Estimating the prevalence of potential and actionable drug-gene interactions in Irish primary care: A cross-sectional study.

AIMS: Pharmacogenetics (PGx) is increasingly recognized as a strategy for medicines optimisation and prevention of adverse drug reactions. According to guidelines produced by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG), most medicines with drug-gene interactions (DGIs) are prescribed in primary care. This study aimed to estimate the prevalence of potential and actionable DGIs involving all medicines dispensed in Irish primary care. METHODS: Dispensings of 46 drugs to General Medical Services (GMS) patients in the Health Service Executive Primary Care Reimbursement Service Irish pharmacy claims database from 01 January 2021 to 31 December 2021 were analysed to estimate the national prevalence of total dispensings and incidence of first-time dispensings of drugs with potential DGIs according to the CPIC and/or DPWG guidelines. Phenotype frequency data from the UK Biobank and the CPIC were used to estimate the incidence of actionable DGIs. RESULTS: One in five dispensings (12 443 637 of 62 754 498, 19.8%) were medicines with potential DGIs, 1 878 255 of these dispensed for the first time. On application of phenotype frequencies and linked guideline based therapeutic recommendations, 2 349 055 potential DGIs (18.9%) required action, such as monitoring and guarding against maximum dose, drug or dose change. One in five (369 700, 19.7%) first-time dispensings required action, with 139 169 (7.4%) requiring a change in prescribing. Antidepressants, weak opioids and statins were most commonly identified as having actionable DGIs. CONCLUSIONS: This study estimated a high prevalence of DGIs in primary care in Ireland, identifying the need and opportunity to optimize drug therapy through PGx testing.

Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up.

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype.

The objective of this study was to investigate the nature and biomechanical properties of collagen fibers within the human myocardium. Targeting cardiac interstitial abnormalities will likely become a major focus of future preventative strategies with regard to the management of cardiac dysfunction. Current knowledge regarding the component structures of myocardial collagen networks is limited, further delineation of which will require application of more innovative technologies. We applied a novel methodology involving combined confocal laser scanning and atomic force microscopy to investigate myocardial collagen within ex-vivo right atrial tissue from 10 patients undergoing elective coronary bypass surgery. Immuno-fluorescent co-staining revealed discrete collagen I and III fibers. During single fiber deformation, overall median values of stiffness recorded in collagen III were 37±16% lower than in collagen I [p<0.001]. On fiber retraction, collagen I exhibited greater degrees of elastic recoil [p<0.001; relative percentage increase in elastic recoil 7±3%] and less energy dissipation than collagen III [p<0.001; relative percentage increase in work recovered 7±2%]. In atrial biopsies taken from patients in permanent atrial fibrillation (n=5) versus sinus rhythm (n=5), stiffness of both collagen fiber subtypes was augmented (p<0.008). Myocardial fibrillar collagen fibers organize in a discrete manner and possess distinct biomechanical differences; specifically, collagen I fibers exhibit relatively higher stiffness, contrasting with higher susceptibility to plastic deformation and less energy efficiency on deformation with collagen III fibers. Augmented stiffness of both collagen fiber subtypes in tissue samples from patients with atrial fibrillation compared to those in sinus rhythm are consistent with recent published findings of increased collagen cross-linking in this setting.

A comparison of HFrEF vs HFpEF's clinical workload and cost in the first year following hospitalization and enrollment in a disease management program.

