Frozen/Thawed Samples Can Replace Fresh Samples for Assignment of ISI to Secondary Thromboplastin Standards for Multiple Reagent/Instrument Combinations: Data to Support Possible Revision of WHO Guidelines.

BACKGROUND: Calibration of thromboplastins is required for accurate calculation of the international normalised ratio (INR). Accurate INR results are required for optimal dosing of vitamin K antagonists. Decreases in vitamin K antagonist usage have made the recruitment of sample sets for international sensitivity index (ISI) calibrations more difficult. A possible solution to this would be to allow the use of frozen-thawed samples in place of fresh plasmas in the calibration of secondary standards. OBJECTIVES: We investigated the effect of freezing and thawing samples before usage in ISI calibrations of secondary standards. METHODS: Multiple reagent/instruments were tested to identify the degree of difference between a fresh sample ISI calibration and one performed on frozen-thawed samples. Where possible, the two ISI calibrations were performed on the same sample set. Alternatively, a separate set of samples from different patients was used. RESULTS: The difference in ISI values was <3% for those datasets where the same samples were used, and <6% for those datasets where two sample sets were used. Additionally, other parameters required for a valid ISI calibration showed only minor differences-some calibrations showed fewer outliers in the frozen-thawed datasets. Mean normal prothrombin time for the international reference thromboplastins was <3.5% different across four different calibrations (two for rabbit thromboplastin and two for recombinant human thromboplastin). CONCLUSIONS: This modification to the WHO guidelines would facilitate the recruitment of test plasmas in advance of calibration solving the problem of requiring availability of fresh patient samples with a range of INRs in a 5-h window. TRIAL REGISTRATION: Not a part of any clinical trial.

Characterization of Ganciclovir Dosing for the Management of Cytomegalovirus in Solid Organ Transplant Recipients Receiving Sustained Low-Efficiency Dialysis.

BACKGROUND: The optimal dosing of intravenous ganciclovir in patients receiving sustained low-efficiency dialysis (SLED) remains unclear. OBJECTIVE: The primary objective is to characterize the dosing of ganciclovir for treating and preventing cytomegalovirus (CMV) in Solid Organ Transplant Recipients receiving SLED. The secondary objective is to evaluate the safety and efficacy of the dosing practices described in this study. METHODS: Retrospective review of electronic medical records from solid organ transplant recipients (SOTRs) admitted to the Medical Surgical Intensive Care Unit at the Toronto General Hospital (TGH) between November 28, 2016, and September 1, 2021, was conducted. Patients concurrently receiving ganciclovir and SLED were included. RESULTS: Among the 27 encounters for CMV prevention, 18 patients underwent 8-hour SLED, 6 underwent 24-hour SLED, and 3 received other SLED durations. Most patients (80%) on 8-hour SLED began ganciclovir at 2.5 mg/kg/d, whereas 80% of those on 24-hour SLED started at 5 mg/kg/d. No breakthrough viremia occurred at 5 mg/kg/d, with 1 instance at 2.5 mg/kg/d. Cytopenia rates were higher at 5 mg/kg/d (33% vs 20%). For treatment (n = 20), 16 patients underwent 8-hour SLED, 2 underwent 24-hour SLED, and 2 underwent 12-hour SLED. Most (75%) on 8-hour SLED started at 2.5 mg/kg/d, whereas all on 24-hour SLED began at 5 mg/kg/d. Viral eradication rates were 75% and 60% at 2.5 and 5 mg/kg/d, respectively, with higher cytopenia rates at 5 mg/kg/d (37.5% vs 0%). Dose adjustments were primarily in response to refractory disease or cytopenia. CONCLUSION AND RELEVANCE: At our institution, ganciclovir dosing patterns suggest that for patients requiring 8-hour SLED, there is clinician comfort in using 2.5 mg/kg/d for prevention and 5 mg/kg/d for treatment. In 24-hour SLED, 5 mg/kg/d may be considered for prevention. Higher doses may be considered for CMV treatment; however, we found greater variability in the dosing practices for these patients. Further research with larger sample sizes and ganciclovir drug-level assessments is needed to optimize dosing strategies for CMV treatment.

