based TB diagnostics especially in CLHIV. TRIAL REGISTRATION: NCT03862261, first registration 05/03/2019.

Multi-site nerve block catheters for postoperative analgesia in extended scapulectomy and free-flap reconstruction.

Scapulectomy is performed as a limb-sparing procedure in the management of tumours of the proximal humerus and shoulder girdle. Analgesic outcomes following this procedure are poorly documented in the literature. In our case, satisfactory analgesia following extended scapulectomy and free-flap reconstruction was achieved with a combination of multi-site continuous nerve block catheters and patient-controlled analgesia, for a patient with chronic pain who had a high pre-operative opioid requirement. Multiple continuous nerve block catheters were used, including interscalene and paravertebral catheters to provide analgesia for the shoulder resection, with a fascia iliaca compartment catheter providing analgesia to free-flap donor site on the the anterolateral thigh. These continuous nerve block catheters contributed to effective postoperative analgesia and low postoperative intravenous opioid requirements in this case.

Developing Integrated Approaches for Testing and Assessment (IATAs) in order to support nanomaterial safety.

Due to the unique characteristics of nanomaterials (NM) there has been an increase in their use in nanomedicines and innovative medical devices (MD). Although large numbers of NMs have now been developed, comprehensive safety investigations are still lacking. Current gaps in understanding the potential mechanisms of NM-induced toxicity can make it challenging to determine the safety testing necessary to support inclusion of NMs in MD applications. This article provides guidance for implementation of pre-clinical tailored safety assessment strategies with the aim to increase the translation of NMs from bench development to clinical use. Integrated Approaches to Testing and Assessment (IATAs) are a key tool in developing these strategies. IATAs follow an iterative approach to answer a defined question in a specific regulatory context to guide the gathering of relevant information for safety assessment, including existing experimental data, integrated with in silico model predictions where available and appropriate, and/or experimental procedures and protocols for generating new data to fill gaps. This allows NM developers to work toward current guidelines and regulations, while taking NM specific considerations into account. Here, an example IATA for NMs with potential for direct blood contact was developed for the assessment of haemocompatibility. This example IATA brings together the current guidelines for NM safety assessment within a framework that can be used to guide information and data gathering for the safety assessment of intravenously injected NMs. Additionally, the decision framework underpinning this IATA has the potential to be adapted to other testing needs and regulatory contexts.

Management of haematoma after thyroid surgery: systematic review and multidisciplinary consensus guidelines from the Difficult Airway Society, the British Association of Endocrine and Thyroid Surgeons and the British Association of Otorhinolaryngology, Head and Neck Surgery.

Haematoma after thyroid surgery can lead to airway obstruction and death. We therefore developed guidelines to improve the safety of peri-operative care of patients undergoing thyroid surgery. We conducted a systematic review to inform recommendations, with expert consensus used in the absence of high-quality evidence, and a Delphi study was used to ratify recommendations. We highlight the importance of multidisciplinary team management and make recommendations in key areas including: monitoring; recognition; post-thyroid surgery emergency box; management of suspected haematoma following thyroid surgery; cognitive aids; post-haematoma evacuation care; day-case thyroid surgery; training; consent and pre-operative communication; postoperative communication; and institutional policies. The guidelines support a multidisciplinary approach to the management of suspected haematoma following thyroid surgery through oxygenation and evaluation; haematoma evacuation; and tracheal intubation. They have been produced with materials to support implementation. While these guidelines are specific to thyroid surgery, the principles may apply to other forms of neck surgery. These guidelines and recommendations provided are the first in this area and it is hoped they will support multidisciplinary team working, improving care and outcomes for patients having thyroid surgery.

Preferential responses to faces in superior temporal and medial prefrontal cortex in three-year-old children.

Perceiving faces and understanding emotions are key components of human social cognition. Prior research with adults and infants suggests that these social cognitive functions are supported by superior temporal cortex (STC) and medial prefrontal cortex (MPFC). We used functional near-infrared spectroscopy (fNIRS) to characterize functional responses in these cortical regions to faces in early childhood. Three-year-old children (n = 88, M(SD) = 3.15(.16) years) passively viewed faces that varied in emotional content and valence (happy, angry, fearful, neutral) and, for fearful and angry faces, intensity (100%, 40%), while undergoing fNIRS. Bilateral STC and MPFC showed greater oxygenated hemoglobin concentration values to all faces relative to objects. MPFC additionally responded preferentially to happy faces relative to neutral faces. We did not detect preferential responses to angry or fearful faces, or overall differences in response magnitude by emotional valence (100% happy vs. fearful and angry) or intensity (100% vs. 40% fearful and angry). In exploratory analyses, preferential responses to faces in MPFC were not robustly correlated with performance on tasks of early social cognition. These results link and extend adult and infant research on functional responses to faces in STC and MPFC and contribute to the characterization of the neural correlates of early social cognition.