BACKGROUND: Admission with heart failure (HF) is a milestone in the progression of the disease, often resulting in higher intensity medical care and ensuing readmissions. Whilst there is evidence supporting enrolling patients in a heart failure disease management program (HF-DMP), not all reported HF-DMPs have systematically enrolled patients with HF with preserved ejection fraction (HFpEF) and there is a scarcity of literature differentiating costs based on HF-phenotype. METHODS: 1292 consenting, consecutive patients admitted with a primary diagnosis of HF were enrolled in a hospital based HF-DMP and categorized as HFpEF (EF≥45%) or HFrEF (EF<45%). Hospitalizations, primary care, medications, and DMP workload with associated costs were evaluated assessing DMP clinic-visits, telephonic contact, medication changes over 1year using a mixture of casemix and micro-costing techniques. RESULTS: The total average annual cost per patient was marginally higher in patients with HFrEF €13,011 (12,011, 14,078) than HFpEF, €12,206 (11,009, 13,518). However, emergency non-cardiovascular admission rates and average cost per patient were higher in the HFpEF vs HFrEF group (0.46 vs 0.31 per patient/12months) & €655 (318, 1073) vs €584 (396, 812). In the first 3months of the outpatient HF-DMP the HFrEF population cost more on average €791 (764, 819) vs €693 (660, 728). CONCLUSION: There are greater short-term (3-month) costs of HFrEF versus HFpEF as part of a HF-DMP following an admission. However, long-term (3-12month) costs of HFpEF are greater because of higher non-cardiovascular rehospitalisations. As HFpEF becomes the dominant form of HF, more work is required in HF-DMPs to address prevention of non-cardiovascular rehospitalisations and to integrate hospital based HF-DMPs into primary healthcare structures.

Elevated BNP with normal systolic function in asymptomatic individuals at-risk for heart failure: a marker of diastolic dysfunction and clinical risk.

BACKGROUND: B-type natriuretic peptide (BNP) is widely accepted in the evaluation of left ventricular systolic dysfunction and heart failure. However, little is known of the implications of elevated BNP levels in individuals with preserved systolic function (PSF). AIMS: To investigate the drivers and clinical implications of elevated BNP levels in asymptomatic individuals with established PSF. METHODS: We enrolled 154 individuals who all underwent physical examination, BNP evaluation and Doppler-echocardiographic studies. They were divided into those above and below the median BNP level (50 pg/ml). RESULTS: Independent predictors of higher BNP were older age, more severe left ventricular hypertrophy (LVH), reduced E/A ratio and ischaemic heart disease. Survival and multivariable analysis demonstrated more death and/or admission in those above the median BNP (HR: 4.79, p=0.007). CONCLUSIONS: Elevated BNP is the strongest, independent predictor of serious adverse cardiovascular outcomes in this population and requires closer clinical follow-up.

Importance of risk factor management in diabetic patients and reduction in Stage B heart failure.

BACKGROUND: A number of studies have demonstrated the presence of a diabetic cardiomyopathy, increasing the risk of heart failure development in this population. Improvements in present-day risk factor control may have modified the risk of diabetes-associated cardiomyopathy. AIM: We sought to determine the contemporary impact of diabetes mellitus (DM) on the prevalence of cardiomyopathy in at-risk patients with and without adjustment for risk factor control. DESIGN: A cross-sectional study in a population at risk for heart failure. METHODS: Those with diabetes were compared to those with other cardiovascular risk factors, unmatched, matched for age and gender and then matched for age, gender, body mass index, systolic blood pressure and low density lipoprotein cholesterol. RESULTS: In total, 1399 patients enrolled in the St Vincent's Screening to Prevent Heart Failure (STOP-HF) cohort were included. About 543 participants had an established history of DM. In the whole sample, Stage B heart failure (asymptomatic cardiomyopathy) was not found more frequently among the diabetic cohort compared to those without diabetes [113 (20.8%) vs. 154 (18.0%), P = 0.22], even when matched for age and gender. When controlling for these risk factors and risk factor control Stage B was found to be more prevalent in those with diabetes [88 (22.2%)] compared to those without diabetes [65 (16.4%), P = 0.048]. CONCLUSION: In this cohort of patients with established risk factors for Stage B heart failure superior risk factor management among the diabetic population appears to dilute the independent diabetic insult to left ventricular structure and function, underlining the importance and benefit of effective risk factor control in this population on cardiovascular outcomes.

Elimination of early rehospitalization in a randomized, controlled trial of multidisciplinary care in a high-risk, elderly heart failure population: the potential contributions of specialist care, clinical stability and optimal angiotensin-converting enzyme inhibitor dose at discharge.

