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Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Summary: Background: Provision of feeds containing hydrolysed, peptide-based proteins and medium-chain triglycerides (MCT), can help mitigate gastrointestinal (GI) intolerance in adults with impaired GI function, maldigestion and/or malabsorption. Aim: This study evaluated a high-protein, peptide-based, MCT-containing oral nutritional supplement (PEHP; 1.5 kcal/mL and 7.5 g protein/100 mL). Methods: Adults with impaired GI function were recruited by their managing dietitian and took PEHP orally for 28-days, with GI tolerance, compliance, weight, energy and protein intake assessed via non-validated questionnaires and a 24-hour dietary recall at baseline and at intervention end. Results: Fifteen, adults (56 years (16), 67 kg (26.0), 24 kg/m2 (7.6)) took part in this study. Intensity of nausea (Z= -2.070, p=0.038, n=15) and abdominal pain (Z= -2.236, p=0.025, n=15) improved significantly compared to baseline. Reductions in the intensity of diarrhoea, constipation, vomiting, flatulence, and burping were observed but were not statistically significant (p>0.05 for all). Compliance was higher with PEHP (81% (24)) than baseline feeds (63% (42)) but not significantly. Weight remained stable between baseline (67 kg (26)) and at intervention end (67 kg (27), p=0.414, n=15). Compared to baseline, total energy intake increased with PEHP albeit not significantly (1661 kcal/day (572) vs 1981 kcal/day (592), p=0.137, n=15). Increases in total protein intake were also observed, this time significantly (61 g/day (23) vs 78 g/day (29), p=0.042, n=15). Conclusions: This study in adults with impaired GI function found that PEHP improved GI tolerance and protein intake compared to feeds taken at baseline (including both polymeric and peptide-based feeds).

Background: Osteoid osteoma accounts for 5% of bone tumours. Uncommon in the foot, although with predisposition for the talus. Methods: Retrospective review of four cases of osteoid osteoma in the foot and ankle with focus on investigation and management. Results: Equal male to female ratio. Mean age of 29.5 (±21.3). Nocturnal pain was present in 100% of cases. Three patients have had definitive treatment with resection. Mean time to diagnosis was 67 weeks (±65), and to treatment 46 weeks (±35). Diagnosis was established on imaging and histology, with sizes from 6mm to 15mm. The mean pre intervention Foot and Ankle Outcome Scores was 45%, improved to post intervention of 97%. Mean follow up time 17.6 months (±16). Conclusion: Osteoid osteomas are a challenging diagnosis. Remains an important differential in longstanding foot pain with minimal or no history of trauma. Treatment options include ablation or surgical resection. Level of evidence: IV.

