Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Induction cyclophosphamide with maintenance immunosuppression in high-risk myasthenia gravis: long-term follow-up and safety profile.

BACKGROUND: Patients with refractory or high-risk myasthenia gravis (MG) respond poorly to conventional immunosuppressive therapy, requiring rescue therapies and often experiencing treatment toxicity. Rescue and injectable therapies do not induce remission and require repetitive administration leading to significant constraints on patients and the healthcare system. This long-term follow-up study demonstrates cyclophosphamide as a rapidly effective and safe treatment in patients with refractory or high-risk MG. METHODS: Retrospective cohort study of MG patients treated with cyclophosphamide between January 2000 and June 2022 conducted at a quaternary neuroimmunology clinic in New South Wales, Australia. RESULTS: 31 patients were treated: mean age of 64 years; median follow-up 3.6 years (5 months to 11 years); 94% seropositive to acetylcholine receptor (AChR) antibodies and 45% had thymoma. A reduced intensity cyclophosphamide induction protocol followed by oral antiproliferative maintenance is described.Median myasthenia gravis composite scores reduced by >50% after the third cycle of cyclophosphamide. Complete cessation of prednisolone was possible in 11 patients while 20 remained on prednisolone with a median daily dose of 5 mg. Plasma exchange was ceased in 62% of patients and intravenous immunoglobulin ceased in 55%. Cyclophosphamide was generally well tolerated with mild cytopenias. There were no malignancies or cases of haemorrhagic cystitis. CONCLUSION: We describe a large cohort of high-risk MG patients treated with cyclophosphamide in a retrospective single-clinic cohort. We suggest cyclophosphamide should be considered for rapid remission induction, corticosteroid reduction and long-term freedom from recurrent injectable therapies in selected patients, typically those with AChR antibodies.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.

OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.

Clinical competence, communication ability and adherence to choosing wisely recommendations for lipid reducing drug use in older adults.

BACKGROUND: Although lipid-lowering drugs are not recommended for primary prevention in patients 75+, prevalence of use is high and there is unexplained variation in prescribing between physicians. The objective of this study was to determine if physician communication ability and clinical competence are associated with prescribing lipid-lowering drugs for primary and secondary prevention. METHODS: We used a cohort of 4,501 international medical graduates, 161,214 U.S. Medicare patients with hyperlipidemia (primary prevention) and 49,780 patients with a history of cardiovascular disease (secondary prevention) not treated with lipid-lowering therapy who were seen by study physicians in ambulatory care. Clinical competence and communication ability were measured by the ECFMG clinical assessment examination. Physician citizenship, age, gender, specialty and patient characteristics were also measured. The outcome was an incident prescription of lipid-lowering drug, evaluated using multivariable GEE logistic regression models for primary and secondary prevention for patients 75+ and 65-74. RESULTS: Patients 75+ were less likely than those 65-74 to receive lipid-lowering drugs for primary (OR 0.62, 95% CI 0.59-0.66) and secondary (OR 0.70, 95% CI 0.63-0.78) prevention. For every 20% increase in clinical competence score, the odds of prescribing therapy for primary prevention to patients 75+ increased by 24% (95% CI 1.02-1.5). Communication ability had the opposite effect, reducing the odds of prescribing for primary prevention by 11% per 20% score increase (95% CI 0.8-0.99) for both age groups. Physicians who were citizens of countries with higher proportions of Hispanic (South/Central America) or Asian (Asia/Oceania) people were more likely to prescribe treatment for primary prevention, and internal medicine specialists were more likely to treat for secondary prevention than primary care physicians. CONCLUSION: Clinical competence, communication ability and physician citizenship are associated with lipid-lowering drug prescribing for primary prevention in patients aged 75+.

Do clinical and communication skills scores on credentialing exams predict potentially inappropriate antibiotic prescribing?