BACKGROUND: Despite a growing body of data demonstrating the benefits of multidisciplinary care in heart failure, persistently high rates of readmission, especially within the first month of discharge, continue to be documented. AIMS: As part of an ongoing randomized study on the value of multidisciplinary care in a high risk (NYHA Class IV), elderly (mean age 69 years) heart failure population, we examined the effects of this intervention on previously high (20%) 1-month readmission rates. METHODS: Unlike previous studies of this approach, both multidisciplinary (MC) and routine care (RC) populations were cared for by the cardiology service, complied with adherence to clinical stability criteria prior to discharge (100% of patients) and received at least target dose angiotensin-converting enzyme (ACE) inhibition with perindopril prior to discharge (94% of indicated patients). We analysed death and unplanned readmission for heart failure at 1 month. RESULTS: This early report from the first 70 patients (67% male, 71% systolic dysfunction with a mean ejection fraction of 31.0+/-6.7%) enrolled in this study demonstrates elimination of 1-month hospital readmission in both RC and MC groups. This unexpected result represents a dramatic improvement both for this patient cohort (20% 30-day readmission rate prior to enrollment reduced to 0% following the index admission in both care groups) and in comparison with available data. CONCLUSIONS: Critical contributors to this improvement appear to be specialist cardiology care, adherence to clinical stability criteria prior to discharge and routine use of target or high-dose ACE inhibitor therapy prior to discharge. Widespread application of this approach may have a dramatic improvement in morbidity of CHF while limiting the escalating costs of this condition.

Physicochemical characterization of diclofenac N-(2-hydroxyethyl)pyrrolidine: anhydrate and dihydrate crystalline forms.

This study on diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) characterizes and compares the anhydrate (DHEPA) and dihydrate (DHEPH) solid state forms using powder X-ray diffraction, infrared spectroscopic, and thermal analyses. Heats of solution and intrinsic dissolution rates are determined. The thermodynamics of hydration are discussed and the entropic cost of dihydrate formation is calculated. Reported differences in the solution behavior of DHEP crystallized from different solvents are explained. The molecular structures of both solid forms were determined and are presented. Crystal data for DHEPA: triclinic, space group P-1 (No 2), a = 11.662(2) A, b = 11.874(2) A, c = 15.296(3) A, alpha = 76.183(14) degrees, beta = 84.575(12) degrees, gamma = 87.028(12) degrees V = 2046.8(6)A3, Z = 4. Crystal data for DHEPH: triclinic, space group P-1 (No 2), a = 9.356(3) A, b = 9.920(2) A, c = 13.5413(12) A, alpha = 69.915(12) degrees, beta = 82.05(2) degrees, gamma = 71.51(2) degrees, V = 1118.9(4) A3, Z = 2. The experimentally observed ease of dehydration under conditions of nitrogen purge is explained in terms of crystal packing within the dihydrate.

Strategies for reduction of neonatal mortality.

Infant mortality rates in developed countries have shown significant decreases in recent years. Two-thirds of infant mortality still occurs in the neonatal period and our aim in this study was to review the causes of these neonatal deaths and see where further improvements may be possible. A 6-yr review of all neonatal deaths of live-born infants over 500 g birthweight from 1991 to 1996 was made. The 1989 amended Wigglesworth classification was used to categorize cause of death and other perinatal variables were also recorded. Results show there were 34,375 births and 153 neonatal deaths. Classification of these deaths by Wigglesworth found 78 (51 per cent) due to congenital malformations, 58 (38 per cent) due to prematurity, 6 (4 per cent) due to asphyxia and 11 (7 per cent) due to specific other causes. The corrected neonatal mortality was 2.18. Neural tube defects alone accounted for 10 per cent of the total neonatal mortality. Fifty-five out of 58 infants who died due to prematurity had birthweight < 1000 g and survival rates in this group compared well to international standards. We conclude that a reduction in neonatal mortality is possible but is most likely to result from community focused measures such as increased use of pre- and peri-conceptional folate.

Diagnostics and therapeutic interventions in myocardial interstitial disease, a previously neglected pathology.

The emergence of cardiac fibrosis (the prototypal myocardial interstitial disease) as an important adverse predictor of risk in heart disease is not surprising given that it is largely responsible for cardiac stiffness, provides a substrate for rhythm disturbances and promotes tissue hypoxia and development of heart failure. Yet, this diagnosis remains difficult, treatment options remain limited and underlying mechanisms remain elusive. More recently, however, many notable advances in imaging techniques and biomarker discovery have been made to improve our understanding of remodelling changes that occur within the myocardial interstitium. Ground-breaking new evidence now suggests that fibrosis within the heart may not only be reversible but that it also may be amenable to pharmacological intervention. In this review, we discuss these recent advances and highlight the pressing urgency to better detect myocardial interstitial disease and to understand the underlying molecular biology that may enable discovery of more specific anti-remodelling therapies.