NR2F2 regulation of interstitial to fetal Leydig cell differentiation in the testis: insights into differences of sex development.

Testicular fetal Leydig cells are a specialized cell type responsible for embryo masculinization. Fetal Leydig cells produce androgens, that induce the differentiation of male reproductive system and sexual characteristics. Deficiencies in Leydig cell differentiation leads to various disorders of sex development and male reproductive defects such as ambiguous genitalia, hypospadias, cryptorchidism, and infertility. Fetal Leydig cells are thought to originate from proliferating progenitor cells in the testis interstitium, marked by genes like Arx , Pdgfra , Tcf21 and Wnt5a . However, the precise mechanisms governing the transition from interstitial cells to fetal Leydig cells remain elusive. Through integrated approaches involving mouse models and single-nucleus multiomic analyses, we discovered that fetal Leydig cells originate from a Nr2f2 -positive non-steroidogenic interstitial cell population. Embryonic deletion of Nr2f2 in mouse testes resulted in disorders of sex development, including dysgenic testes, Leydig cell hypoplasia, cryptorchidism, and hypospadias. We found that NR2F2 promotes the progenitor cell fate while suppresses Leydig cell differentiation by directly and indirectly controlling a cohort of transcription factors and downstream genes. Bioinformatic analyses of single-nucleus ATAC-seq and NR2F2 ChIP-seq data revealed putative transcription factors co-regulating the process of interstitial to Leydig cell differentiation. Collectively, our findings not only highlight the critical role of Nr2f2 in orchestrating the transition from interstitial cells to fetal Leydig cells, but also provide molecular insight into the disorders of sex development as a result of Nr2f2 mutations.

Cardiovascular Risk Factors and Disparities in Management of Embolic Stroke: A Western Sydney Perspective.

BACKGROUND: Ischaemic stroke remains one of the leading causes of death and disability worldwide. The population of Western Sydney has a unique demographic with lower socioeconomic status and a culturally and linguistically diverse population. This study aims to investigate the demographics and cardiovascular risk factors of patients in Western Sydney, focusing on the prevalence and profile of cardioembolic (CE) strokes and embolic strokes of undetermined source (ESUS). METHOD: Prospective data were collected in 463 patients with ischaemic stroke presenting to a tertiary centre in Western Sydney, who underwent predischarge transthoracic echocardiography. Patients with haemorrhagic strokes or unclear stroke diagnosis were excluded. Analysis of stroke subtype (CE, ESUS, or non-embolic) and clinical characteristics was performed based on age, gender, and prior atrial fibrillation (AF) prevalence. RESULTS: Of the 463 patients, 147 (32%) had CE strokes, and 147 (32%) had ESUS. Cardioembolic (CE) strokes were associated with older age (≥65 years) and a history of congestive cardiac failure. Older patients had higher rates of hypertension, ischaemic heart disease, AF, and congestive heart failure. History of AF was present in 67 patients (14.5%); however, only 51% received anticoagulation before admission despite a low bleeding risk. The transthoracic echocardiography characteristics of ESUS/non-embolic strokes differed from those of CE strokes; 20% of patients with ESUS had an enlarged left atrium, suggesting a subset of patients with ESUS with a left atrial myopathy. CONCLUSIONS: Patients with ischaemic stroke in Western Sydney have a high prevalence of cardiovascular risk factors which were often undertreated. Half of the patients with prior AF did not receive anticoagulation despite low bleeding risk, indicating a gap in optimal stroke prevention. There were distinct echocardiographic characteristics among stroke subtypes. Further analysis of left atrium parameters may provide greater insights into the pathogenesis and prevention of embolic strokes.

Consent for Research Involving Spanish- and English-Speaking Latinx Adults With Schizophrenia.