Arthropathy in hereditary haemochromatosis segregates with elevated erythrocyte mean corpuscular volume.

Objective: To evaluate the relationship between erythrocyte parameters and the presence or absence of arthritis in HFE C282Y homozygous hereditary haemochromatosis (HH) subjects compared to control groups of non-HH subjects with arthritis.Method: Erythrocyte and arthritis parameters [mean corpuscular volume (MCV) and mean cell haemoglobin (MCH)] were obtained from consecutive HH subjects (n = 119) who were referred for initial evaluation and management. For comparison, MCV and MCH values were collected from randomly selected non-HH subjects with rheumatoid arthritis (n = 100) and osteoarthritis (n = 100), consisting of equal numbers of men and women. Two other comparison groups comprised 16 men and women who were heterozygous for C282Y with arthritis, and 38 non-HH subjects with type 2 polyarticular osteoarthritis (T2POA).Results: MCV values were significantly higher in HH subjects with arthritis (95 ± 0.56 fL) than in HH subjects without arthritis (92.75 ± 0.50 fL, p = 0.037). HH subjects with or without arthritis demonstrated a higher mean MCV than the control groups of non-HH osteoarthritis (90.12 ± 0.46 fL, p < 0.001) and non-HH rheumatoid arthritis (90.94 ± 0.57 fL, p < 0.001). HH subjects with arthritis also demonstrated a higher MCV than heterozygous C282Y subjects with arthritis (93.18 ± 1.55 fL, p = 0.025) and non-HH subjects with a similar pattern of arthritis, notably T2POA (91.13 ± 0.50 fL, p < 0.01). An MCV of ≥ 97.85 fL provided a likelihood ratio of 2.2 for development of arthritis in HH subjects.Conclusion: This study demonstrated a relationship between elevated MCV and arthritis in incident cases of HH.

Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.

BACKGROUND: Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120. METHODS: We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions. We used an RNA in situ detection technique called RNAscope to characterise ARL3 and CEP120 expression patterns in human embryos and foetuses in collaboration with the MRC-Wellcome Trust Human Developmental Biology Resource. RESULTS: Both ARL3 and CEP120 are expressed in early human brain development, including the cerebellum and in the developing retina and kidney, consistent with the clinical phenotypes seen with pathogenic variants in these genes. CONCLUSIONS: This study provides insights into the potential pathogenesis of JSRD by uncovering the spatial expression of two JSRD-causative genes during normal human development.

A Multicenter Study of the Clinical Utility of Nontargeted Systematic Transperineal Prostate Biopsies in Patients Undergoing Pre-Biopsy Multiparametric Magnetic Resonance Imaging.

PURPOSE: The added value of nontargeted systematic prostate biopsies when performed alongside magnetic resonance imaging targeted biopsies in men referred with a suspicion of prostate cancer is unclear. We aimed to determine the clinical utility of transperineal nontargeted systematic prostate biopsies, when performed alongside targeted systematic prostate biopsies, using pre-biopsy multiparametric magnetic resonance imaging. MATERIALS AND METHODS: Consecutive patients referred with a suspicion of prostate cancer (April 2017 to October 2019) underwent pre-biopsy multiparametric magnetic resonance imaging. A transperineal biopsy was advised if multiparametric magnetic resonance imaging PI-RADS® (v.2.0) score was 4 or 5, and score 3 required a prostate specific antigen density 0.12 ng/ml or greater. Primary threshold for clinically significant prostate cancer was defined as any Gleason 3+4 or greater. Multivariable logistic regression analysis identified pre-biopsy predictors of clinically significant prostate cancer in nontargeted systematic prostate biopsies, regardless of targeted pathology (p <0.05, R, version 3.5.1). RESULTS: A total of 1,719 men underwent a pre-biopsy multiparametric magnetic resonance imaging, with 679 (39.5%) proceeding to combined targeted systematic prostate biopsies and nontargeted systematic prostate biopsies. In these men clinically significant prostate cancer was detected in 333 (49%) and 139 (20.5%) with targeted systematic prostate biopsies and nontargeted systematic prostate biopsies, respectively. In those men with clinically significant prostate cancer in targeted systematic prostate biopsies, clinically significant prostate cancer was also present in nontargeted systematic prostate biopsies in 117 (17.2%); Gleason 3+3 was present in 50 (7.4%). In 287 men without any cancer in the targeted systematic prostate biopsies, 13 (1.9%) had clinically significant prostate cancer in nontargeted systematic prostate biopsies. In addition 18/679 (2.7%) had Gleason 3+3 disease and no Gleason greater than 4+3 was detected. Predictors associated with clinically significant prostate cancer in nontargeted systematic prostate biopsies were prostate specific antigen 5 ng/ml or greater (OR 2.05, 95% CI 1.13-3.73, p=0.02), PI-RADS score 5 (OR 2.26, 95% CI 1.51-3.38, p <0.001) and prostate volume less than 50 cc (OR 2.47, 95% CI 1.57-3.87, p <0.001). CONCLUSIONS: Detection of clinically significant prostate cancer in exclusively nontargeted transperineal systematic biopsies in a pre-biopsy multiparametric magnetic resonance imaging pathway was low (1.9%).