BACKGROUND: There is considerable variation among physicians in inappropriate antibiotic prescribing, which is hypothesized to be attributable to diagnostic uncertainty and ineffective communication. The objective of this study was to evaluate whether clinical and communication skills are associated with antibiotic prescribing for upper respiratory infections and sinusitis. METHODS: A cohort study of 2,526 international medical graduates and 48,394 U.S. Medicare patients diagnosed by study physicians with an upper respiratory infection or sinusitis between July 2014 and November 2015 was conducted. Clinical and communication skills were measured by scores achieved on the Clinical Skills Assessment examination administered by the Educational Commission for Foreign Medical Graduates (ECFMG) as a requirement for entry into U.S residency programs. Medicare Part D data were used to determine whether patients were dispensed an antibiotic following an outpatient evaluation and management visit with the study physician. Physician age, sex, specialty and practice region were retrieved from the ECFMG databased and American Medical Association (AMA) Masterfile. Multivariate GEE logistic regression was used to evaluate the association between clinical and communication skills and antibiotic prescribing, adjusting for other physician and patient characteristics. RESULTS: Physicians prescribed an antibiotic in 71.1% of encounters in which a patient was diagnosed with sinusitis, and 50.5% of encounters for upper respiratory infections. Better interpersonal skills scores were associated with a significant reduction in the odds of antibiotic prescribing (OR per score decile 0.93, 95% CI 0.87-0.99), while greater proficiency in clinical skills and English proficiency were not. Female physicians, those practicing internal medicine compared to family medicine, those with citizenship from the US compared to all other countries, and those practicing in southern of the US were also more likely to prescribe potentially unnecessary antibiotics. CONCLUSIONS: Based on this study, physicians with better interpersonal skills are less likely to prescribe antibiotics for acute sinusitis and upper respiratory infections. Future research should examine whether tailored interpersonal skills training to help physicians manage patient expectations for antibiotics could reduce unnecessary antibiotic prescribing.

Diagnosis, differential diagnosis and misdiagnosis of Susac syndrome.

BACKGROUND AND PURPOSE: Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common. METHODS: This is a retrospective review of the medical records of 32 adult patients from an Australasian cohort of SuS patients. RESULTS: An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5-100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty-two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain-eye-ear involvement, 14 with brain-ear (44%), six with brain-eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1-9 months) compared to 5.25 months (range 0.5-100 months) for patients with encephalopathy and ocular symptoms at presentation. CONCLUSIONS: Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.

Study protocol: MyoFit46-the cardiac sub-study of the MRC National Survey of Health and Development.

BACKGROUND: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD. METHODS: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. DISCUSSION: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

Voltage-gated potassium channel blanket testing in first-episode psychosis: Diagnostic nihilism?

OBJECTIVE: Voltage-gated potassium channel antibodies are implicated in limbic encephalitis and currently included in first-episode psychosis organic screening guidelines. Individuals with high-positive voltage-gated potassium channel titres most commonly present with neurological symptoms as well as sleep, cognitive, behaviour, psychosis and mood disturbance. The significance of low-positive voltage-gated potassium channel antibody titres in psychiatric patients is unclear and has not been previously examined. We aim to describe a statewide cohort of psychiatric patients with low- and high-positive voltage-gated potassium channel titres and explore if this finding influenced clinical management and patient outcomes. METHODS: A retrospective review of all voltage-gated potassium channel antibodies testing performed in public psychiatric services in Queensland, Australia, with comparison of the clinical presentation and long-term outcomes of low- and high-positive voltage-gated potassium channel titre cases. Specific antigen targets (leucine-rich glioma-inactivated protein 1 and contactin-associated protein 2 antibodies) were also assessed. RESULTS: The overall prevalence of voltage-gated potassium channel antibody positivity in Queensland, public, psychiatric service testing was 0.3% (14/4098), with 12 cases of low-positive voltage-gated potassium channel titre, 2 cases of high-positive (leucine-rich glioma-inactivated protein 1 antibody positive) cases and a voltage-gated potassium channel negative contactin-associated protein 2 antibody positive case. No low-positive case developed neurological abnormalities or had abnormal paraclinical investigations. In comparison, both high-positive voltage-gated potassium channel/leucine-rich glioma-inactivated protein 1 cases and the contactin-associated protein 2 antibody positive case rapidly developed neurological symptoms, had abnormal paraclinical testing and improved only with immunotherapy. There was no later development of encephalitic symptoms in the low-positive cases over an average of 1067 days follow-up. CONCLUSION: Voltage-gated potassium channel antibody-associated limbic encephalitis was rare, and always associated with high antibody titres. Low-positive titres were not associated with the development of encephalitis over a long period of follow-up. The value of universal voltage-gated potassium channel antibody screening is unclear, and further prospective studies in first-episode psychosis populations are required.