BACKGROUND: Latinxs are vastly underrepresented in mental health research; one of many contributing factors may be complexities in the research consent process, including language preferences. We examined determinants of comprehension of research consent procedures and tested the effects of a preconsent research schema condition among 180 adults with schizophrenia (60 Latinx-English and 60 Latinx-Spanish preference, and 60 non-Latinx White). STUDY DESIGN: Participants were randomly assigned (equal allocation) to an educational session regarding clinical research concepts and processes (schema condition) or to an attention control. Following a subsequent simulated consent procedure for a hypothetical drug trail, comprehension of consent disclosures was measured with 2 standard measures. STUDY RESULTS: One-way ANOVAs showed significant medium effect size differences between ethnicity/language groups on both measures of comprehension (η2s = 0.066-0.070). The Latinx-Spanish group showed lower comprehension than non-Latinx White participants; differences between the 2 Latinx groups did not reach statistical significance. Group differences were not statistically significant after adjusting for differences in education, or on scores from structured measures of acculturation, health literacy, or research literacy. Two-way ANOVAs showed no significant main effects for consent procedure on either comprehension measure (Ps > .369; partial η2s < 0.006) and no significant group-by-consent interactions (Ps > .554; partial η2s < 0.008). CONCLUSIONS: Although the preconsent procedure was not effective, the results suggest health and research literacy may be targets for reducing disparities in consent comprehension. The onus is on researchers to improve communication of consent information as an important step to addressing health care disparities.

Stigma and the Intersection of Ethnicity, Gender, Romantic Relationships, and Serious Mental Illness: Perspectives from Latinxs with Schizophrenia and Their Family Members.

Romantic relationships are a fundamental part of the human experience and contribute to quality of life and recovery of people with serious mental illness (SMI). However, few psychosocial interventions exist to address this issue among people with schizophrenia, and no existing intervention focuses on Latinxs. The intersectionality of being Latinx and having schizophrenia can create a unique experience regarding stigma, romantic relationships, and gender. Guided by intersectionality theory, this study used qualitative content analysis and an intersectionality template analysis to examine data from interviews with 22 participants-11 people with diagnosed schizophrenia and their identified primary family member. Overall, findings illustrate perspectives about romantic relationships in a sample of Latinxs with schizophrenia and highlight the stigma that people with schizophrenia and their families can experience. Five key themes emerged from the data: obstacles to romantic relationships, advantages of romantic relationships, disadvantages of romantic relationships, gender-role issues and satisfaction with life, and hope for the future. Participants reported that stigma related to schizophrenia and the lack of employment were the main obstacles to establishing and maintaining romantic relationships. These findings provide an insider perspective on romantic relationships in a sample of Latinxs with schizophrenia and elucidate the importance of using an intersectionality lens to guide culturally responsive approaches.

WNK1 is required during male pachynema to sustain fertility.

WNK1 is an important regulator in many physiological functions, yet its role in male reproduction is unexplored. In the male germline, WNK1 is upregulated in preleptotene spermatocytes indicating possible function(s) in spermatogenic meiosis. Indeed, deletion of Wnk1 in mid-pachytene spermatocytes using the Wnt7a-Cre mouse led to male sterility which resembled non-obstructive azoospermia in humans, where germ cells failed to complete spermatogenesis and produced no sperm. Mechanistically, we found elevated MTOR expression and signaling in the Wnk1-depleted spermatocytes. As MTOR is a central mediator of translation, we speculated that translation may be accelerated in these spermatocytes. Supporting this, we found the acrosome protein, ACRBP to be prematurely expressed in the spermatocytes with Wnk1 deletion. Our study uncovered an MTOR-regulating factor in the male germline with potential implications in translation, and future studies will aim to understand how WNK1 regulates MTOR activity and impact translation on a broader spectrum.

Echocardiographic Assessment in Patients Recovered from Acute COVID-19 Illness.

