Management of pregnancy in women with monogenic diabetes due to mutations in GCK, HNF1A and HNF4A genes.

Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive ß-cell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use.

Justifying quarantine in preventing the spread of COVID-19 in healthcare.

BACKGROUND: The first COVID-19-positive patient was identified in Ireland on 29 February 2020 (Department of Health, Government of Ireland; https://www.gov.ie/en/pressrelease/2f75fd-statement-from-the-national-public-healthemergency-team-sat-29-feb/). Healthcare worker (HCW) quarantining became a core intervention for those identified as 'close contacts' to reduce onward transmission within the workplace to patients and colleagues. Whether a quarantining strategy could be justified at a time when there was an increased demand for the services of HCWs remained unknown. AIMS: To establish whether quarantining staff away from a healthcare setting during a pandemic is justified. METHODS: This retrospective study examined close contacts of COVID-19-positive index cases (both residents and HCWs) in a community hospital over a 4-week period from 1 to 28 April 2020. Close contacts were identified in accordance with national guidelines. Zones of the hospital were examined to determine the number of COVID-positive index cases and their close contacts. A cumulative result for the hospital was recorded. RESULTS: While outcomes varied over time, per zone and per HCW category, the overall conversion rate from close contact to an index case was 30%. CONCLUSIONS: This study vindicates the policy of quarantining close contact HCWs from their workplaces as they pose a significant threat to both their patients and fellow workers.

An international survey of clinicians regarding their management of venous thromboembolism following the initial 3-6 months of anticoagulation.

After an initial treatment period for venous thromboembolism (VTE), indefinite anticoagulation may be considered, depending upon individual risks. The aim of the study was to determine if there is consensus amongst clinicians that manage VTE regarding which patients require 3-6 months versus indefinite anticoagulation. The importance of VTE site and severity in decision making was also evaluated. An international survey of clinicians involved in VTE management was undertaken. Respondents were asked about long-term treatment of six patients that had completed 3-6 months initial anticoagulation. These included four cases of VTE not associated with a major reversible risk factor and two control cases; one unprovoked VTE and one VTE associated with a major reversible risk factor. For consensus, there was a pre-defined equivalence boundary whereby at least 70% of clinicians had to decide either to stop or consider indefinite anticoagulation for each case. 351 responses were collected. In the control cases, there was a ≥ 95% consensus on long-term management (stop versus indefinite anticoagulation). In three of the four test cases, there was no consensus about duration of anticoagulation. In case 3, 78% (99% confidence interval 73-84%) would stop anticoagulation after 3-6 months. When analysed by grade or specialty of doctor, a lack of consensus remained. Opinion on whether site or severity of VTE influenced decision making was variable. For patients with unprovoked VTE or VTE associated with a major transient risk factor there is treatment consensus. For the remainder, there is a lack consensus regarding the need for indefinite anticoagulation.

Vaccine-induced thrombosis and thrombocytopenia (VITT) in Ireland: A review of cases and current practices.

Since the beginning of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus pandemic, several highly effective and safe vaccines have been produced at remarkable speed. Following global implementation of vaccination programmes, cases of thrombosis with thrombocytopenia following administration of adenoviral vector-based vaccines started being reported. In this review we discuss the known pathogenesis and epidemiology of so-called vaccine induced thrombocytopenia and thrombosis (VITT). We consider the available guidelines, diagnostic laboratory tests and management options for these patients. Finally, we discuss important unanswered questions and areas for future research in this novel pathoclinical entity.

Self-monitoring diabetes with multiple mobile health devices.