Embryonic and foetal expression patterns of the ciliopathy gene CEP164.

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited genetic disorders that share a defect in the formation, maintenance or functioning of the primary cilium complex, causing progressive cystic kidney disease and other clinical manifestations. Mutations in centrosomal protein 164 kDa (CEP164), also known as NPHP15, have been identified as a cause of NPHP-RC. Here we have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) to perform immunohistochemistry studies on human embryonic and foetal tissues to determine the expression patterns of CEP164 during development. Notably expression is widespread, yet defined, in multiple organs including the kidney, retina and cerebellum. Murine studies demonstrated an almost identical Cep164 expression pattern. Taken together, these data support a conserved role for CEP164 throughout the development of numerous organs, which, we suggest, accounts for the multi-system disease phenotype of CEP164-mediated NPHP-RC.

Nurse-Led Phone Call Follow-Up Clinics Are Effective for Patients With Prostate Cancer.

INTRODUCTION: The rising cost of healthcare requires rethinking in terms of resource utilisation care delivery. Nurse-led PSA phone follow-up clinics may provide a suitable option. MATERIALS AND METHODS: 815 patients were recruited for the nurse-led stable prostate cancer telephone follow-up service. A convenience sample was selected for postal questionnaire assessment of their satisfaction. RESULTS: 815 patients had 3683 phone-call follow ups over 10 years. Patients' own understanding of condition varied from average (76.3%) and good (9.2%) in the majority. 87.2% found the service convenient and 75.6% informative. 95.3% found the telephone assessment preferable to attending the outpatient department. 87.2% were keen on savings on transport/travel. 53.5% found it more reassuring. 91.9% of patients felt that everything they wanted to talk about was covered. DISCUSSION: This service can be delivered in a high volume nurse-led service, with high levels of patient satisfaction, as an innovative service development.

Using the robust design framework and relative abundance to predict the population size of pallid sturgeon Scaphirhynchus albus in the lower Missouri River.

Several population viability models were constructed to aid recovery in endangered Scaphirhynchus albus, but these models are dependent upon accurate and precise input parameters that are not provided with standard catch per unit effort (CPUE) indices. Nine years of sampling efforts, under the robust design framework, provided 1223 unique captures with an 18·3% recapture rate. The annual population estimates varied from 4·0-7·3 fish rkm-1 for wild and 8·4-18·4 fish rkm-1 for hatchery-reared S. albus. The relationship between abundance (N) and annual trot-line CPUE indices (x = 70.726y + 2·533, R2 = 0·91, P < 0·001) was used to predict an abundance of 13 616 ± 7142 s.e. S. albus in the lower Missouri River. The use of small-scale intensive sampling to develop a relationship with relative abundance indices reported here, may provide a framework for other fisheries management applications where large-scale intensive sampling is not feasible, but catch data are available.

Co-Localization of Macrophage Inhibitory Factor and Nix in Skeletal Muscle of the Aged Male Interleukin 10 Null Mouse.

Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagonistic cross-talk between macrophage migration inhibitory factor (Mif), an anti-apoptotic cytokine and NIP3-like protein X (Nix), a pro-apoptotic mitochondrial protein, may play a role in mitochondrial free radical homeostasis and inflammatory myopathies. We examined Nix-Mif interaction in inflammation and aging using young and old, IL-10tm/tm (a rodent model of chronic inflammation) and C57BL/6 mice. In this study, we observed that Nix and Mif were co-localized in skeletal muscles of aged and inflamed mice. We show an inflammation- and age-related association between Nix and Mif gene expression, with the strongest positive correlation observed in old IL-10tm/tm skeletal muscles. The IL-10tm/tm skeletal muscles also had the highest levels of oxidative stress damage. These observations suggest that Nix-Mif cross-talk may play a role in the interface between chronic inflammation and oxidative stress in aging skeletal muscles.

Alginate oligosaccharides modify hyphal infiltration of Candida albicans in an in vitro model of invasive human candidosis.

AIMS: A novel alginate oligomer (OligoG CF-5/20) has been shown to potentiate antifungal therapy against a range of fungal pathogens. The current study assessed the effect of this oligomer on in vitro virulence factor expression and epithelial invasion by Candida species. METHODS AND RESULTS: Plate substrate assays and epithelial models were used to assess Candida albicans (CCUG 39343 and ATCC 90028) invasion, in conjunction with confocal laser scanning microscopy and histochemistry. Expression of candidal virulence factors was determined biochemically and by quantitative PCR (qPCR). Changes in surface charge of C. albicans following OligoG treatment were analysed using electrophoretic light scattering. OligoG induced marked alterations in hyphal formation in the substrate assays and reduced invasion in the epithelial model (P < 0·001). Significant dose-dependent inhibition of phospholipase activity in C. albicans was evident following OligoG treatment (P < 0·05). While OligoG binding failed to affect alterations in surface charge (P > 0·05), qPCR demonstrated a reduction in phospholipase B (PLB2) and SAPs (SAP4 and SAP6) expression. CONCLUSION: OligoG CF-5/20 reduced in vitro virulence factor expression and invasion by C. albicans. SIGNIFICANCE AND IMPACT OF THE STUDY: These results, and the previously described potentiation of antifungal activity, define a potential therapeutic opportunity in the treatment of invasive candidal infections.

Feasibility of brachytherapy as monotherapy for high-volume, low-risk prostate cancer.

BACKGROUND: We sought to determine whether patients with high-volume, low-risk prostate cancer are suitable candidates for ultrasound-guided brachytherapy, monotherapy alone, without supplemental external beam radiation. MATERIALS AND METHODS: The study cohort comprised 200 consecutive patients who received ultrasound.guided monotherapy from November 02, 1998 to March 26, 2010. Real.time intraoperative treatment planning was performed for all patients. 145. Gy with I125 was prescribed to the prostate with no margin. The primary endpoint was time to prostate-specific antigen. (PSA) failure using the phoenix definition. Cox multivariable regression analysis was used to determine the factors significantly associated with time to PSA failure. RESULTS: Median follow-up was 59 months (range 1.2-146.8 months). The median PSA was 5.0 ng/ml. For the overall cohort, both 5- and 8-year PSA failure-free survival was 92.3% (95% confidence interval [95% CI]: 86.5-95.7%). Low-risk patients per the NCCN criteria had 5- and 8-year PSA failure-free survival of 93.6%. On cox multivariable analysis, only baseline PSA (adjusted hazard ratio: 1.29 [95% CI: 1.02-1.65], P = 0.036) was associated with outcome. Among patients with Conclusions: Our analysis indicates that patients with a high number of cores positive for cancer can be adequately treated with modern brachytherapy as monotherapy and be spared the additional morbidity and cost of supplemental external beam radiation or androgen deprivation therapy.

BRIGHTEN Heart: Design and baseline characteristics of a randomized controlled trial for minority older adults with depression and cardiometabolic syndrome.