Coronavirus (COVID-19) infections have spread rapidly worldwide and posed an immense public health problem. COVID-19 infection can affect the cardiovascular system both acutely and in patients followed up some period after COVID-19 infection. The aim of this study was to evaluate left ventricular (LV) and right ventricular (RV) function by echocardiography in COVID-19 recovered patients (hospitalized and non-hospitalized). Forty-two patients who recovered from COVID-19 but had ongoing symptoms were included in this retrospective observational cross-sectional study. Patients were followed-up at a median time of 112 days from confirmed COVID-19 diagnosis and a comprehensive echocardiogram was performed. COVID-19 patients were age- and sex-matched to healthy controls. Traditional TTE parameters and advanced echocardiographic parameters including two-dimensional LV global longitudinal strain (GLS) and RV free wall strain (FWS) were measured. LV volumes and LV ejection fraction were similar in COVID-19 patients and controls; however, LV GLS was significantly worse in the COVID-19 group (p = 0.002). Similarly, RV volumes and traditional RV function parameters were similar, but RV FWS (p = 0.009) and RV global strain (p = 0.015) were reduced. Alterations in LV and RV strain were observed in both hospitalized and non-hospitalized patients. In the subset of COVID-19 patients without any co-morbidities (n = 30), LV GLS remained reduced compared to controls. According to multivariate analysis, COVID-19 infection was the only independent determinant of reduced LV GLS (p = 0.012), while COVID-19 infection, diastolic blood pressure, and RV fractional area change were determinants of RV FWS. In this observational study, prior COVID-19 infection demonstrated LV dysfunction in patients with persistent symptoms. Abnormal LV strain was evident in both hospitalized and non-hospitalized patients, suggesting that these changes are independent of the severity of COVID-19 infection at presentation. The use of LV GLS in COVID-19 patients could have potential clinical utility to support the indication for cardiac magnetic resonance imaging in patients with possible COVID-19 related myocarditis. Future longitudinal studies are needed to evaluate its correlation with adverse cardiovascular events.

Systemic lupus erythematosus associated with development of macrophage activation syndrome and disseminated aspergillosis.

PURPOSE: Macrophage activation syndrome (MAS) is a rare illness, especially in critically ill adults. The diagnosis of MAS is challenging, requiring the expertise of multiple specialists, and treatments for MAS can be associated with catastrophic complications. CLINICAL FEATURES: We describe the case of a 31-yr-old Vietnamese student who was diagnosed with cutaneous systemic lupus erythematosus (SLE) in November 2020 and was initiated on treatment with low-dose corticosteroids and hydroxychloroquine as an outpatient. Ten days later, she presented to hospital with decreased consciousness, fever, periorbital swelling, and hypotension necessitating intubation. Computed tomography angiography (CTA) and lumbar puncture did not show a stroke or central nervous system infection. Serology and clinical presentation were consistent with MAS. She was initially treated with 4.5 g pulse methylprednisolone and subsequently with the interleukin-1 receptor antagonist, anakinra, and maintenance corticosteroids because of persistently elevated inflammatory markers. Her intensive care unit stay was complicated by aspiration, airway obstruction due to fungal tracheobronchitis necessitating extracorporeal membrane oxygenation (ECMO), and ring-enhancing cerebral lesions, and, ultimately, massive hemoptysis resulting in death. CONCLUSIONS: Four features of this case merit discussion, including the: 1) infrequent association of SLE with MAS; 2) short interval between SLE diagnosis and critical illness; 3) manifestation of fungal tracheobronchitis with airway obstruction; and 4) lack of response to antifungal treatment while receiving ECMO.