OBJECTIVE: The purpose of this study was to examine the use of multiple mobile health technologies to generate and transmit data from diverse patients with type 2 diabetes mellitus (T2DM) in between clinic visits. We examined the data to identify patterns that describe characteristics of patients for clinical insights. METHODS: We enrolled 60 adults with T2DM from a US healthcare system to participate in a 6-month longitudinal feasibility trial. Patient weight, physical activity, and blood glucose were self-monitored via devices provided at baseline. Patients also responded to biweekly medication adherence text message surveys. Data were aggregated in near real-time. Measures of feasibility assessing total engagement in device submissions and survey completion over the 6 months of observation were calculated. RESULTS: It was feasible for participants from different socioeconomic, educational, and racial backgrounds to use and track relevant diabetes-related data from multiple mobile health devices for at least 6 months. Both the transmission and engagement of the data revealed notable patterns and varied by patient characteristics. DISCUSSION: Using multiple mobile health tools allowed us to derive clinical insights from diverse patients with diabetes. The ubiquitous adoption of smartphones across racial, educational, and socioeconomic populations and the integration of data from mobile health devices into electronic health records present an opportunity to develop new models of care delivery for patients with T2DM that may promote equity as well.

Non-obstructive vas deferens and epididymis loss in cystic fibrosis rats.

This study utilizes morphological and mechanistic endpoints to characterize the onset of bilateral atresia of the vas deferens in a recently derived cystic fibrosis (CF) rat model. Embryonic reproductive structures, including Wolffian (mesonephric) duct, Mullerian (paramesonephric) duct, mesonephric tubules, and gonad, were shown to mature normally through late embryogenesis, with involution of the vas deferens and/or epididymis typically occurring between birth and postnatal day 4 (P4), although timing and degree of atresia varied. No evidence of mucus obstruction, which is associated with pathology in other CF-affected tissues, was observed at any embryological or postnatal time point. Reduced epididymal coiling was noted post-partum and appeared to coincide with, or predate, loss of more distal vas deferens structure. Remarkably, α smooth muscle actin expression in cells surrounding duct epithelia was markedly diminished in CF animals by P2.5 when compared to wild type counterparts, indicating reduced muscle development. RNA-seq and immunohistochemical analysis of affected tissues showed disruption of developmental signaling by Wnt and related pathways. The findings have relevance to vas deferens loss in humans with CF, where timing of ductular damage is not well characterized and underlying mechanisms are not understood. If vas deferens atresia in humans begins in late gestation and continues through early postnatal life, emerging modulator therapies given perinatally might preserve and enhance integrity of the reproductive tract, which is otherwise absent or deficient in 97% of males with cystic fibrosis.

A Multicentre Study of Thromboprophylaxis in Pregnancy.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. The risk increases with increasing maternal age, mode of delivery and medical co-morbidities. Thromboprophylaxis with low molecular weight heparin (LMWH) has been shown to be both safe and efficacious. The aim of this study was to prospectively investigate the incidence of maternal risk factors in pregnant women admitted to hospital, to calculate their VTE risk status and to investigate if they were receiving appropriate thromboprophylaxis. All patients admitted to the participating hospitals on the day of investigation were assessed for risk of VTE on the basis of hospital chart review. Five Hundred and forty women were recruited from 16 hospitals. Almost 32% (31.7%) were receiving thromboprophylaxis with LMWH. Just under 80% of patients were on the correct thromboprophylaxis strategy as defined by the RCOG guideline but 49% were under-dosed. The odds of receiving appropriate thromboprophylaxis were significantly increased if the woman was >35 years 0or with parity>3.

Reversal of warfarin anticoagulation using prothrombin complex concentrate at 25 IU kg-1 : results of the RAPID study.

BACKGROUND: Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit. OBJECTIVE: To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation. METHODS: We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively. RESULTS: Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39-520) and 30 min (range 5-100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009). CONCLUSION: The RAPID protocol reduces unwarranted delays without compromising efficacy.

Brain responses to biological motion predict treatment outcome in young children with autism.