Decision rule to predict pneumonia in children presented with acute febrile respiratory illness.

BACKGROUND: It is a frequent challenge for physicians to identify pneumonia in patients with acute febrile respiratory symptoms, particularly in stable pediatric patients without respiratory distress. A decision rule is required to assist judgement on the need of ordering a chest radiograph. METHOD: This was a multicenter prospective study in 3 emergency departments. Children younger than 6 years old with an acute onset of fever and respiratory symptoms were recruited. Split sample method was adopted for derivation and validation of the Pediatric Acute Febrile Respiratory Illness rule (PAFRI Rule). PAFRI was derived from logistic regression with weighting based on adjusted odds ratios. RESULTS: Out of 967 children evaluated, 530 had taken chest radiograph examination, with 91 demonstrated evidence of pneumonia on radiograph. PAFRI Rule was derived from logistic regression with 5 weighed predictors: duration of fever <3 days (0 points), 3-4 days (2 points), 5-6 days (4 points), ≥7 days (5 points), chills (2 points), nasal symptoms (-2 points), abnormal chest examination (3 points), SpO2 ≤96% or tachypnea (3 points). The Area under ROC curve of the PAFRI Rule, the Bilkis Decision Rule and Bilkis Simpler Rule were 0.733, 0.600 and 0.579 respectively. A PAFRI score of ≥0 gives a sensitivity of 91.7% and negative predictive value of 97.7%. CONCLUSION: PAFRI rule can be used as a reference tool for guiding the need for taking Chest radiograph examination for pediatric patients. While promising, the PAFRI rule requires further validation. WHAT'S KNOWN ON THIS SUBJECT: It is often a challenge for physicians to identify pneumonia in children acutely febrile with respiratory symptoms, particularly in those who are stable without respiratory distress. The decision to order chest radiograph was based on clinical assessment with heterogenous practice. A valid and verified clinical prediction rule for ordering chest radiograph examination for stable febrile children without signs of respiratory distress would therefore assist in management of this group of patients. WHAT THIS STUDY ADDS: The PAFRI rule, based on parameters from clinical bedside assessment, can be used as a reference tool for guiding the need for referral to emergency department or taking use of chest radiograph for pediatric patients, and triaging for higher priority of clinical care.

Switching to peginterferon for chronic hepatitis B patients with hepatitis B e antigen seroconversion on entecavir - A prospective study.

Nucleos(t)ide analogues (NA) are effective in suppressing hepatitis B virus (HBV) replication, but most patients require long-term treatment. This study aimed to investigate switching to peginterferon as a strategy to stop NA. Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who developed HBeAg seroconversion during NA treatment were studied. All patients received open-label peginterferon alfa-2a 180 µg/wk for 48 weeks, and NA was stopped at week 4 of peginterferon treatment. The primary endpoint was sustained response, which was defined as negative HBeAg, positive anti-HBe and HBV DNA <2000 IU/mL at week 72. Other secondary endpoints including HBsAg loss at week 72 were also studied. Forty-one patients treated with entecavir for 56 ± 23 months were recruited. Sustained response was achieved in 30 patients (73%, 95% confidence interval 58%-84%). At week 72, 31 (76%) patients had HBeAg seroconversion, 56 (23%) patients had undetectable HBV DNA, 31 (76%) patients had normal ALT, and 6 patients (15%) had HBsAg loss. Baseline HBsAg level was the best predictor for both sustained response and HBsAg loss; the best HBsAg cut-off for sustained response was <1500 IU/mL and that for HBsAg loss was <500 IU/mL by receiver operating characteristic curve analysis. Twenty-two of 25 (88%) patients with baseline HBsAg <1500 IU/mL had sustained response. Five of 10 (50%) patients with baseline HBsAg <500 IU/mL developed HBsAg loss. Switching to peginterferon can be considered as a treatment option in NA-treated patients with HBeAg seroconversion, particularly among those with lower HBsAg levels.

Impact of brand drug discount cards on private insurer, government and patient expenditures.

