Cardio-Obstetrics de novo: A State-level, Evidence-based Approach for Addressing Maternal Mortality and Severe Maternal Morbidity in Georgia.

Georgia has a high rate of severe maternal morbidity and mortality when compared to the rest of the United States1-6. Evidence gained from the Georgia Maternal Mortality Review Committee identified areas of focus for high yield clinical initiatives for improvement in maternal health outcomes2,7,8. Cardiovascular disease, including cardiomyopathy, coronary conditions, and pre-eclampsia/eclampsia, is the most common cause of pregnancy-related death in non-Hispanic, Black women in Georgia9-11. Development of a Cardio-Obstetrics program is an initiative to advance health equity by decreasing cardiovascular morbidity and mortality. This report describes the following: (1) state-level advocacy for improving maternal health outcomes with funding gained through the legislative process and partnership with a governmental agency; (2) Cardio-Obstetrics program development based on evidence gained from the maternal mortality review process; and (3) implementation of a Cardio-Obstetrics service, beginning with a focused approach for capacity building and understanding barriers to care.

Practitioner characteristics, diagnostic accuracy metrics and discovering-individual with respect to 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Knowledge of accuracy for melanoma diagnosis and melanoma discovering-individual in primary care is limited. We describe general practitioner (GP) characteristics and analyse defined diagnostic accuracy metrics for GPs in the current study comparing this with a previous study for GPs common to both, and we analyse the individual first discovering each melanoma as a lesion of concern. METHODS: The characteristics and diagnostic accuracy of 27 Australasian GPs documenting 637 melanomas on the Skin Cancer Audit Research Database (SCARD) in 2013 were described and analysed. The number needed to treat (NNT) and percentage of melanomas that were in situ (percentage in situ) were analysed as surrogates for specificity and sensitivity, respectively. The discovering-individual was analysed according to patient age and sex and lesion Breslow thickness. RESULTS: The average NNT and percentage in situ were 5.73% and 65.07%, respectively. For 21 GPs in both a 2008-2010 study and the current study, the NNT was 10.78 and 5.56, respectively (p = 0.0037). A consistent trend of decreasing NNT and increasing percentage in situ through increasingly subspecialised GP categories did not reach statistical significance. NNT trended high at ages and sites for which melanoma was rare. While the patient or family member was more likely to discover thick melanomas and melanomas in patients under 40 years, GPs discovered 73.9% of the melanomas as lesions of concern. CONCLUSIONS: GPs were the discovering-individuals for the majority of melanomas in the current study and their accuracy metrics compared favourably with published figures for dermatologists and GPs.

Reelin and APP Cooperatively Modulate Dendritic Spine Formation In Vitro and In Vivo.

Amyloid precursor protein (APP) plays an important role in the pathogenesis of Alzheimer's disease (AD), but the normal function of APP at synapses is poorly understood. We and others have found that APP interacts with Reelin and that each protein is individually important for dendritic spine formation, which is associated with learning and memory, in vitro. However, whether Reelin acts through APP to modulate dendritic spine formation or synaptic function remains unknown. In the present study, we found that Reelin treatment significantly increased dendritic spine density and PSD-95 puncta number in primary hippocampal neurons. An examination of the molecular mechanisms by which Reelin regulates dendritic spinogenesis revealed that Reelin enhanced hippocampal dendritic spine formation in a Ras/ERK/CREB signaling-dependent manner. Interestingly, Reelin did not increase dendritic spine number in primary hippocampal neurons when APP expression was reduced or in vivo in APP knockout (KO) mice. Taken together, our data are the first to demonstrate that Reelin acts cooperatively with APP to modulate dendritic spine formation and suggest that normal APP function is critical for Reelin-mediated dendritic spinogenesis at synapses.