Profiling B-type natriuretic peptide in a stable heart failure population: a valuable adjunct to care.

AIM: To examine the prognostic importance of absolute values and change in values of BNP in patients with stable heart failure (HF). METHODS: Five-hundred and fifty-nine patients attending a disease management programme were categorized into tertiles of BNP (group 1; ≤ 95 pg/ml, group 2; 96-249 pg/ml and group 3; ≥ 250 pg/ml). A change in BNP between two stable visits was recorded. Patients were followed up for 1 year for death and a composite morbidity measure of HF hospitalization, all-cause hospitalization, unscheduled visits for clinical deterioration(UC) of HF using survival analysis. RESULTS: The risk of the combined morbidity outcome increased with increasing tertiles of BNP (Log rank = 17.8 (2), p < 0.001). Furthermore, a 50 and 25% increase in BNP predicted morbidity in stable HF patients with an initial BNP > 200 pg/ml (p = 0.02) and > 450 pg/ml (p = 0.03), respectively. CONCLUSION: In a stable community HF population, an elevated BNP or an increase in BNP predicts an adverse prognosis thereby potentially identifying a population in need of closer clinical follow-up.

Clinical and psychological impact of prophylactic implantable cardioverter-defibrillators in a community heart failure population.

AIMS: ICD implantation for primary prevention of sudden cardiac death in patients with left ventricular systolic dysfunction (ejection fraction ≤ 35%) has increased since the publication of the SCD-HEFT and MADIT-II data. The aim of this study is to examine the effectiveness and safety of prophylactic ICD use in a community heart failure population and to assess the impact on patient's quality of life. METHODS AND RESULTS: Seventy-one ICDs were inserted between the years 2002 and 2006. The mean follow-up from time of insertion was 24 ± 11 months. Eighteen patients (25%) had potentially life-saving therapy. Seven (10%) patients received inappropriate shocks. Complications were encountered in five patients (7%). CONCLUSION: In a community heart failure population, prophylactic ICD implantation is associated with a high incidence of life-saving therapy, a low complication rate and a high level of tolerability. These data indicate translation of clinical trial benefits to the general heart failure population.

Can we reduce preventable heart failure readmissions in patients enrolled in a Disease Management Programme?

BACKGROUND: Disease Management Programmes (DMPs) are successful in reducing hospital readmissions in heart failure (HF). However, there remain a number of patients enrolled in a DMP who are readmitted with HF. The primary aim of the study was to determine the proportion of preventable readmissions (PR). The secondary aim was to recognise patient characteristics which would identify certain patients at risk of having a PR. METHODS: A retrospective chart search was performed on patients readmitted over a 1-year period. RESULTS: 38.5% of readmissions were classified as PR. None of these patients made prior contact with the DMP. Admission levels of BNP, potassium, urea and creatinine were significantly lower in the PR group. CONCLUSION: DMP have proven benefits in reducing hospital readmission nonetheless a significant proportion of these readmissions are preventable. Further work is required to prospectively analyse why these patients fail to contact the DMP.

Diagnosis of new onset heart failure in the community: the importance of a shared-care approach and judicious use of BNP.

BACKGROUND: Brain natriuretic peptide (BNP) may help general practitioners (GPs) to "rule-out" heart failure (HF) and reduce referral burden on specialist assessment clinics. AIMS: To determine the diagnostic value of BNP in HF referrals by GPs to a specialist unit. METHODS: From 2003 to 2007, 327 GP referrals were made to a HF new patient diagnostic clinic (NDC) with a provisional diagnosis of HF. The NDC provides rapid assessment of potential HF patients and ensures appropriate therapy and follow-up for those with a confirmed diagnosis. HF diagnosis was confirmed by the Framingham criteria. RESULTS: HF was present in 39% of cases referred (mean age 75 +/- 10 years, 49% male). The inclusion of BNP as a "rule-out" test with a cut-off value of 100 pg/mL would have reduced the number of patients originally referred to the NDC by 175. However, this would have resulted in delayed diagnosis and treatment of 20 (16%) "false-negative" patients. CONCLUSIONS: Availability of BNP to GPs would improve referral patterns but with high risk of delayed diagnosis. The data underline the need for a shared-care approach to the new diagnosis of HF.