Purpose: To identify novel susceptibility loci for retinal vascular tortuosity, to better understand the molecular mechanisms modulating this trait, and reveal causal relationships with diseases and their risk factors. Design: Genome-wide Association Studies (GWAS) of vascular tortuosity of retinal arteries and veins followed by replication meta-analysis and Mendelian randomization (MR). Participants: We analyzed 116 639 fundus images of suitable quality from 63 662 participants from 3 cohorts, namely the UK Biobank (n = 62 751), the Swiss Kidney Project on Genes in Hypertension (n = 397), and OphtalmoLaus (n = 512). Methods: Using a fully automated retina image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, we computed the median arterial, venous and combined vessel tortuosity measured by the distance factor (the length of a vessel segment over its chord length), as well as by 6 alternative measures that integrate over vessel curvature. We then performed the largest GWAS of these traits to date and assessed gene set enrichment using the novel high-precision statistical method PascalX. Main Outcome Measure: We evaluated the genetic association of retinal tortuosity, measured by the distance factor. Results: Higher retinal tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, metacohort. We estimated heritability at ∼25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 116 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that retinal tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, MR revealed causal effects between tortuosity, body mass index, and low-density lipoprotein. Conclusions: Several alleles associated with retinal vessel tortuosity suggest a common genetic architecture of this trait with ocular diseases (glaucoma, myopia), cardiovascular diseases, and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Purpose: Bone metastases are common, occurring in 60% to 70% of patients with advanced malignancies. Historically, bone-directed radiation therapy regimens of 30 Gy over 10 fractions were used. However, prospective randomized data suggest equivalent pain relief with shorter-course regimens. The American Society for Radiation Oncology Choosing Wisely Campaign encourages clinicians to consider shorter-course palliative regimens in patients with limited prognosis. A retrospective analysis was performed to assess patterns of short-course and single-fraction radiation therapy during the past 5 years. Methods and Materials: We queried our electronic medical record (MOSAIQ) from 2016 to 2020 for patients with bone metastases who received palliative radiation therapy. Patients receiving >10 fractions or Medicare-approved palliative courses of radiation (30 Gy/10 fractions, 24 Gy/6 fractions, 20 Gy/5 fractions, 8 Gy/1 fraction) were included. Treatment department was defined as academic (n = 2) versus community (n = 12). Short-course treatment was defined as 10 fractions. Patients were subdivided based on age and disease site. Physicians were grouped according to their year of residency completion. Multivariable logistic regression analysis identified predictors of short-course and single-fraction treatment. Results: We identified 1004 patients with 1768 bony metastases meeting inclusion criteria. The spine was the most common site, followed by pelvis/hip, extremity, and other site. Use of short-course treatment increased from 40% in 2016 to 50% in 2020. Single-fraction treatment increased from 7% in 2016 to 11% in 2020. Predictors of shorter courses included treatment at academic centers, more recent treatment, patient age >76 years, and nonspine anatomic site. Predictors of single-fraction treatment included treatment at academic centers, treating physician residency completion after 2010, patient age >76 years, and treatment to extremity or other site. Conclusions: Rates of short-course and single-fraction bone-directed radiation therapy increased within our health system over time. Treatment receipt at academic centers was associated with both short-course and single-fraction regimens. Physicians completing residency after 2010 were more likely to deliver single-fraction therapy.

Summary: Sustained elevated levels of reactive oxygen species (ROS) have been shown to be essential for regeneration in many organisms. This has been shown primarily via the use of pharmacological inhibitors targeting the family of NADPH oxidases (NOXes). To identify the specific NOXes involved in ROS production during adult caudal fin regeneration in zebrafish, we generated nox mutants for duox, nox5 and cyba (a key subunit of NOXes 1–4) and crossed these lines with a transgenic line ubiquitously expressing HyPer, which permits the measurement of ROS levels. Homozygous duox mutants had the greatest effect on ROS levels and rate of fin regeneration among the single mutants. However, duox:cyba double mutants showed a greater effect on fin regeneration than the single duox mutants, suggesting that Nox1-4 also play a role during regeneration. This work also serendipitously found that ROS levels in amputated adult zebrafish fins oscillate with a circadian rhythm.

ABSTRACT: Background: Older adults with COVID-19 are more likely to present with atypical symptoms, notably delirium. The main objective of this meta-analysis is to identify risk factors for delirium and outcomes of delirium in hospitalized older adults (65 years or above) with COVID-19. Methods: Comprehensive literature search of Embase, CINAHIL, Medline and Web of Science was performed for published literature until 31st August 2021. Two independent researchers evaluated study eligibility and assessed study quality using the Newcastle Ottawa Scale (NOS) for cohort studies and Joanna Briggs Institute (JBI) critical appraisal tools for case series. The association of various predisposing factors with delirium in this cohort was reported as odds ratio (OR) and its 95% confidence interval (CI). Results: A total of 31 studies from 11 countries were included in this review. Most of the included studies investigated patients from non-ICU settings (n = 24; 77.4%). Frailty (OR 3.52, 95% CI: 1.96–6.31, p

Summary: Serotonin-1A receptor (5HT1AR) is highly expressed in corticolimbic regions and its deficit is associated with anxiety and depression. A similar reduction in 5HT1AR heterozygous knockout (Het) mice results in anxiety-like and increased stress-reactivity phenotypes. Here we describe immunological abnormalities in Het females, characterized by an activated state of innate and adaptive immune cells. Het males showed only limited immune dysregulation. Similar immune abnormalities were present in the genetically WT female (F1) but not male offspring of Het mothers, indicating sex-specific immune system abnormalities that are dependent on the mother’s 5HT1AR deficit, known as maternal genetic effect or “genetic nurture”. Expression profiling of the maternal-fetal interface revealed reduced immune cell invasion to decidua and accelerated trophoblast migration. These data suggest that 5HT1AR deficit, by altering the maternal immune system and midgestational in utero environment, leads to sex-biased outcomes, predominantly immune dysregulation in the female and anxiety-like behavior in the male offspring.