BACKGROUND: Brand discount cards have become a popular way for patients to reduce out-of-pocket spending on drugs; however, controversy exists over their potential to increase insurers' costs. We estimated the impact of brand discount cards on Canadian drug expenditures. METHODS: Using national claims-level pharmacy adjudication data, we performed a retrospective comparison of prescriptions filled using a brand discount card matched to equivalent generic prescriptions between September 2014 and September 2017. We investigated the impact on expenditures for 3 groups of prescriptions: those paid only through private insurance, those paid only through public insurance and those paid only out of pocket. RESULTS: We studied 2.82 million prescriptions for 89 different medications for which brand discount cards were used. Use of discount cards resulted in 46% higher private insurance expenditures than comparable generic prescriptions (+$23.09 per prescription, 95% confidence interval [CI] $22.97 to $23.21). Public insurance expenditures were only slightly higher with cards: an increase of 1.3% or $0.37 per prescription (95% CI $0.33 to $0.41). Finally, out-of-pocket transactions using a card resulted in mean patient savings of 7% or $3.49 per prescription (95% CI -$3.55 to -$3.43). The impact varied widely among medicines across all 3 analyses. INTERPRETATION: The use of brand discount cards increased costs to private insurers, had little impact on public insurers and resulted in mixed impacts for patients. These effects likely resulted from private insurers reimbursing brand drug prices even when generics were available and from discount cards being adjudicated after claims were sent to other insurers in most cases. Patients and their clinicians should recognize that discount cards have mixed impacts on out-of-pocket costs.

Cognitive screening in treatment-naïve HIV-infected individuals in Hong Kong - a single center study.

BACKGROUND: HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known. METHODS: Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment. RESULTS: Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p < 0.001) but their MoCA performance was similar at both assessments. Of note, 17 participants in this subgroup scored below the IHDS cut-off at both assessments. CONCLUSIONS: Poor IHDS performance, and likely cognitive impairment, was frequently observed in treatment-naïve HIV-infected individuals in our locality. A considerable proportion continued to score below the IHDS cut-off at 6 months after cART. Depression was frequently observed in this vulnerable population and was associated with poor IHDS performance.

Fatal Strongyloides hyperinfection syndrome in an immunocompetent adult with review of the literature.

Strongyloides hyperinfection syndrome is rarely described in immunocompetent individuals. We present a case of fatal Strongyloides hyperinfection syndrome, and a literature review identifying nine other cases occurring in immunocompetent individuals, highlighting the challenges of diagnosis and treatment in this setting. While overall mortality is lower compared to immunocompromised patients, fatal outcomes still occur. A high index of suspicion is required for early diagnosis and treatment.

Food safety labelling of chicken to prevent campylobacteriosis: consumer expectations and current practices.

BACKGROUND: Campylobacter is the leading cause of bacterial gastroenteritis worldwide, and contaminated chicken is a significant vehicle for spread of the disease. This study aimed to assess consumers' knowledge of safe chicken handling practices and whether their expectations for food safety labelling of chicken are met, as a strategy to prevent campylobacteriosis. METHODS: We conducted a cross-sectional survey of 401 shoppers at supermarkets and butcheries in Wellington, New Zealand, and a systematic assessment of content and display features of chicken labels. RESULTS: While 89% of participants bought, prepared or cooked chicken, only 15% knew that most (60-90%) fresh chicken in New Zealand is contaminated by Campylobacter. Safety and correct preparation information on chicken labels, was rated 'very necessary' or 'essential' by the majority of respondents. Supermarket chicken labels scored poorly for the quality of their food safety information with an average of 1.7/5 (95% CI, 1.4-2.1) for content and 1.8/5 (95% CI, 1.6-2.0) for display. CONCLUSIONS: Most consumers are unaware of the level of Campylobacter contamination on fresh chicken and there is a significant but unmet consumer demand for information on safe chicken preparation on labels. Labels on fresh chicken products are a potentially valuable but underused tool for campylobacteriosis prevention in New Zealand.

Impact of income-based deductibles on drug use and health care utilization among older adults.

