Fetal echocardiographic predictors of biventricular circulation in hypoplastic left heart complex.

OBJECTIVES: To determine which echocardiographic features of hypoplastic left heart complex (HLHC) in the fetal period are predictive of biventricular (BV) circulation and to evaluate the long-term outcome of patients with HLHC, including rates of mortality, reintervention and development of further cardiac disease. METHODS: Echocardiograms of fetuses with HLHC obtained at 18-26 weeks and 27-36 weeks' gestation between 2004 and 2017 were included in the analysis. The primary outcome was successful BV circulation (Group 1). Group 2 included patients with single-ventricle palliation, death or transplant. Univariate analysis was performed on data obtained at 18-26 and 27-36 weeks and multivariate logistic regression was performed on data obtained at 27-36 weeks only. RESULTS: Of the 51 included cases, 44 achieved successful BV circulation (Group 1) and seven did not (Group 2). Right-to-left/bidirectional foramen ovale (FO) flow and a higher mitral valve (MV) annulus Z-score were associated with successful BV circulation on both univariate and multivariate analysis. Bidirectional or left-to-right FO flow, left ventricular length (LVL) Z-score of < -2.4 and a MV Z-score of < -4.5 correctly predicted 80% of Group 2 cases. Late follow-up was available for 41 patients. There were two late deaths in Group 2. Thirteen patients in Group 1 required reintervention, 12 developed mitral stenosis and five developed isolated subaortic stenosis. CONCLUSIONS: BV circulation is common in fetuses with HLHC. Higher MV annulus and LVL Z-scores and right to left direction of FO flow are important predictors of BV circulation. Long-term sequelae in those with BV circulation may include mitral and subaortic stenosis. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

General practice-based undergraduate pharmacy longitudinal clerkship: a theoretically underpinned qualitative evaluation.

BACKGROUND: A Pharmacy Longitudinal Clerkship (PLC) was designed to develop student pharmacists' (SPs) competence in a general practice setting. AIM: The aim was to carry out a theoretically underpinned qualitative evaluation of stakeholder perceptions of influences of behavioural determinants on SP development for clinical practice in general practice. METHOD: General practice-based PLCs were delivered in 2019/20 and 2020/21 for two cohorts of SPs in NHS Highland, Scotland. Qualitative semi-structured interviews were used to explore stakeholder perceptions of influences of behavioural determinants on SP development. Informed written consent was obtained. An interview schedule was developed and piloted using the Theoretical Domains Framework (TDF). Interviews were recorded, transcribed verbatim and analysed using thematic methodology. Ethics approval was granted. RESULTS: Seven SPs and five general practitioner (GP) tutors were interviewed. Key themes were identified mapped to TDF domains and included: knowledge-utilisation and practical application of knowledge; skills-triangulation of skills under clinical supervision; beliefs about capabilities-confidence building with clinical and patient contact; professional role and identity-elucidation of professional roles within general practice. CONCLUSION: This evaluation shows benefits of embedding SPs within clinical teams and immersing them in a clinical environment over a prolonged period in a general practice Pharmacy Longitudinal Clerkship. It is expected this will translate into a more confident transition to postgraduate professional clinical practice. Funding should be sought to test alternative PLC arrangements including: multiple full-time longitudinal placement blocks; or ultimately a year-long longitudinal clerkship programme with an IPE element.

Intrabony mandibular metastases caused by papillary thyroid carcinoma masquerading as a parotid swelling.

Papillary carcinoma is the most common type of thyroid cancer, accounting for 80-90% of cases. Distant metastasis of papillary thyroid cancer is uncommon, but when it does occur, it is most commonly to the lungs, liver and bone. Bone metastases to the mandible are rarely reported. We present a 68-year-old man who was referred due to a right parotid mass. Appropriate imaging and biopsy revealed a thyroid malignancy with bone metastases. The patient subsequently underwent thyroidectomy, with histology revealing multifocal papillary carcinoma. Radioactive iodine treatment was then commenced to control the metastatic disease.

Transforming the Nation's Health: next steps in mental health promotion.

The National Research Council and the Institute of Medicine have called for making the healthy mental, emotional, and behavioral development of young people a national priority. The Substance Abuse and Mental Health Services Administration (SAMHSA) in the US Department of Health and Human Services is uniquely positioned to help develop national mental health policies that promote mental health and prevent mental illnesses. In this article I describe the role of mental health in overall health, I make the case for a public health approach to mental health promotion and mental illness prevention, and I outline a strategy to promote individual, family, and community resilience. I also describe how SAMHSA works to achieve these goals. Ultimately, true health reform will not succeed without a comprehensive, committed focus on the mental health needs of all Americans.

Synovial chondromatosis of the temporomandibular joint: a case report.