Autism spectrum disorders (ASDs) are common yet complex neurodevelopmental disorders, characterized by social, communication and behavioral deficits. Behavioral interventions have shown favorable results-however, the promise of precision medicine in ASD is hampered by a lack of sensitive, objective neurobiological markers (neurobiomarkers) to identify subgroups of young children likely to respond to specific treatments. Such neurobiomarkers are essential because early childhood provides a sensitive window of opportunity for intervention, while unsuccessful intervention is costly to children, families and society. In young children with ASD, we show that functional magnetic resonance imaging-based stratification neurobiomarkers accurately predict responses to an evidence-based behavioral treatment-pivotal response treatment. Neural predictors were identified in the pretreatment levels of activity in response to biological vs scrambled motion in the neural circuits that support social information processing (superior temporal sulcus, fusiform gyrus, amygdala, inferior parietal cortex and superior parietal lobule) and social motivation/reward (orbitofrontal cortex, insula, putamen, pallidum and ventral striatum). The predictive value of our findings for individual children with ASD was supported by a multivariate pattern analysis with cross validation. Predicting who will respond to a particular treatment for ASD, we believe the current findings mark the very first evidence of prediction/stratification biomarkers in young children with ASD. The implications of the findings are far reaching and should greatly accelerate progress toward more precise and effective treatments for core deficits in ASD.

Ionizing radiation exposure as a result of diagnostic imaging in patients with lymphoma.

PURPOSE: Survival rates among patients with lymphoma continue to improve. Strategies aimed at reducing potential treatment-related toxicity are increasingly prioritized. While radiological procedures play an important role, ionizing radiation exposure has been linked to an increased risk of malignancy, particularly among individuals whose cumulative radiation exposure exceeds a specific threshold (75 millisieverts). METHODS: Within this retrospective study, the cumulative radiation exposure dose was quantified for 486 consecutive patients with lymphoma. RESULTS: The median estimated total cumulative effective dose (CED) of ionizing radiation per subject was 69 mSv (42-118). However, younger patients (under 40 years) had a median CED of 89 mSv (55-124). CONCLUSION: This study highlights the considerable radiation exposure occurring among patients with lymphoma as a result of diagnostic imaging. To limit the risk of secondary carcinogenesis, consideration should be given to monitoring cumulative radiation exposure in individual patients as well as considering imaging modalities, which do not impart an ionizing radiation dose.

The impact of violence reduction initiatives on emergency department attendance.

BACKGROUND: Recent violence reduction initiatives in Glasgow have led to a reduction in recorded levels of violent crime.(1) This study evaluates the impact of these initiatives on assault-related emergency department attendances and admissions. METHODS: A retrospective observational study conducted in Glasgow Royal Infirmary's emergency department comparing assault-related emergency department attendances and hospital admissions over two 30-day study periods (April 2010 and April 2012). The primary outcome measure was the change in assault-related emergency department attendances. The secondary outcome measure was the impact on assault-related hospital and critical care admissions. RESULTS: In April 2010, there were 6098 emergency department attendances, 301 (4.9%) were due to assault. In April 2012, there were 7236 emergency department attendances, 263 (3.6%) were due to assault, representing a significant reduction in assault-related attendances (p < 0.01). There were significant reductions in level 1 admissions 2010 n = 56 (19.2%), 2012 n = 36 (14.0%) p = 0.04 and critical care admissions, 2010 n = 5 (1.7%), 2012 n = 1 (0.4%) p = 0.04. CONCLUSIONS: Violence reduction initiatives in Glasgow have contributed to a reduction in assault-related emergency department attendance at Glasgow Royal Infirmary. The reduction in hospital admissions, in particular critical care admissions, suggests a reduction in morbidity and cost to the National Health Service.

Thromboprophylaxis in myeloma: what is happening outside of clinical trials?