Neurocardiogenic syncope: a model for SIDS.

A 5 1/2 month old male infant who had suffered three acute life threatening episodes was admitted for overnight sleep studies but was found dead after their completion while still in hospital. A necropsy classified the cause of death as sudden infant death syndrome (SIDS). The sleep studies had shown no periods of apnoea (> 20 seconds) or bradycardia (< 90 beats/min), and a rapid response to nasal occlusion (5 seconds). However, autonomic function during sleep was poor, with reduced heart rate variability (6 beats/min v control 24 beats/min, SD 6.2) and postural hypotension (a 12-14% fall in resting systolic blood pressure) associated with a fall in heart rate when tilted to a vertical position. Postural hypotension with bradycardia occurs in adults with unexplained syncopal episodes and is called a neurocardiac reflex. It involves poor vasomotor tone with peripheral pooling of blood, a consequent reduction in central venous return and cardiac distension, and in some individuals a neurally mediated bradycardia, as seen in this infant, rather than the expected tachycardia. A progressive bradycardia is the predominant mechanism of death seen in SIDS infants dying on cardiorespiratory monitors at home. This case suggests that a neurocardiac reflex occurs in infants, may have been involved in this infant's death, and deserves further study in the context of SIDS.

The myth of 100% oxygen delivery through manual resuscitation bags.

OBJECTIVE: To determine the actual oxygen delivery of the manual resuscitation bags (MRBs) hanging at the bedsides of patients receiving mechanical ventilation. DESIGN: Descriptive study of 24 MRBs in use at the patient's bedside from six adult ICUs at a 1100-bed Mid-Atlantic medical center. METHODS: MRBs were Puritan Manual Resuscitators with reservoir. Oxygen concentration delivered was measured with a Ventronic Oxygen Analyzer Model 5575. Oxygen flow to the MRB was recorded before collecting data and then set at 15 L/min. The MRBs were compressed three times, with a 5-second interval between compressions. RESULTS: Oxygen flow before data collection varied from 6 L/min to 15 L/min. Measurements taken at the exit port before MRB compression ranged from 23% to 97%. Oxygen concentration ranged from 26% to 95%, with a mean of 59%. The oxygen values for each compression time were significantly lower than 100% (p < 0.001). The first compression values differed significantly from the second compression (p < 0.001) and the second differed from the third compression (p < 0.01). CONCLUSION: MRBs are not delivering the level of oxygen nurses have assumed. In addition, variation in oxygen delivery occurs from compression to compression.

Perinatal factors influencing survival in extremely low-birthweight infants.

The majority of deaths in normally formed infants occur in extremely low birth weight infants (< 1000 g). Survival rates for these infants have improved greatly but still vary from centre to centre and accurate local outcome figures are important for counselling parents and upholding standards of care. In the Rotunda Hospital, Dublin, over the 6 year period from 1 January 1990 to 31 December 1995, there were 34 474 deliveries over 500 g birthweight. One hundred and twenty-six of these were normally formed infants between 500 g and 999 g. Our objective was to analyse the factors influencing survival in these extremely low birthweight (ELBW) infants. Overall survival in the group was 63%. The most significant factors influencing survival to 28 days were gestation and birthweight. Survival increased from 33% at 24 weeks to 100% at 28 weeks' gestation and from 29% at 500-599 g to 87% at 900-999 g birthweight. Having controlled for gestational age, none of the following variables had a significant effect on survival: year of birth; gender; multiple pregnancy; 1-minute Apgar score; maternal age; parity; use of antenatal steroids; a history of antepartum haemorrhage, pre-eclamptic toxaemia or prolonged rupture of membranes. A 5-min Apgar score > 5 increased the chance of survival by 3.97 (95% CI: 1.46- 10). Both mode of delivery and incidence of chorioamnionitis had an influence on survival which varied according to the gestational age. A larger cohort of survivors would illustrate the effect of these variables more clearly.