Convolutional Neural Networks (CNNs) are a promising technique to predict highly localized fine particulate matter (i.e., PM2.5 levels) based on high-resolution satellite imagery. Unfortunately, CNNs typically require large amounts of supervised data to perform well, whereas this application generally has lots of unsupervised data (all satellite imagery) and relatively sparse supervised data (measurements from ground sensors). Previous work used transfer learning from another visual task to initialize the CNN weights; however, we hypothesize that standard transfer learning strategies would bias the CNN to focus on irrelevant details of the image for our applications. Instead, we develop a novel framework called Spatiotemporal Contrastive Learning (SCL) to pre-train the CNN. We test both regular contrastive learning and SCL on predicting PM2.5 levels from satellite images in two different cities, Delhi and Beijing, and compare to CNNs with parameters initialized randomly and by transfer learning. Our results show that regular contrastive learning and our SCL frameworks both manage to better capture spatial variation of ground-level PM2.5 concentrations compared to traditional initialization schemes, and that this performance gap increases as the number of ground sensors decreases, implying that the approach will be even more valuable in cities with fewer ground sensors. Our work demonstrates that contrastive learning is a powerful pre-training technique to build better spatial maps of PM2.5, and can be broadly applied in related situations.

SARS-CoV-2 infection causes a wide spectrum of disease severity. Identifying the immunological characteristics of severe disease and the risk factors for their development are important in the management of COVID-19. This study aimed to identify and rank clinical and immunological features associated with progression to severe COVID-19 in order to investigate an immunological signature of severe disease. One hundred and eight patients with positive SARS-CoV-2 PCR were recruited. Routine clinical and laboratory markers were measured, as well as myeloid and lymphoid whole-blood immunophenotyping and measurement of the pro-inflammatory cytokines IL-6 and soluble CD25. All analysis was carried out in a routine hospital diagnostic laboratory. Univariate analysis demonstrated that severe disease was most strongly associated with elevated CRP and IL-6, loss of DLA-DR expression on monocytes and CD10 expression on neutrophils. Unbiased machine learning demonstrated that these four features were strongly associated with severe disease, with an average prediction score for severe disease of 0.925. These results demonstrate that these four markers could be used to identify patients developing severe COVID-19 and allow timely delivery of therapeutics.

Pulmonary artery intimal sarcoma (PAIS) is a very rare tumour. The prevalence of PAIS is estimated to be between 0.001% and 0.003%, but this may be an underestimation because of potential misdiagnosis due to its similar presentation to that of pulmonary thromboembolism. The prognosis is very poor, with median overall survival between 11 and 18 months. We report a case of a 36-year-old man who presented to our cardiac surgery clinic reporting nonspecific symptoms and was found to have PAIS requiring surgical resection and adjuvant chemotherapy. We outline the radiologic features, pathologic characteristics, surgical approach, and chemotherapy treatment utilized. Résumé: Le sarcome intimal de l’artère pulmonaire est une tumeur très rare. On estime que sa prévalence se situe entre 0,001 % et 0,003 %. Elle pourrait cependant être plus élevée, étant donné que sa présentation est comparable à celle des thromboembolies pulmonaires et que les erreurs diagnostiques sont possibles. Le pronostic du sarcome intimal de l’artère pulmonaire est très sombre, la survie globale médiane variant de 11 à 18 mois. Nous décrivons le cas d’un homme de 36 ans qui s’est présenté à notre clinique de chirurgie cardiaque en décrivant des symptômes non distinctifs et qui a reçu un diagnostic de sarcome intimal de l’artère pulmonaire nécessitant une résection chirurgicale ainsi qu’une chimiothérapie adjuvante. Nous soulignons les ca-ractéristiques radiologiques et pathologiques du patient, l’approche chirurgicale adoptée et la chimiothérapie sélectionnée.