Patients with myeloma are at high risk of venous thromboembolism (VTE). There is no consensus about what agent to use or what haematologists are doing in clinical practice. A survey was sent to haematologists treating patients with myeloma in Ireland. 32/45 (71%) responded. 13/28 (46%) felt that VTE affected < 5% of patients. However, 8/28 (29%) felt it affected 10-19%. Thromboprophylaxis was most commonly used in patients on lenalidomide; 25/28 (89%) and thalidomide; 23/28 (82%). 23/28 (82%) used LMWH and 20/28 (71%) used aspirin either very frequently or frequently. 3/28 (11%) had used dabigatran/rivaroxaban despite there being little evidence to support their use. Efficacy was the most important factor in choosing an agent for 25/28 (89%). Bleeding was not felt to be an issue 15/29 (52%) were not using thromboprophylaxis guidelines. This survey demonstrated wide variation in the beliefs and practices regarding the burden of VTE in patients with myeloma and the need for thromboprophylaxis.

Irreversible transformations of native celluloses, upon exposure to elevated temperatures.

Current research, basic and applied, assumes that observed recalcitrance of celluloses is an inherent characteristic associated with their state of aggregation in their native state; it is thought that processes of isolation remove other components of plant cell walls leaving the celluloses unchanged, even though elevated temperatures are routinely used during isolation. Since temperature elevation is known to influence the structures of all polymers, it is important to explore its influence on the character of isolated celluloses, almost always assumed to be still in their native state. Deuterium exchange is a measure of accessibility of reactive sites in celluloses. We report significant reduction in accessibility to deuterium and other probe molecules for celluloses isolated at ambient temperature and then exposed to elevated temperatures. Our results indicate that native celluloses, which are highly ordered biological structures, are irreversibly transformed and develop polymeric semi-crystalline character upon isolation at elevated temperatures.

Intercellular adhesion molecule-1 (ICAM-1) is upregulated in aggressive papillary thyroid carcinoma.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is implicated in carcinogenesis. In this study we examined the expression of ICAM-1 in papillary thyroid cancer (PTC). We hypothesized that ICAM-1 correlates with indicators of tumor aggressiveness in PTC. METHODS: Thirty-five primary and metastatic PTCs, five follicular adenomas, five Hashimoto thyroiditis, five nodular hyperplasia, and eight normal thyroid tissue samples were analyzed for ICAM-1 gene expression using quantitative reverse-transcription polymerase chain reaction (RT-PCR). ICAM-1 gene expression was analyzed at protein level by immunohistochemistry (IHC) using a semiquantitative score. Gene expression and intensity levels were correlated with markers of tumor aggressiveness including BRAF V600E mutation, tumor size, extrathyroidal extension (ETE), angiolymphatic invasion, and lymph node metastasis. RESULTS: ICAM-1 gene expression was higher in PTC (p = 0.01) and lymph node metastases (p = 0.03) when compared with benign tumors and Hashimoto's. Furthermore, PTCs exhibiting BRAF V600E mutation (p = 0.01), ETE (p < 0.01), and lymph node metastasis (p = 0.02) were associated with higher ICAM-1 levels. Gene expression correlated with protein levels on IHC. Additionally, poorly differentiated thyroid carcinoma had a higher ICAM-1 intensity score compared with well-differentiated carcinoma (p = 0.03). CONCLUSIONS: ICAM-1 expression is upregulated in papillary thyroid carcinoma. Furthermore, ICAM-1 upregulation correlated with aggressive tumor features such as BRAF V600E mutation, ETE, and lymph node metastasis, suggesting that ICAM-1 plays a role in thyroid cancer progression.

how r u??? Lesbian and bi-identified youth on MySpace.

For lesbian/bi youth, MySpace Groups have become virtual gathering places to flirt, joke, and occasionally engage one another on issues of identity and relationships. These Groups offer them opportunities to connect in ways unknown to previous generations of lesbian/bi women. This article identifies types of Topic Forums within Groups that members use to initiate ongoing exchanges as a form of virtual conversation. Four topic threads that emerged from these Forums were explored to gather information on the kinds of issues discussed by young lesbian/bi women online. The topics were "should frequent sex be relevant to a great relationship?"; "Random"; "r u out?? how did u come out?? how did ur parents take it?? when did u come out??"; and "bi or lesbian"). They provide the basis for a descriptive analysis of the ways in which young lesbian/bi women present themselves to others, react to one another, and share thoughts, experiences, and emotions in cyberspace.