Characteristics, treatment and outcomes of 589 melanoma patients documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: General practitioners manage more melanomas than dermatologists or surgeons in Australia. Previously undescribed, the management and outcomes of melanoma patients treated by multiple Australasian general practitioners are examined. METHODS: The characteristics, management and outcomes of 589 melanoma patients, managed by 27 Australasian general practitioners and documented on the Skin Cancer Audit Research Database (SCARD), were analysed. RESULTS: Most patients (58.9%) were males with mean age at diagnosis of 62.7 years (range 18-96), and most melanomas were in situ or thin-invasive. Patients aged under 40 years had fewer melanomas, but a higher proportion (the majority) were invasive, compared with older patients (P < 0.0001). Most (55.9%) melanomas were diagnosed following elliptical excision biopsy, the rate of unintended involved margins being eightfold higher for shave biopsies. Wide re-excision was performed by the treating general practitioner for most (74.9%) melanomas, with thick melanomas preferentially referred to surgeons. The average Breslow thickness of invasive melanomas re-excised by general practitioners was 0.67 mm compared with 1.99 mm for those referred to other specialists (P < 0.0001). Of 205 patients with invasive melanoma, 14 progressed to metastatic disease, 50% of these being associated with nodular melanoma. Nine patients progressed to melanoma-specific death. The 5-year survival rate for patients with invasive melanoma was 95.2% (95% CI: 91.2-98.5%). CONCLUSIONS: Diagnostic and therapeutic management of a series of melanoma patients by Australasian general practitioners were closely aligned with current guidelines and 5-year survival with respect to invasive melanoma was at least as favourable as national population-based metrics.

Engaging With Farmers to Explore Correlates of Bovine Tuberculosis Risk in an Internationally Important Heritage Landscape: The Burren, in the West of Ireland.

Bovith recene tuberculosis (bTB) continues to be a pathogen of concern in several countries globally. Analysis of areas that have higher incidences of bTB outbreaks has demonstrated how risk is not equally distributed, and local data collection, analysis and participatory engagement is required to develop tailored approaches. The Burren, an internationally important heritage landscape, has been an area of higher bTB incidence for many years in Ireland, and owing to its unique geology and farming heritage a survey was developed to engage with local farmers to gain greater insight into farming practices and bTB control to inform tailored approaches. The survey gathered data on the farm and animal management approaches being used within the Burren, including local farming techniques like the use of "winterage" (grazing exposed limestone dominated uplands). Thematic analysis of free text responses was undertaken. Quantitative data were then explored using statistical models to assess associations with recent (<3 years) self-reported bTB breakdown risk. There was a high number of responses demonstrating a high degree of willingness to engage on the issue. Thematic analysis suggested that wildlife and its management (culling and vaccination), testing quality, and its impact on the bTB scheme, and pessimism around eradication were important themes. Statistical analysis suggested that increasing bTB risk was primarily related to increasing herd-size and the percentage of herd owner's land inaccessible to those attempting to locate badger setts. There was less evidence for associations relating to the amount of time, or which season (i.e., summer), farmers utilized "winterage". The results of the study will feed back directly to local bTB management plans and further stakeholder engagement and is an exemplar for local tailoring of national control measures in situations of high incidences of bTB outbreaks in particular areas.

Characteristics of 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Most melanomas (including melanomas in situ), in Australasia, are treated by general practitioners (GPs). Previously undescribed, the characteristics of a series of melanomas treated by multiple GPs are examined. PATIENTS AND METHODS: Six hundred and thirty-seven melanomas treated by 27 Australasian GPs during 2013 and documented on the Skin Cancer Audit Research Database (SCARD) were analysed by anatomical site, subtype, Breslow thickness, diameter, associated naevi and linked adverse outcomes. RESULTS: Most melanomas (59.7%) were on males, mean age at diagnosis being 62.7 years (range 18-96). Most (65.0%) were in situ, with a high incidence of lentiginous melanoma (LM) (38.8%) and 32% were naevus associated. Most LM (86.4%) were in situ, compared to 55% of superficial spreading melanoma (SSM) (P < 0.0001). There was male predominance on the head, neck and trunk and female predominance on extremities. There was no significant association between Breslow thickness and diameter, with small melanomas as likely to be thick as large melanomas, and melanomas ≤3 mm diameter, on average, more likely to be invasive than larger melanomas. There was a positive correlation between age and both melanoma diameter and Breslow thickness. Seven cases progressed to melanoma-specific death: Five nodular melanoma (NM) and two SSM, one of which was thin (Breslow thickness 0.5 mm). CONCLUSIONS: A large series of melanomas treated by Australasian GPs were predominantly in situ, with a high proportion of LM subtype. With implications for GP training, NM linked to death was over-represented and there was a novel finding that older patients had larger diameter melanomas.