Summary: Organoids can enable the study of solid tumors initiated from a single cancer stem cell (CSC) ex vivo. We describe a serial tumor organoid plating protocol using primary colorectal cancer (CRC) tissues as a rapid and cost-efficient approach to evaluate the impact of therapeutic interventions on CSC functions. We detail the isolation of primary colorectal CSCs, organoid embedding, serial passaging, and CSC-related analytical techniques.For complete details on the use and execution of this protocol, please refer to Masibag et al. (2021) and Bergin et al. (2021).

Diagnosis of invasive fungal disease remains an ongoing challenge for clinicians, while continuously evolving treatment regimens increase patient risk for invasive infection. This case highlights how molecular testing led to the diagnosis of co-infection with two fungal pathogens producing invasive disease in a hematopoietic stem cell transplant recipient with graft-versus-host disease (GVHD). Keywords: Invasive fungal infection, Molecular diagnostics, Ibrutinib, Aspergillus, Cunninghamella

Summary: Cancer stem cells (CSCs) are documented to play a key role in tumorigenesis and therapy resistance. Despite significant progress in clinical oncology, CSC reservoirs remain elusive and difficult to eliminate. Reverse-turn peptidomimetics were characterized as disruptors of CBP/beta-Catenin interactions and represent a promising avenue to curb hyperactive canonical Wnt/beta-Catenin signaling in CSCs. Recent studies suggested Sam68 as a critical mediator of reverse-turn peptidomimetics response in CSC populations. Using computational and biochemical approaches we confirmed Sam68 as a primary target of reverse-turn peptidomimetics. Furthermore, we executed an in silico drug discovery pipeline to identify yet uncharacterized reverse-turn peptidomimetic structures displaying superior anti-CSC activity in transformed pluripotent and colorectal cancer cell models. Thus, we identified YB-0158 as a reverse-turn peptidomimetic small molecule with enhanced translational potential, altering key hallmarks of human colorectal CSCs in patient-derived ex vivo organoids and in vivo serial tumor transplantation.

Introduction: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. Methods: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. Results: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. Discussion: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.

Introduction: Pragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow. Methods: Given the broad eligibility criteria and high fracture volume at participating clinical sites in the PREPARE trial, a pragmatic sampling strategy was needed. Using data from PREPARE, descriptive statistics were used to describe the use of the sampling strategy across clinical sites. A Chi-square test was performed to explore whether use of the sampling strategy was associated with a reduction in the number of missed eligible patients. Results: 7 of 20 clinical sites (35%) elected to adopt a sampling strategy. There were 1539 patients excluded due to the use of the sampling strategy, which represents 30% of all excluded patients and 20% of all patients screened for participation. Use of the sampling strategy was associated with lower odds of missed eligible patients (297/4545 (6.5%) versus 341/3200 (10.7%) p

Epileptogenesis, the gradual process that leads to epilepsy after brain injury or genetic mutations, is a complex network phenomenon, involving a variety of morphological, biochemical and functional brain alterations. Although risk factors for developing epilepsy are known, there is currently no treatment available to prevent epilepsy. We recently proposed a multitargeted, network-based approach to prevent epileptogenesis by rationally combining clinically available drugs and provided first proof-of-concept that this strategy is effective. Here we evaluated eight novel rationally chosen combinations of 14 drugs with mechanisms that target different epileptogenic processes. The combinations consisted of 2-4 different drugs per combination and were administered systemically over 5 days during the latent epileptogenic period in the intrahippocampal kainate mouse model of acquired temporal lobe epilepsy, starting 6 h after kainate. Doses and dosing intervals were based on previous pharmacokinetic and tolerability studies in mice. The incidence and frequency of spontaneous electrographic and electroclinical seizures were recorded by continuous (24/7) video linked EEG monitoring done for seven days at 4 and 12 weeks post-kainate, i.e., long after termination of drug treatment. Compared to vehicle controls, the most effective drug combination consisted of low doses of levetiracetam, atorvastatin and ceftriaxone, which markedly reduced the incidence of electrographic seizures (by 60%; p