Three types of memory for childhood sexual abuse: relationships to characteristics of abuse and psychological symptoms.

ABSTRACT. Data from a clinical sample (N = 88) reporting childhood sexual abuse was compared by types of memory, abuse characteristics, and psychological symptoms. Three types of memory were identified from a questionnaire ("Always" n = 27 [31%], "Recovered" n = 41 [46%], and "Both" n = 20 [23%]). When compared with narrative reports from a subset (n = 30) of the sample, the lines between "Always," "Recovered," and "Both" types of memory were ambiguous. Consistency across reports, however, was 83%. Memories classified as either "Recovered" or "Both" were associated with earlier age-at-onset and more severe psychological symptoms compared to those who "Always" remembered CSA. No significant differences were found between the "Both" and "Recovered" groups.

Memories of childhood sexual abuse: narrative analyses of types, experiences, and processes of remembering.

The study explored types of memory for childhood sexual abuse (CSA) in a clinical sample of 30 women and identified factors that led some women (n = 24) to report recovered memories. Questionnaires produced three types of memory: always (n = 6), recovered (n = 14), both (n = 10); however, analysis of narrative data also revealed the use of language that could not be categorized into discrete types. Recovered memories were linked to three categories of experience (cumulative reactions, atypical reactions, and atypical experiences). Subcategories identified specific contexts associated with those experiences. Findings suggest that further research is needed on the phenomenology of memory experiences using language derived from CSA survivors and a better understanding of the long-term process of interpretations of key experiences that result in reports of recovered memories.

Mouse models of transforming growth factor beta impact in breast development and cancer.

It is now recognized that transforming growth factor beta (TGF-beta) is an important factor that regulates normal breast development as well as breast cancer. Genetically engineered mouse models have been used to determine the role and mechanism of TGF-beta action in normal development and diseases of the breast. Using these models, it has been determined that TGF-beta regulates many steps of normal mammary gland development including branching morphogenesis, functional differentiation, cell-lineage decisions, and involution. Effects of TGF-beta on normal development are mediated through signaling in both the epithelial and stromal compartments. In cancer, mouse models have indicated that TGF-beta has biphasic effects on tumor progression, acting as a tumor suppressor in early stages of cancer and promoting invasion and metastasis at later stages. In addition, TGF-beta may play a role in tumor progression through effects on the microenvironment. Recently, experiments in several mouse models have suggested that antagonism of TGF-beta signaling may provide a therapeutic target for late-stage breast cancer, blocking metastasis without detrimental side effects. In the future, genetically altered mice will be used to establish models of human breast disease providing opportunities to test strategies for disease prevention and treatment.

Outcome of bone marrow transplantation in acquired and inherited aplastic anaemia in the Republic of Ireland.

BACKGROUND: Severe Aplastic Anaemia (SAA) and Fanconi Anaemia (FA) are rare haematological disorders characterised by pancytopenia and bone marrow hypoplasia. AIMS: We performed a retrospective study of all patients who underwent BMT for SAA and FA at St James's Hospital, Dublin, and at OLHSC, Crumlin, between 1985 and 2002. METHODS: The medical records of 63 patients, 50 with acquired SAA and 13 with FA, were reviewed. RESULTS: The median age at the time of transplant was 14 years (range 3-43 years). The actuarial survival (OS) (n = 63) was 76% at 17 years. The transplant related mortality (TRM) was 22% (n = 14). The most common cause of death was infection (46%). The survival was significantly better in patients receiving their transplant after 1995 (p = 0.002). Outcome was superior in those receiving less than 20 red cell transfusions prior to transplant: OS 91% (< 20 Units) versus 62% (> or = 20 Units). CONCLUSIONS: These national results are comparable to those of published international series and support the use of BMT in the treatment of SAA and FA. The known adverse effect of prior transfusion was confirmed.