RéSUMé: OBJECTIF: Le syndrome d'activation macrophagique (SAM) est une maladie rare, en particulier chez les adultes gravement malades. Le diagnostic d'un SAM est difficile à poser, nécessitant l'expertise de plusieurs spécialistes, et les traitements de ce syndrome peuvent être associés à des complications catastrophiques. CARACTéRISTIQUES CLINIQUES: Nous décrivons le cas d'une étudiante vietnamienne de 31 ans ayant reçu un diagnostic de lupus érythémateux disséminé (LED) cutané en novembre 2020; un traitement par corticostéroïdes à faible dose et hydroxychloroquine a été amorcé en ambulatoire. Dix jours plus tard, elle s'est présentée à l'hôpital avec une diminution de la conscience, de la fièvre, un gonflement périorbitaire et une hypotension nécessitant une intubation. L'angiographie par tomodensitométrie et la ponction lombaire n'ont pas révélé d'accident vasculaire cérébral ou d'infection du système nerveux central. La sérologie et la présentation clinique correspondaient à celles d'un SAM. Elle a d'abord été traitée avec 4,5 g de méthylprednisolone en injection ponctuelle, puis avec un antagoniste du récepteur à l'interleukine-1, l'anakinra et des corticostéroïdes d'entretien en raison de marqueurs inflammatoires élevés persistants. Son séjour en soins intensifs a été compliqué par une aspiration, une obstruction des voies aériennes due à une trachéobronchite fongique nécessitant une oxygénation par membrane extracorporelle (ECMO) et des lésions cérébrales avec rehaussement en anneau, et finalement une hémoptysie massive entraînant la mort. CONCLUSION: Quatre caractéristiques de ce cas méritent d'être discutées, soit: 1) l'association peu fréquente du lupus érythémateux disséminé avec un syndrome d'activation macrophagique; 2) le court intervalle entre le diagnostic de LED et la maladie grave; 3) l'apparition d'une trachéobronchite fongique avec obstruction des voies aériennes; et 4) l'absence de réponse au traitement antifongique pendant le traitement par ECMO.

Tropoelastin Improves Post-Infarct Cardiac Function.

BACKGROUND: Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI. METHODS AND RESULTS: We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.7±4.4% versus 46.0±3.1% control) and reduced left ventricular dyssynchrony (11.4±3.5 ms versus 31.1±5.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.9±1.5% versus 20.9±2.7% control) and increased scar elastin (22±5.8% versus 6.2±1.5% control) as determined by histological assessments. RNA sequencing (RNAseq) analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac samples and showed an increase in tropoelastin within fibrotic areas. Using RNA-seq we also demonstrated the tropoelastin gene ELN is upregulated in human ischemic heart disease and during human cardiac fibroblast-myofibroblast differentiation. Furthermore, we showed by immunocytochemistry that human cardiac fibroblast synthesize increased elastin in direct response to tropoelastin treatment. CONCLUSIONS: We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis.

Somatic cell fate maintenance in mouse fetal testes via autocrine/paracrine action of AMH and activin B.

Fate determination and maintenance of fetal testes in most mammals occur cell autonomously as a result of the action of key transcription factors in Sertoli cells. However, the cases of freemartin, where an XX twin develops testis structures under the influence of an XY twin, imply that hormonal factor(s) from the XY embryo contribute to sex reversal of the XX twin. Here we show that in mouse XY embryos, Sertoli cell-derived anti-Mullerian hormone (AMH) and activin B together maintain Sertoli cell identity. Sertoli cells in the gonadal poles of XY embryos lacking both AMH and activin B transdifferentiate into their female counterpart granulosa cells, leading to ovotestis formation. The ovotestes remain to adulthood and produce both sperm and oocytes, although there are few of the former and the latter fail to mature. Finally, the ability of XY mice to masculinize ovaries is lost in the absence of these two factors. These results provide insight into fate maintenance of fetal testes through the action of putative freemartin factors.

Substance Use in Relation to Mental Illness: A Study of Mexican-Origin Latinos with Schizophrenia and Their Family Members.

Little is known about family context and substance use behaviors among Latinos with schizophrenia. Learning about patient and family caregiver perceptions of use is critical to our understanding of how best to support these vulnerable patients and family caregivers. This study explored perceptions of substance use in relation to mental illness among Latinos primarily of Mexican origin with schizophrenia and their family caregivers. Semistructured interviews were conducted with 34 participants (20 family caregivers; 14 patients) with direct and indirect substance use experience, in their preferred language. Data were analyzed using thematic analysis, which consisted of comparing codes across and within patient and family caregiver transcripts. Findings revealed that substance use affected well-being, particularly patient recovery and caregiver burden. Strategies to address well-being included limiting substance use, being vigilant about patient use, and communicating the negative impact of use. The environmental impact and stigma of substance use were major contextual challenges. Patients addressed these by limiting their socialization. Family social context was important to how substance use was perceived and managed by patients and caregivers. As such, treatment models should consider a holistic perspective that incorporates family context when addressing substance use among Latinos with schizophrenia.