Summary: Background: Coronaviruses are known to precipitate disorders of smell and taste function. With the emerging global coronavirus disease (CoVID19) pandemic due to the severe acute respiratory syndrome coronavirus 2, early reports suggested that smell and taste dysfunction were clinical features of CoVID19. Our study aimed to investigate the prevalence of smell and taste disturbances in a cohort of CoVID19 positive patients who were isolated at home and being medically managed through telephone consultation. Methods: This was a retrospective cross-sectional study conducted at St. James’s Hospital Dublin, an urban 850 bed tertiary referral centre. 46 out of 50 CoVID19 positive patients, managed through a telephone clinic from the hospital infectious disease department, were assessed for olfactory and gustatory function loss. Results: The median age of participants was 36.5 years (interquartile range (IQR) 27 - 48) and 19 (41%) were male. The majority (31; 67%) never smoked and 17 (37%) reported co-morbidities. Approximately half of patients reported some degree of smell (22; 48%) or taste (25; 54%) function loss. 13 patients (28%) reported a complete loss of sense of smell, 8 (17%) reported a complete loss of sense of taste and 7 (15%) reported simultaneous total loss of both. The median age of patients with any degree of smell disturbance was significantly lower than patients without (median 30.5 years (IQR 24 – 43.25) versus 41 years (IQR 28.25 – 52.75), p = 0.025). The median age of patients with any degree of taste disturbance was lower than those without, but did not reach statistical significance (median 34 years (IQR 24 - 45) versus 40 years (IQR 27.5 – 52.5) p = 0.174). Conclusion: Smell or taste dysfunction were present in our defined subgroup of patients. Further research is required in different population cohorts to build the evidence base for smell and taste dysfunction as clinical indicators of CoVID19 disease and to assess if these symptoms persist after disease resolution.

Summary: Regular physical activity improves physical and mental health. Here we found that the effect of physical activity extends to the next generation. Voluntary wheel running of dams, from postpartum day 2 to weaning, increased the social dominance and reproductive success, but not the physical/metabolic health, of their otherwise sedentary offspring. The individual's own physical activity did not improve dominance status. Maternal exercise did not disrupt maternal care or the maternal and offspring microbiota. Rather, the development of dominance behavior in the offspring of running mothers could be explained by the reduction of LIF, CXCL1, and CXCL2 cytokines in breast milk. These data reveal a cytokine-mediated lactocrine pathway that responds to the mother's postpartum physical activity and programs offspring social dominance. As dominance behaviors are highly relevant to the individual's survival and reproduction, lactocrine programming could be an evolutionary mechanism by which a mother promotes the social rank of her offspring.

Background: The importance of airway mechanics has been increasingly recognized in pediatric asthma. However, no studies have examined responses of airway mechanics to air pollution exposure in asthmatic children. Methods: In this panel study involving indoor air filtration manipulation that created a large gradient of personal exposure to PM2.5, the airway mechanics and lung function of 43 asthmatic children 5–13 years old in a suburb of Shanghai were measured four times within 3 consecutive months. Concentrations of indoor and outdoor PM2.5 and ozone were coupled with individual time-activity data to calculate personal exposures. Linear mixed effects models were used to examine the relationships of personal exposure with indicators of airway mechanics and lung function, respectively. Results: An interquartile range (IQR) increase in 24-hour average PM2.5 personal exposure (30.3 µg/m3) in the prior day was associated with significant increases in small airway resistance (R5-R20) of 15.8%, total airway resistance (R5) of 6.3%, and airway inflammation (FeNO) of 9.6%. These associations were stronger in children with lower blood eosinophil counts (

Globally, drug-resistant epilepsy affects one third of people living with epilepsy. With limitations in treatment options for refractory epilepsy in resource-limited regions, ketogenic diet therapy is an important option to consider. Utilizing the 2015 International League Against Epilepsy recommended minimum requirements for ketogenic diet therapy, three male children with refractory epilepsy, aged 2.5, 6.5 and 10 years, were initiated on the classical ketogenic diet using locally available food in August 2017 at University Teaching Hospitals-Children's Hospital in Lusaka, Zambia, through partnership with the Epilepsy Program at Boston Children's Hospital in the United States. Following successful initiation in all three children, the diet was discontinued in the 10-year-old due to difficulties complying with the diet. The youngest child demonstrated an over 50% seizure reduction and gained developmental milestones. The third child achieved seizure freedom and showed marked improvement in behaviour. This pilot demonstrates the feasibility of ketogenic diet as an important therapeutic option for refractory epilepsy in Zambia. Given the limitations in treatment choices and medication accessibility, dietary therapy offers an alternative management strategy in our setting. Collaboration with an established ketogenic diet centre contributes to a successful program.

Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, Vif, inhibits effective IFN-α signalling via degradation of essential JAK/STAT pathway components. We found that STAT1 and STAT3 are specifically reduced in HEK293T cells expressing Vif and that full length, infectious HIV-1 IIIB strain promotes their degradation in a Vif-dependent manner. HIV-1 IIIB infection of myeloid ThP-1 cells also reduced the IFN-α-mediated induction of the anti-viral gene, ISG15, but not MxA, revealing a functional consequence of this HIV-1-mediated immune evasion strategy. Interestingly, while total STAT levels were not reduced upon in vitro IIIB infection of primary human PBMCs, IFN-α-mediated phosphorylation of STAT1 and STAT3 and ISG induction were starkly reduced, with removal of Vif (IIIBΔVif), partially restoring pSTATs, ISG15 and MxB induction. Similarly, pSTAT1 and pSTAT3 expression and IFN-α-induced ISG15 were reduced in PBMCs from HIV-infected patients, compared to healthy controls. Furthermore, IFN-α pre-treatment of a CEM T lymphoblast cells significantly inhibited HIV infection/replication (measured by cellular p24), only in the absence of Vif (IIIBΔVif), but was unable to suppress full length IIIB infection. When analysing the mechanism by which Vif might target the JAK/STAT pathway, we found Vif interacts with both STAT1 and STAT3, (but not STAT2), and its expression promotes ubiquitination and MG132-sensitive, proteosomal degradation of both proteins. Vif's Elongin-Cullin-SOCS-box binding motif enables the formation of an active E3 ligase complex, which we found to be required for Vif's degradation of STAT1 and STAT3. In fact, the E3 ligase scaffold proteins, Cul5 and Rbx2, were also found to be essential for Vif-mediated proteasomal degradation of STAT1 and STAT3. These results reveal a target for HIV-1-Vif and demonstrate how HIV-1 impairs the anti-viral activity of Type 1 IFNs, possibly explaining why both endogenous and therapeutic IFN-α fail to activate more effective control over HIV infection. Keywords: HIV-1, Type 1 IFNs, JAK/STAT, Viral immune evasion, Proteasomal degradation, ISG

The United States Environmental Protection Agency held an international two-day workshop in June 2018 to deliberate possible performance targets for non-regulatory fine particulate matter (PM2.5) and ozone (O3) air sensors. The need for a workshop arose from the lack of any market-wide manufacturer requirement for documented sensor performance evaluations, the lack of any independent third party or government-based sensor performance certification program, and uncertainty among all users as to the general usability of air sensor data. A multi-sector subject matter expert panel was assembled to facilitate an open discussion on these issues with multiple stakeholders. This summary provides an overview of the workshop purpose, key findings from the deliberations, and considerations for future actions specific to sensors. Important findings concerning PM2.5 and O3 sensors included the lack of consistent performance indicators and statistical metrics as well as highly variable data quality requirements depending on the intended use. While the workshop did not attempt to yield consensus on any topic, a key message was that a number of possible future actions would be beneficial to all stakeholders regarding sensor technologies. These included documentation of best practices, sharing quality assurance results along with sensor data, and the development of a common performance target lexicon, performance targets, and test protocols. Keywords: Low-cost air quality sensors, Performance targets, PM2.5, Ozone

Epidemiological studies investigating seroprevalence of vaccine preventable infections at both individual and population level are important in guiding screening and vaccination practices. Data on seroprevalence of common vaccine preventable infections in HIV-infected individuals is lacking.We carried out a retrospective cohort study to investigate serological immunity and factors associated with immunity to hepatitis A virus (HAV), hepatitis B virus (HBV) and varicalla virus (VZV) in a cohort of HIV-infected individuals attending a large ambulatory HIV specialist centre in Ireland.Basic demographic data including risk of acquisition of HIV and region of origin was recorded. Between-group prevalence was compared using the Chi2 test and Wilkoxin signed rank test. Univariate variables with p