Synovial chondromatosis is a rare benign condition. It most commonly affects the large joints. Presentation in the temporomandibular joint is rare. Our case was an incidental radiological finding and not diagnosed immediately, highlighting the ease with which conditions such as this can be missed, particularly in asymptomatic patients. Only 45% of patients with synovial chondromatosis show radiographic changes. Findings as significant as ours are unusual. An increased professional awareness of the radiological signs of synovial chondromatosis would be beneficial to improve diagnosis and prognosis for patients.

Agricultural intensification and ecosystem properties.

Expansion and intensification of cultivation are among the predominant global changes of this century. Intensification of agriculture by use of high-yielding crop varieties, fertilization,irrigation, and pesticides has contributed substantially to the tremendous increases in food production over the past 50 years. Land conversion and intensification,however, also alter the biotic interactions and patterns of resource availability in ecosystems and can have serious local, regional, and global environmental consequences.The use of ecologically based management strategies can increase the sustainability of agricultural production while reducing off-site consequences.

Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations.

Prion propagation involves the conversion of cellular prion protein (PrPC) into a disease-specific isomer, PrPSc, shifting from a predominantly alpha-helical to beta-sheet structure. Here, conditions were established in which recombinant human PrP could switch between the native alpha conformation, characteristic of PrPC, and a compact, highly soluble, monomeric form rich in beta structure. The soluble beta form (beta-PrP) exhibited partial resistance to proteinase K digestion, characteristic of PrPSc, and was a direct precursor of fibrillar structures closely similar to those isolated from diseased brains. The conversion of PrPC to beta-PrP in suitable cellular compartments, and its subsequent stabilization by intermolecular association, provide a molecular mechanism for prion propagation.

Advances and innovations in dialysis in the 21st century.

Patients with end stage renal failure (ESRD) require renal replacement therapy in the form of dialysis or renal transplantation. There is an increasing number of people receiving maintenance dialysis as patients with ESRD are increasing faster than the supply of transplantable organs. The mortality rate on dialysis is 4-6 times that of the general population and is substantially reduced by transplantation. For the past 8 years, dialysis research has focused on improving patient outcomes and quality of life on dialysis. This review examines recent advances in haemodialysis and peritoneal dialysis in a historical context and considers future research possibilities.

Management of the dialysis patient for the hospital physician.

As a relative shortage of organs limits transplantation rates in many countries, the number of patients on dialysis is increasing. Nephrologists in specialist centres supervise their dialysis, but increasingly in the context of acute medical emergencies, such patients present to district general hospitals. Experience in managing patients on dialysis varies among institutions. This review aims to provide a practical guide to aid general physicians involved in the delivery of hospital care, by outlining the principles of dialysis (haemodialysis and peritoneal dialysis) and examining relevant medical issues specific to dialysis patients.

Heavy metal pollution and co-selection for antibiotic resistance: A microbial palaeontology approach.

Frequent and persistent heavy metal pollution has profound effects on the composition and activity of microbial communities. Heavy metals select for metal resistance but can also co-select for resistance to antibiotics, which is a global health concern. We here document metal concentration, metal resistance and antibiotic resistance along a sediment archive from a pond in the North West of the United Kingdom covering over a century of anthropogenic pollution. We specifically focus on zinc, as it is a ubiquitous and toxic metal contaminant known to co-select for antibiotic resistance, to assess the impact of temporal variation in heavy metal pollution on microbial community diversity and to quantify the selection effects of differential heavy metal exposure on antibiotic resistance. Zinc concentration and bioavailability was found to vary over the core, likely reflecting increased industrialisation around the middle of the 20th century. Zinc concentration had a significant effect on bacterial community composition, as revealed by a positive correlation between the level of zinc tolerance in culturable bacteria and zinc concentration. The proportion of zinc resistant isolates was also positively correlated with resistance to three clinically relevant antibiotics (oxacillin, cefotaxime and trimethoprim). The abundance of the class 1 integron-integrase gene, intI1, marker for anthropogenic pollutants correlated with the prevalence of zinc- and cefotaxime resistance but not with oxacillin and trimethoprim resistance. Our microbial palaeontology approach reveals that metal-contaminated sediments from depths that pre-date the use of antibiotics were enriched in antibiotic resistant bacteria, demonstrating the pervasive effects of metal-antibiotic co-selection in the environment.

Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy.