Von Willebrand factor assays in patients with acquired immune thrombotic thrombocytopenia purpura treated with caplacizumab.

Acquired immune thrombotic thrombocytopenic purpura (iTTP) is a rare disease with a poor prognosis if undiagnosed. It is caused by autoantibody production to the von Willebrand factor (VWF) cleaving protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Caplacizumab, an immunoglobulin directed to the platelet glycoprotein Ibα receptor of VWF, has been reported to induce quicker resolution of iTTP compared to placebo. The laboratory measurement of VWF activity was significantly reduced in clinical trials of caplacizumab. Several VWF assays are available in the UK and this study investigated whether differences in VWF parameters were present in 11 patients diagnosed with iTTP and treated with daily caplacizumab. Chromogenic factor VIII activity, VWF antigen, collagen binding activity, VWF multimers and six VWF activity assays were measured prior to caplacizumab therapy and on several occasions during treatment. VWF antigen and collagen binding activity levels were normal or borderline normal in all patients. Ultra-large molecular weight multimers were present in all patients following treatment. VWF activity assays were normal or reduced during treatment, but this was reagent and patient dependant. In the unusual scenario of a caplacizumab-treated patient requiring measurement of VWF activity, it is important that laboratories understand how their local reagents perform as results cannot be predicted.

Left atrial strain in cardiac surveillance of bone marrow transplant patients with prior anthracycline exposure.

BACKGROUND: Bone marrow transplantation (BMT) has significantly improved survival rates in various hematological malignancies. However, this has led to an increased prevalence of long-term cardiotoxicity, particularly in those with prior anthracycline (AC) therapy. OBJECTIVES: To evaluate changes in left atrial (LA) volume and function, including LA strain, in BMT patients with prior AC exposure and evaluate its utility as a marker of diastolic dysfunction. METHODS: This was a cross-sectional analysis of 79 BMT patients with prior AC exposure who underwent a comprehensive surveillance transthoracic echocardiogram compared to age-matched healthy volunteers. Left ventricular (LV) and LA parameters were evaluated between the 2 groups. BMT patients were stratified using traditional measures of diastolic function and additionally utilizing LA strain. RESULTS: LV systolic dysfunction with reduced LVEF (13/79) or global longitudinal strain (29/79) was present in BMT patients. There were no differences in LA volumes between the two groups. LA reservoir strain (30.1 ± 11.2% vs 34.1 ± 9.6%, p < 0.001) and LA conduit strain (13.6 ± 8.4% vs 17.0 ± 10.5%, p < 0.001) were reduced in the BMT group compared to controls. LA reservoir strain had modest correlation with mitral annular e' velocity (r = 0.468, p < 0.001). Using current diastolic function guidelines, 26/79 BMT patients had evidence of diastolic dysfunction. However, utilizing LA reservoir strain, an additional 35 patients were identified. CONCLUSIONS: LA strain can identify early diastolic dysfunction in BMT patients with prior AC treatment. With diastolic dysfunction known to precede systolic dysfunction post AC, changes in LA reservoir strain may identify more patients with cardiac dysfunction, prompting increased surveillance and treatment.

The predictive value of patient, therapist, and in-session ratings of motivational factors early in remote cognitive behavioural therapy for severe health anxiety.