Exploring the Opinions of Irish Beef Farmers Regarding Dairy Beef Integration.

Background: There has been very little previous research in Ireland on the opinions of farmers regarding dairy beef integration. The need for increased dairy beef integration has assumed a greater importance in Ireland in recent years due to a rapid expansion in dairy production, and associated increase in numbers of male dairy calves born on Irish farms. The objective of this study was to explore beef farmers' views on a broad range of issues related to dairy beef integration, using a survey methodology. The survey was distributed to approximately 4,250 beef farmers via email and 1,203 participated in the study. Results: The sample was composed almost entirely of beef farmers, although a very small proportion also had a dairy enterprise on their farm. Eighty percent of the farmers were concerned with the increase in the number of male dairy calves in recent years. Fifty seven percent of farmers responded that they were not willing to rear dairy bred calves for beef. Limousin, Aberdeen Angus and Hereford were the breeds farmers would be most willing to rear for beef. Good health, breed, and conformation were ranked as the main factors calf rearers consider when buying calves. Expectation of poor profit margin, expectation of poor-quality calves, and price volatility/market uncertainty were the top ranked factors dissuading farmers from rearing dairy calves for beef. The main themes arising from the qualitative question related to beef price/ability to make a profit, breed, and calf quality. Conclusions: While it is concerning that the majority of respondents expressed an unwillingness to rear dairy bred calves for beef, approximately a quarter of beef farmers indicated a willingness to rear beef-sired dairy calves for beef. In the qualitative responses, farmers described how their concerns about calf quality and their ability to make a profit from dairy bred calves would make it difficult for them to rear these calves for beef. Future strategy will have to consider how these challenges can be overcome and the issues of who bears the risks and costs associated with greater integration will have to be carefully considered.

Exploring the Opinions of Irish Dairy Farmers Regarding Male Dairy Calves.

Background: There has been very little previous research in Ireland on the farmers' opinions regarding calf welfare issues. Calf welfare, particularly for male dairy calves, has assumed greater importance in Ireland in recent years due, in part, to an increase in the number of dairy cattle over the past decade. The objective of this study was to explore dairy farmers' views on a broad range of issues related to the expansion in the dairy herd. Methods: A survey was developed to capture the views of farmers regarding male dairy calves. The majority of questions were quantitative, and a final open-ended question collected qualitative data. The survey was distributed to ~2,900 dairy farmers via text message and 881 responses were received. Results: The sample was composed almost entirely of dairy farmers, although ~20% also had a beef enterprise on their farm. Fifty eight percent of the farmers were concerned with the increase in the number of male dairy calves in recent years. The EU's abolition of milk quotas, the profitability of dairy farming compared to other farm types, and guidance from farm advisors were the three highest ranked drivers behind the increase in the number of male dairy calves. The three highest ranked options for managing the number of male dairy calves were to increase exports, encourage greater use of sexed semen, and improve the beef merit of these calves. Eighty five percent of respondents stated that individual farmers had responsibility for making changes to the number of male dairy calves. The main themes arising from analysis of the responses to the open-ended question, seeking any additional comments, were breed, beef price, live exports, and sexed semen. Conclusions: Dairy farmers recognized the responsibility they have for making changes in respect of male dairy calves, and many demonstrated a willingness to make changes in this regard. The important role of other stakeholders, particularly suckler (system where reared from calf to beef) farmers, in rearing male dairy calves for beef production was also recognized. However, the issues of who bears the risks and costs associated with greater integration will have to be carefully considered.