Live cells offer unique advantages as vehicles for systemic oncolytic virus (OV) delivery. Recent studies from our laboratory and others have shown that virus-infected cells can serve as Trojan horse vehicles to evade antiviral mechanisms encountered in the bloodstream, prevent uptake by off-target tissues and act as microscale factories to produce OV upon arrival in tumor beds. However to be employed effectively, OV-infected cells are best viewed as dynamic biological systems rather than static therapeutic agents. The time-dependent processes of infection and in vivo cell trafficking will inevitably vary depending on which particular OV is being delivered, as well as the type of carrier cells (CC) employed. Understanding these parameters with respect to each unique CC/OV combination will therefore be required in order to effectively evaluate and harness their potential in preclinical study. In the following review, we discuss how early studies of OV delivery led us to investigate the use of cell carriers in our laboratory, and the approaches we are currently undertaking to compare the dynamics of different CC/OV systems. On the basis of these studies and others it is apparent that the success of any cell-based system for OV delivery rests upon the coordinated timing of three sequential phases--(1) ex vivo loading, (2) stealth delivery and (3) virus production at the tumor site. While at the current time, the timing of these processes are coupled to the natural cycle of infection and in vivo trafficking properties innate to each cell virus system, a quantitative delineation of their dynamics will lay the foundation for engineering CC/OV biotherapeutic systems that can be clinically deployed in a highly directed and controlled manner.

Policy and practice implications of epidemiological surveys on co-occurring mental and substance use disorders.

This article describes factors that influence national policy and practice, with particular focus on the implications of epidemiological survey research. Examples of areas of concern to policymakers include treatment-seeking patterns, access to care at points of service in public health and social service systems, evidence-based practices, workforce development, and the complexities of reimbursement. In responding to data on systemic barriers to care, the Substance Abuse and Mental Health Services Administration (SAMHSA) has sought to promote a no wrong door strategy to address the needs of persons with co-occurring disorders (CODs) involving their mental health and substance use. Examples of SAMHSA programs and policies addressing CODs discussed in this article include targeted partnerships with the states, mechanisms to enhance system infrastructure, technical assistance, and initiatives with special populations.

Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression.

There is evidence that in rats, partial hippocampal lesions or selective ablation of the CA3 subfield can disrupt retrieval of spatial memory and that hippocampal damage disinhibits hypothalamic-pituitary-adrenocortical (HPA)-axis activity, thereby elevating plasma levels of adrenocorticotropin and corticosterone. Here we report evidence that attenuation of CA3 lesion-induced increases in circulating corticosterone levels with the synthesis inhibitor metyrapone, administered shortly before water-maze retention testing, blocks the impairing effects of the lesion on memory retrieval. These findings suggest that elevated adrenocortical activity is critical in mediating memory retrieval deficits induced by hippocampal damage.

Mantle cell lymphoma: primary oral presentation.

Mantle-cell lymphoma is an uncommon lymphoid malignancy of B-cells. It is often aggressive and prognosis is poor. A 69-year-old gentleman with a history of ischaemic heart disease was referred from primary care with a painless right floor of mouth swelling that had been present for 1 month. He otherwise completely asymptomatic. Incisional biopsy of the lesion was undertaken and marker studies demonstrated mantle cell lymphoma. Positron emission tomography-computed tomography and bone marrow biopsy showed widespread but low volume involvement. The patient was referred to the haematology multidisciplinary team for further assessment and treatment.

Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer's Disease Suggest Disease Modification Potential.

BACKGROUND: Alzheimer's Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aß) pathology and toxic Aß oligomers. Tramiprosate, an oral agent that inhibits Aß monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease. OBJECTIVES: To determine the optimal stage of AD for future trials in APOE4/4 homozygotes. DESIGN: Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration. SETTING: Academic Alzheimer's disease centers, community-based memory clinics, and neuropsychiatric research sites. PARTICIPANTS: Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs. INTERVENTION: Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate. MEASUREMENTS: Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome. RESULTS: In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight. CONCLUSIONS: The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aß oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.

Insect transmission of plant viruses: a constraint on virus variability.

Genetic diversity in viruses is shaped by high rates of recombination and is constrained by host defenses and the requirements of transmission. Recent studies of insect-transmitted plant viruses demonstrate highly conserved molecular motifs in viral genomes that regulate the specificity of insect transmission. In contrast, advances in our understanding of host plant response to virus infection reveal some generalized patterns of host defense to a diversity of viruses.

Perkinsus marinus in coastal Georgia, USA, following a prolonged drought.

Oysters Crassostrea virginica are 'keystone' estuarine species in the southeastern USA, providing essential fish habitat, food for human consumption, filtration of water bodies, and protection against shoreline erosion. Relatively few oyster pathology studies have been conducted in Georgia. The parasitic protozoan Perkinsus marinus was first observed here in the 1960s, but has not been investigated since the late 1990s, when increasing oyster infection levels were apparent. In the late 1990s and early 2000s, the region suffered a prolonged drought, resulting in elevated salinities and the proliferation of various diseases in the marine environment. By 2003, salinities had returned to normal levels, but the effect of the drought on oysters was unknown. In June 2003, oyster reefs throughout Chatham County were sampled to evaluate the prevalence and intensity of P. marinus. The disease appears to have remained prevalent in the coastal waters of Georgia (100% prevalence at some sites), but the intensity was low, ranging from 0 to 1.83 on a scale where heavy infections rated a score of 5. While the disease did not occur at levels high enough to cause oyster mortalities, further monitoring, particularly on a temporal scale, is warranted.