OBJECTIVES: Remote psychotherapy and the prevalence of Severe Health Anxiety (SHA) are both growing as a result of the COVID-19 pandemic. Remotely delivered Cognitive Behavioural Therapy (rCBT) for SHA is evidenced as effective, but many who seek help do not benefit. Motivational processes can influence outcomes, but it is unclear what assessment methods offer the best clinical utility in rCBT for SHA. DESIGN: This study compared the predictive validity of patient, therapist and in-session ratings of motivational factors taken at session two of rCBT for SHA among high healthcare users experiencing multimorbidity. METHODS: Motivational factors were assessed for 56 participants who attended at least two sessions of CBT for SHA delivered via video-conferencing or telephone. Following session two, therapists and patients completed online assessments of patient motivation. Two trained observers also rated motivational factors and therapeutic alliance from in-session interactions using session two recordings and transcripts. Multilevel modelling was used to predict health anxiety and a range of secondary health outcomes from motivation assessments. RESULTS: Where patients were more actively engaged in discussion of positive changes during session two, greater outcome improvements ensued in health anxiety and all secondary outcomes. Conversely, larger proportions of session two spent describing problems predicted poorer outcomes. Therapist and patient assessments of motivation did not predict health anxiety, but therapist assessments of client confidence and motivation predicted all secondary outcomes. CONCLUSIONS: Motivation remains an important process in CBT when delivered remotely, and motivational factors may predict outcomes more consistently from in-session interactions, compared to self-reports.

The utility of strain imaging in the cardiac surveillance of bone marrow transplant patients.

OBJECTIVE: To evaluate the utility of two-dimensional multiplanar speckle tracking strain to assess for cardiotoxicity post allogenic bone marrow transplantation (BMT) for haematological conditions. METHODS: Cross-sectional study of 120 consecutive patients post-BMT (80 pretreated with anthracyclines (BMT+AC), 40 BMT alone) recruited from a late effects haematology clinic, compared with 80 healthy controls, as part of a long-term cardiotoxicity surveillance study (mean duration from BMT to transthoracic echocardiogram 6±6 years). Left ventricular global longitudinal strain (LV GLS), global circumferential strain (LV GCS) and right ventricular free wall strain (RV FWS) were compared with traditionl parameters of function including LV ejection fraction (LVEF) and RV fractional area change. RESULTS: LV GLS (-17.7±3.0% vs -20.2±1.9%), LV GCS (-14.7±3.5% vs -20.4±2.1%) and RV FWS (-22.6±4.7% vs -28.0±3.8%) were all significantly (p=0.001) reduced in BMT+AC versus controls, while only LV GCS (-15.9±3.5% vs -20.4±2.1%) and RV FWS (-23.9±3.5% vs -28.0±3.8%) were significantly (p=0.001) reduced in BMT group versus controls. Even in patients with LVEF >53%, ~75% of patients in both BMT groups demonstrated a reduction in GCS. CONCLUSION: Multiplanar strain identifies a greater number of BMT patients with subclinical LV dysfunction rather than by GLS alone, and should be evaluated as part of post-BMT patient surveillence. Reduction in GCS is possibly due to effects of preconditioning, and is not fully explained by AC exposure.

Determinants of Exercise Capacity Following ST-Elevation Myocardial Infarction (STEMI).

BACKGROUND: Abnormal left ventricular systolic and diastolic function and reduced exercise capacity are associated with worse prognosis following ST-elevation myocardial infarction (STEMI). However, evidence is lacking on the determinants of exercise capacity following STEMI. We sought to determine the impact of systolic and diastolic dysfunction on exercise capacity and outcomes following first-ever STEMI. METHODS: In a retrospective analysis of 139 consecutive STEMI patients who had a transthoracic echocardiogram following STEMI and completed exercise treadmill testing, the primary outcome was to identify clinical and echocardiographic determinants of exercise capacity, and the secondary outcome was to identify determinants of major adverse cardiac events (MACEs). RESULTS: Mean number of metabolic equivalents (METs > 8) was used as a cut-off. Age, female sex, anterior infarction, abnormal diastolic function, minimum left atrial indexed volume (LAVImin) ≥ 18 mL/m2, average e', and E/e' were associated with METs ≤ 8, but not left ventricular ejection fraction (LVEF). On multivariate analysis, LAVImin (OR 4.3, 95%CI 1.3-14.2; p = 0.017), anterior infarction (OR 2.6, 95%CI 1.2-5.9; p = 0.022), and abnormal diastolic function (OR 3.73, 95%CI 1.7-8.4; p = 0.001) were independent predictors of METs ≤ 8. On Kaplan-Meier analysis, METs ≤ 8 (p = 0.01) and abnormal diastolic function (p = 0.04) were associated with MACEs (median follow-up 2.3 years). METs ≤ 8 was an independent predictor of MACEs (HR 3.4, 95%CI 1.2-9.8; p = 0.02). CONCLUSIONS: Following first-ever STEMI, increased LAVImin, anterior infarction, and abnormal diastolic function were independent predictors of reduced exercise capacity. Furthermore, reduced exercise capacity was an independent predictor of MACEs. These results highlight important prognostic and therapeutic implications related to abnormal diastolic function in STEMI patients that are distinct from those with LV systolic impairment.