Opioid-free anesthesia for adenotonsillectomy in children.

INTRODUCTION: Opioids are administered during the intraoperative and postoperative periods in pediatric adenotonsillectomy and tonsillectomy. Non-opioid analgesics are often used as an analgesic during pediatric adenotonsillectomy and tonsillectomy. In this hypothesis generating study, we are evaluating safety and efficacy of stand-alone opioid analgesia for adenotonsillectomy and tonsillectomy. METHODS: This is a single-center retrospective chart review of patients ages 2 to 13 who underwent elective adenotonsillectomy and tonsillectomy. We used a convenience sampling method to select patients who received intraoperative intravenous fentanyl, acetaminophen, ibuprofen, or any combination thereof. The following outcomes were analyzed in this study: (i) the length of Post Anesthesia Care Unit stay, (ii) administration of postoperative opioids; (iii) postoperative opioid equivalents required; (iv) administration of postoperative non-opioid analgesics; and (v) inpatient admission from ED within 30 days. We used univariate analysis to compare the data points. RESULTS: We analyzed data from 323 patients who underwent adenotonsillectomy and tonsillectomy. The Post Anesthesia Care Unit length stay was similar for the intraoperative opioid-free and intraoperative opioid groups, 146.68 (±67.35) and 143.18 (±37.85) minutes, respectively (p = 0.586). Additionally, 102 patients (73.4%) in the intraoperative opioid-free group and 184 patients (83.2%) in the intraoperative opioid group did not receive any postoperative opioids (p = 0.033). The incidence of adverse events was similar between the intraoperative opioid-free and intraoperative opioid groups 3 (2.2%) and 5 (2.7%) respectively, p-value 0.749. A subgroup analysis comparing extracapsular 235 (72.8%) versus intracapsular 88 (27.2%) tonsillectomy yielded similar results. CONCLUSION: In this study, our data indicates that American Society of Anesthesiologists I- II pediatric patients undergoing adenotonsillectomy and tonsillectomy can be efficiently and safely managed with an opioid-free intraoperative and postoperative analgesic regimen. Due to the explained limitations, our study results should be interpreted cautiously.

Rifabutin-Based Triple Therapy (RHB-105) for Helicobacter pylori Eradication: A Double-Blind, Randomized, Controlled Trial.

BACKGROUND: Although consensus supports eradication of Helicobacter pylori infections, antimicrobial resistance has substantially reduced eradication rates with most current therapies. OBJECTIVE: To assess the effectiveness of a novel rifabutin-based therapy (RHB-105) for H pylori eradication. DESIGN: Phase 3, double-blind trial (ERADICATE Hp2). (ClinicalTrials.gov: NCT03198507). SETTING: 55 clinical research sites in the United States. PARTICIPANTS: 455 treatment-naive adults with epigastric discomfort and confirmed H pylori infection. INTERVENTION: RHB-105 (amoxicillin, 3 g; omeprazole, 120 mg; and rifabutin, 150 mg) versus active comparator (amoxicillin, 3 g, and omeprazole, 120 mg), given as 4 capsules every 8 hours for 14 days. MEASUREMENTS: Between-group difference for H pylori eradication rate, demonstrated by 13C urea breath test 4 weeks after treatment, analyzed by using the χ2 test. RESULTS: In the intention-to-treat population, the eradication rate was higher with RHB-105 than with the active comparator (228 vs. 227 patients, respectively; 83.8% [95% CI, 78.4% to 88.0%] vs. 57.7% [95% CI, 51.2% to 64.0%]; P < 0.001). Eradication rates were unaffected by resistance to clarithromycin or metronidazole. No rifabutin resistance was detected. The most commonly reported adverse events (incidence ≥5%) were diarrhea (10.1% with RHB-105 vs. 7.9% with active comparator), headache (7.5% vs. 7.0%), and nausea (4.8% vs. 5.3%). LIMITATION: Persons of Asian descent were excluded because of their higher prevalence of poor cytochrome P450 2C19 metabolizers. CONCLUSION: These findings suggest potential for RHB-105 as first-line empirical H pylori therapy, addressing an unmet need in the current environment of increasing antibiotic resistance. PRIMARY FUNDING SOURCE: RedHill Biopharma Ltd.