OBJECTIVES: African American and Hispanic elderly are at elevated risk of both depression and cardiovascular disease, relative to non-Hispanic whites. Effective interventions are therefore needed to address depressive symptoms and to reduce these disparities. BRIGHTEN Heart was a behavioral randomized controlled trial to test the efficacy of a virtual team intervention in reducing depressive symptoms in minority elderly as measured by the 9-item Patient Health Questionnaire (PHQ9). STUDY DESIGN: 250 African American and Hispanic adults, age ≥60 years, with comorbid depression and overweight/obesity were randomized. Participants randomized to the Intervention condition received a social work evaluation, team-based electronic consultation, case management, and psychotherapy over a 12 month period. Control participants were enrolled in a membership program that provided health classes and other services to support chronic disease self-management. Blinded research assistants completed assessments at baseline, and 6 and 12 months postrandomization. RESULTS: The study population was characterized by low socioeconomic status, with 81.4% having a household income of less than $20,000. Although median depression scores were in the mild range, 25% of participants had scores showing moderate to severe depression at baseline. 75% of participants had four or more chronic conditions. Significant demographic and clinical differences were observed between the African American and Hispanic populations. CONCLUSIONS: BRIGHTEN Heart was designed to rigorously test the efficacy of a multi-level intervention to reduce comorbid depressive symptoms and cardiovascular risk in minority elderly. Investigators successfully recruited a cohort well suited to testing the study hypothesis.

A prevalence study of Salmonella spp., Yersinia spp., Toxoplasma gondii and porcine reproductive and respiratory syndrome virus in UK pigs at slaughter.

An abattoir-based study was undertaken between January and May 2013 to estimate the prevalence of Salmonella spp. and Yersinia spp. carriage and seroprevalence of antibodies to Toxoplasma gondii and porcine reproductive and respiratory syndrome virus (PRRSv) in UK pigs at slaughter. In total, 626 pigs were sampled at 14 abattoirs that together process 80% of the annual UK pig slaughter throughput. Sampling was weighted by abattoir throughput and sampling dates and pig carcasses were randomly selected. Rectal swabs, blood samples, carcass swabs and the whole caecum, tonsils, heart and tongue were collected. Salmonella spp. was isolated from 30·5% [95% confidence interval (CI) 26·5-34·6] of caecal content samples but only 9·6% (95% CI 7·3-11·9) of carcass swabs, which was significantly lower than in a UK survey in 2006-2007. S. Typhimurium and S. 4,[5],12:i:- were the most commonly isolated serovars, followed by S. Derby and S. Bovismorbificans. The prevalence of Yersinia enterocolitica carriage in tonsils was 28·7% (95% CI 24·8-32·7) whereas carcass contamination was much lower at 1·8% (95% CI 0·7-2·8). The seroprevalence of antibodies to Toxoplasma gondii and PRRSv was 7·4% (95% CI 5·3-9·5) and 58·3% (95% CI 53·1-63·4), respectively. This study provides a comparison to previous abattoir-based prevalence surveys for Salmonella and Yersinia, and the first UK-wide seroprevalence estimates for antibodies to Toxoplasma and PRRSv in pigs at slaughter.

Androgen deprivation therapy reversibly increases endothelium-dependent vasodilation in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is a standard treatment for patients with aggressive prostate cancer. Although ADT improves survival, it increases the risk of diabetes. Emerging evidence suggests that ADT increases adverse cardiovascular events as early as 3 months after initiation in patients with cardiovascular disease, but the mechanism is unknown. We hypothesized that ADT may impair endothelium-dependent vasodilation due to increases in lipids and insulin resistance and may provide a link for heightened cardiovascular risk in this population. METHODS AND RESULTS: We prospectively evaluated conduit artery endothelium-dependent and -independent vasodilation, lipids, and insulin resistance in 16 consecutively treated men (mean age 66 ± 7 years; 25% with diabetes) with prostate cancer before and after 3 months of ADT. High-resolution B-mode ultrasound was used to assess flow-mediated (endothelium-dependent) and nitroglycerine-mediated (endothelium-independent) brachial artery vasodilation. ADT significantly increased insulin resistance, total cholesterol, HDL, and LDL. Endothelium-dependent vasodilation was greater at 3 months than at baseline (10.8% [interquartile range: 7.7% to 14.6%] versus 8.9% [interquartile range: 4.0% to 12.6%], respectively; P=0.046, allometric P=0.037). Nitroglycerine-mediated vasodilation did not change from baseline (P>0.2). The subset of participants on ADT for 6 months returned for reevaluation at 1 year. In this group, endothelium-dependent vasodilation increased from baseline to 3 months and returned to baseline 6 months after ADT withdrawal (9.4% [interquartile range: 6.9% to 10.9%], 11.6% [interquartile range: 7.9% to 15.2%], and 9.0% [interquartile range: 5.1% to 12.5%], respectively; P=0.05). CONCLUSIONS: In contrast to our expectation, ADT improved endothelium-dependent vasodilation and its cessation returned endothelium-dependent vasodilation to baseline. Determining the mechanism of this change requires further investigation.