BACKGROUND: Income-based deductibles are present in several provincial public drug plans in Canada and have been the subject of extensive debate. We studied the impact of such deductibles in British Columbia's Fair PharmaCare plan on drug and health care utilization among older adults. METHODS: We used a quasi-experimental regression discontinuity design to compare the impact of deductibles in BC's PharmaCare plan between older community-dwelling adults registered for the plan who were born in 1928 through 1939 (no deductible) and those born in 1940 through 1951 (deductible equivalent to 2% of household income). We used 1.2 million person-years of data between 2003 and 2015 to study public drug plan expenditures, overall drug use, and physician and hospital resource utilization in these 2 groups. RESULTS: The income-based deductible led to a 28.6% decrease in person-years in which public drug plan benefits were received (95% confidence interval [CI] -29.7% to -27.5%) and to a reduction in the per capita extent of annual benefits by $205.59 (95% CI -$247.81 to -$163.37). Despite this difference in public subsidy, we found no difference in the number of drugs received or in total drug spending once privately paid amounts were accounted for (p = 0.4 and 0.8, respectively). Further, we found only small or nonexistent changes in health care resource utilization at the 1939 threshold. INTERPRETATION: A modest income-based deductible had a considerable impact on the extent of public subsidy for prescription drugs. However, it had only a trivial impact on overall access to medicines and use of other health services. Unlike copayments, modest income-based deductibles may safely reduce public spending on drugs for some population groups.

Interstage somatic growth in children with hypoplastic left heart syndrome after initial palliation with the hybrid procedure.

Introduction The hybrid procedure is one mode of initial palliation for hypoplastic left heart syndrome. Subsequently, patients proceed with either the "three-stage" pathway - comprehensive second stage followed by Fontan completion - or the "four-stage" pathway - Norwood procedure, hemi-Fontan, or Fontan completion. In this study, we describe somatic growth patterns observed in the hybrid groups and a comparison primary Norwood group. METHODS: A retrospective analysis of patients who have undergone hybrid procedure and Fontan completion was performed. Weight-for-age and height-for-age z-scores were recorded at each operation. RESULTS: We identified 13 hybrid patients - eight in the three-stage pathway and five in the four-stage pathway - and 49 Norwood patients. Weight: three stage: weight decreased from hybrid procedure to comprehensive second stage (-0.4±1.3 versus -2.3±1.4, p<0.01) and then increased to Fontan completion (-0.4±1.5 versus -0.6±1.4, p<0.01); four stage: weight decreased from hybrid procedure to Norwood (-2.0±1.4 versus -3.3±0.9, p=0.06), then stabilised to hemi-Fontan. Weight increased from hemi-Fontan to Fontan completion (-2.7±0.6 versus -1.0±0.7, p=0.01); primary Norwood group: weight decreased from Norwood to hemi-Fontan (p<0.001) and then increased to Fontan completion (p<0.001). Height: height declined from hybrid procedure to Fontan completion in the three-stage group. In the four-stage group, height decreased from hybrid to hemi-Fontan, and then increased to Fontan completion. The Norwood group decreased in height from Norwood to hemi-Fontan, followed by an increase to Fontan completion. CONCLUSION: In this study, we show that patients undergoing the hybrid procedure have poor weight gain before superior cavopulmonary connection, before returning to baseline by Fontan completion. This study identifies key periods to target poor somatic growth, a risk factor of morbidity and worse neurodevelopmental outcomes.

Understanding frequency-compressed Mandarin sentences: Role of vowels.

Frequency compression (FC) is an effective alternative to conventional amplification for patients with severe-to-profound middle- and high-frequency hearing loss and with some residual low frequency hearing. The present work investigated the underlying factors accounting for the intelligibility of FC-processed speech. Eighteen normal-hearing participants listened to FC-processed Mandarin sentences, and testing conditions included two compression strategies (i.e., linear and nonlinear), four degrees of compression, and two segmental conditions (i.e., vowel-center and vowel-onset). Results showed that the nonlinear strategy outperformed the linear strategy in enhancing the intelligibility of FC-processed sentences. A small frequency range of source compression region involved a lesser degree of compression, and favored a higher intelligibility score. Vowel segments carried a large amount of intelligibility information contained in nonlinearly frequency-compressed sentences, but could not fully account for the intelligibility improvement from nonlinear frequency-compression. The intelligibility benefit of FC-processed Mandarin sentences may be partially attributed to the additional F1-F2 transitional spectral envelope cue provided by nonlinear FC with the F1-included spectral region preserved.