Development and Application of a Prioritization Tool for Animal Health Surveillance Activities in Ireland.

Decisions around animal health management by stakeholders are often subject to resource limitation, therefore prioritization processes are required to evaluate whether effort is attributed appropriately. The objectives of this study were to develop and apply a surveillance prioritization process for animal health surveillance activities in Ireland. An exploratory sequential mixed research methods design was utilized. A prioritization tool was developed for surveillance activities and implemented over two phases. During the first phase, a survey was conducted which asked stakeholders to prioritize diseases/conditions by importance for Irish agriculture. In the second phase, experts identified the most important surveillance objectives, and allocated resources to the activities that they considered would best meet the surveillance objectives, for each disease/condition. This study developed a process and an accompanying user-friendly practical tool for animal disease surveillance prioritization which could be utilized by other competent authorities/governments. Antimicrobial resistance and bovine tuberculosis were ranked top of the endemic diseases/conditions in the Irish context, while African swine fever and foot and mouth disease were ranked top of the exotic diseases/conditions by the stakeholders. The study showed that for most of the diseases/conditions examined in the prioritization exercise, the respondents indicated a preference for a combination of active and passive surveillance activities. Future extensions of the tool could include prioritization on a per species basis.

A first case of hepatocellular carcinoma in the baboon (Papio spp.) placenta.

We present a case of hepatocellular carcinoma (HCC) in the placenta of healthy baboon (Papio spp.). Grossly, the fetal, maternal, and placental tissues were unremarkable. Histologically, the placenta contained an unencapsulated, poorly demarcated, infiltrative, solidly cellular neoplasm composed of cells that resembled hepatocytes. The neoplastic cells were diffusely positive for vimentin and focally positive for Ae1/Ae3, Arginase -1, glutamine synthetase, and CD10, and negative for ER, vascular markers (CD31 and D240), S100, glypican, C-reactive protein, FABP, desmin, and beta-catenin; INI1 positivity was similar to non-neoplastic tissues. The case likely represents a unique subtype of HCC.

Optical tissue clearing in combination with perfusion and immunofluorescence for placental vascular imaging.

Imaging of placental tissues is a difficult task, because of specific for this organ complex multicellular and 3D tissue structure. The tissue clearing systems (X-CLARITY) system is a valuable tool for the examining the expression of molecular pathways in whole tissues and organs, originally developed for brain imaging.In the present report, we utilized this technology for the examination of placental vasculature and protein expression in perfused human placental tissue.The placental tissue was sufficiently cleared with preservation of endothelial staining and fluorescent markers, allowing visualization using confocal microscopy. The CLARITY method and X-CLARITY system is a valuable tool in placental imaging.

Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome.

Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 28 weeks of gestation, complicates approximately 0.4%-0.7% of all pregnancies. This condition is associated with a very high neonatal mortality rate as well as an increased risk of long- and short-term severe neonatal morbidity. The causes of the mid-trimester PPROM are multifactorial. Altered membrane morphology including marked swelling and disruption of the collagen network which is seen with PPROM can be triggered by bacterial products or/and pro-inflammatory cytokines. Activation of matrix metalloproteinases (MMP) have been implicated in the mechanism of PPROM. The propagation of bacteria is an important contributing factor not only in PPROM, but also in adverse neonatal and maternal outcomes after PPROM. Inflammatory mediators likely play a causative role in both disruption of fetal membrane integrity and activation of uterine contraction. The "classic PPROM" with oligo/an-hydramnion is associated with a short latency period and worse neonatal outcome compared to similar gestational aged neonates delivered without antecedent PPROM. The "high PPROM" syndrome is defined as a defect of the chorio-amniotic membranes, which is not located over the internal cervical os. It may be associated with either a normal or reduced amount of amniotic fluid. It may explain why sensitive biochemical tests such as the Amniosure (PAMG-1) or IGFBP-1/alpha fetoprotein test can have a positive result without other signs of overt ROM such as fluid leakage with Valsalva. The membrane defect following fetoscopy also fulfils the criteria for "high PPROM" syndrome. In some cases, the rupture of only one membrane - either the chorionic or amniotic membrane, resulting in "pre-PPROM" could precede "classic PPROM" or "high PPROM". The diagnosis of PPROM is classically established by identification of nitrazine positive, fern positive watery leakage from the cervical canal observed during in specula investigation. Other more recent diagnostic tests include the vaginal swab assay for placental alpha macroglobulin-1 test or AFP and IGFBP1. In some rare cases amniocentesis and infusion of indigo carmine has been used to confirm the diagnosis of PPROM. The management of the PPROM requires balancing the potential neonatal benefits from prolongation of the pregnancy with the risk of intra-amniotic infection and its consequences for the mother and infant. Close monitoring for signs of chorioamnionitis (e.g. body temperature, CTG, CRP, leucocytes, IL-6, procalcitonine, amniotic fluid examinations) is necessary to minimize the risk of neonatal and maternal complications. In addition to delayed delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or macrolide and corticosteroids have been show to improve neonatal outcome [reducing risk of chorioamnionitis (average risk ratio (RR)=0.66), neonatal infections (RR=0.67) and abnormal ultrasound scan of neonatal brain (RR=0.67)]. The positive effect of continuous amnioinfusion through the subcutaneously implanted perinatal port system with amniotic fluid like hypo-osmotic solution in "classic PPROM" less than 28/0 weeks' gestation shows promise but must be proved in future prospective randomized studies. Systemic antibiotics administration in "pre-PPROM" without infection and hospitalization are also of questionable benefit and needs to be further evaluated in well-designed randomized prospective studies to evaluate if it is associated with any neonatal benefit as well as the relationship to possible adverse effect of antibiotics on to fetal development and neurological outcome.

Chordae Tendineae Rupture in the United States: Trends of Outcomes, Costs and Surgical Interventions.

OBJECTIVES: To describe national trends in the incidence and outcomes of patients with chordae tendineae rupture (CTR). METHODS: Patients who were diagnosed with CTR between 2000 and 2012 were identified in National (Nationwide) Inpatient Sample (NIS) registry. CTR was defined using validated International Classification of Diseases, 9th Edition, Clinical Modification diagnosis (ICD9-CM) codes. Results: A total of 37,287 (14,833 mitral valve repair, 7780 mitral valve replacement) CTR cases were identified. Overall, in-hospital mortality in CTR decreased by 3% from 2000 to 2012 (P < 0.001). From 2000 to 2012, the rate of mitral valve repair increased from 27.2% to 46.4%, (P < 0.001) with a concurrent decrease in the rate of mitral valve replacement (from 27.8 to 17.7%, P < 0.001). After multivariate adjustment, patient age (OR = 1.04, 95% CI 1.03-1.06, P < 0.001), congestive heart failure (CHF) (OR = 2.08, 95% CI 1.19-3.64, P = 0.01), myocardial infarction (MI) (OR = 3.58, 95% CI 2.10-6.11, P < 0.001), Deyo/Charlson comorbidity index (OR = 1.23, 95% CI 1.07-1.41, P < 0.003) and use of the intra aortic balloon pump (IABP) (OR = 4.81 95% CI 2.71-8.55, P < 0.001) were found to be independently associated with greater odds of mortality in these patients. Additionally, mitral valve replacement was significantly associated with higher costs of hospitalization (coefficient 15693, 95% CI 12638-18749, P < 0.001)Conclusion: Mitral valve repair is associated with reduced inpatient mortality and costs compared with mitral valve replacement. A substantial increase in the percentage of cases undergoing mitral valve repair with a concurrent decrease in cases undergoing mitral valve replacement were observed. Increasing age and comorbidity index, history of CHF and MI, and use of IABP were identified as factors that could increase the risk of mortality in patients with CTR.