Pluripotent stem cell-derived mesenchymal stromal cells improve cardiac function and vascularity after myocardial infarction.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been shown to improve cardiac function after injury and are the subject of ongoing clinical trials. In this study, the authors tested the cardiac regenerative potential of an induced pluripotent stem cell-derived MSC (iPSC-MSC) population (Cymerus MSCs) in a rat model of myocardial ischemia-reperfusion (I/R). Furthermore, the authors compared this efficacy with bone marrow-derived MSCs (BM-MSCs), which are the predominant cell type in clinical trials. METHODS: Four days after myocardial I/R injury, rats were randomly assigned to (i) a Cymerus MSC group (n = 15), (ii) a BM-MSC group (n = 15) or (iii) a vehicle control group (n = 14). For cell-treated animals, a total of 5 × 106 cells were injected at three sites within the infarcted left ventricular (LV) wall. RESULTS: One month after cell transplantation, Cymerus MSCs improved LV function (assessed by echocardiography) compared with vehicle and BM-MSCs. Interestingly, Cymerus MSCs enhanced angiogenesis without sustained engraftment or significant impact on infarct scar size. Suggesting safety, Cymerus MSCs had no effect on inducible tachycardia or the ventricular scar heterogeneity that provides a substrate for cardiac re-entrant circuits. CONCLUSIONS: The authors here demonstrate that intra-myocardial administration of iPSC-MSCs (Cymerus MSCs) provide better therapeutic effects compared with conventional BM-MSCs in a rodent model of myocardial I/R. Because of its manufacturing scalability, iPSC-MSC therapy offers an exciting opportunity for an "off-the-shelf" stem cell therapy for cardiac repair.

Ethanol Concentration of Kombucha Teas in British Columbia, Canada.

ABSTRACT: Kombucha is a sweetened tea beverage fermented by bacterial and yeast cultures. Sweeteners, such as glucose, sucrose, fructose, and others are converted by yeasts into ethanol and then by Acetobacter and other bacterial species into a weak acetic acid solution that is diluted, flavored, and packaged into glass or aluminum cans for consumer consumption. Naturally, fermented kombucha contains 0 to 3% alcohol by volume (ABV). However, kombucha containing ethanol is concerning for pregnant women and young children for whom low levels of ethanol consumption (<3% ABV) create adverse medical outcomes. In the province of British Columbia (BC), Canadian beverages containing >1% ABV are regulated as liquor. This study assessed ethanol concentrations in kombucha collected from processors and purchased at retail venues in BC. Ethanol values were compared with the place of manufacture (country or province) and place of purchase (grocery stores, restaurants, farmers' markets, recreational centers, and processors). Ethanol (n = 684) levels were measured by using a headspace gas chromatography-mass spectrometry method with a detection limit of 0.0002% ABV for ethanol. Overall, teas contained mean and median ethanol of 0.77 and 0.62% ABV, respectively, ranging from nondetectable up to 3.62% ABV. Four kombucha teas (0.6%) made by BC processors tested over 3% ABV, and 31.5% of samples contained ethanol that exceeded the BC regulatory limits for nonalcoholic beverages of 1% ABV. Kombucha manufactured in BC had significantly higher mean ethanol values (1.16% ABV) in comparison to all other places of manufacture. Similarly, mean ethanol tea values obtained from BC processors (1.2% ABV) and restaurants (1.01% ABV) were significantly higher than those obtained at other retail venues. This study demonstrates the potential for alcohol harm to at-risk populations consuming kombucha teas sold in BC.