We have recently synthesized a peptide called Disruptin, which comprised the SVDNPHVC segment of the epidermal growth factor receptor (EGFR) that inhibits binding of heat shock protein 90 (Hsp90) to the EGFR and EGF-dependent EGFR dimerization to cause EGFR degradation. The effect is specific for EGFR versus other Hsp90 client proteins [Ahsan et al.: (2013). Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem288, 26879–26886]. Here, we show that Disruptin decreases the clonogenicity of a variety of EGFR-dependent cancer cells in culture but not of EGFR-independent cancer or noncancerous cells. The selectivity of Disruptin toward EGFR-driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR-dependent tumor cells relative to normal cells. When administered by intraperitoneal injection into nude mice bearing EGFR-driven human tumor xenografts, Disruptin causes extensive degradation of EGFR in the tumor but not in adjacent host tissue. Disruptin markedly inhibits the growth of EGFR-driven tumors without producing the major toxicities caused by the Hsp90 inhibitor geldanamycin or by cisplatin. These findings provide proof of concept for development of a new Disruptin-like class of antitumor drugs that are directed specifically against EGFR-driven tumors.

Rasmussen's encephalitis is a rare syndrome characterized by intractable seizures, often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction. Seizures are usually the hallmark of presentation, but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua, which often requires surgical intervention. Co-occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management. We describe a rare case of dual pathology of Rasmussen's encephalitis presenting as a focal cortical dysplasia (FCD) and discuss the literature on this topic.

Summary: Introduction: Hepatitis B virus vaccination (HBVV) in the HIV-infected population has poor reported completion rates and immunological response rates. At our HIV clinic, we established a vaccine clinic to improve HBVV outcomes using interventions such as SMS text reminders and double-dose (DD) HBVV for standard-dose non-responders (SD NRs). Methods: A five-year (2003–2008) retrospective review of the completion rates and immunological response rates for HBVV after the establishment of the dedicated vaccine clinic was conducted. Statistical significance was assumed at p

Valproic acid (VPA) is widely used for the treatment of mood disorders and epilepsy, but its mechanism of action is unclear. In vivo and in vitro studies using rodent models have demonstrated that VPA has both neuroprotective and neurotrophic effects. These beneficial effects are, in part, through modulation of glial cell function. Recently, we and others have shown that VPA selectively induces caspase-3 mediated apoptosis in rodent microglial cells. However, the effect of VPA on human microglia has not been tested. In this study, using microglia derived from adult human brains, we demonstrate that VPA does not induce microglial apoptosis as determined by the absence of caspase-3 cleavage. However, VPA does partially decrease the expression of the microglial markers PU.1 and CD45, as well as dramatically reducing microglial phagocytosis. Due to the many roles of microglia in the brain, these VPA-induced alterations in microglial phenotype could potentially have major effects on physiological and pathological actions of these cells.

We present a case which highlights several areas of concern relating to the prevention and management of varicella in Ireland. We review the pathophysiology of this virus and highlight its greater potential for morbidity in certain groups, most particularly adult males. The experience and opinions with regard to varicella vaccination in the US and other temperate countries is reviewed along with evidence of changing epidemiology of varicella infection. The National Immunisation Advisory Committee (NIAC) guidelines are reviewed in the context of our experience. Keywords: Varicella, Vaccination, Migration, Adult, Brugada

Background: Right ventricular (RV) failure after left ventricular assist device (VAD) implantation is a difficult problem. One solution is the implantation of continuous-flow VADs in a biventricular configuration. Disappointing survival and a concerning incidence of right-sided pump thrombosis have been previously reported., Methods: From May 2017 to April 2020, a total of 12 patients underwent implantation of HeartMate 3 (HM3) biventricular VADs (BiVADs) as a bridge to cardiac transplantation. The right-sided pump was implanted in the right atrium in all cases. Adverse events and patient outcomes were determined., Results: Patients were male, and the mean age was 44 years. The etiology was dilated cardiomyopathy (6 patients), sarcoid heart disease (2 patients), ischemic cardiomyopathy (1 patient), anthracycline cardiomyopathy (1 patient), non-compaction cardiomyopathy (1 patient), and arrhythmogenic RV cardiomyopathy with biventricular involvement (1 patient). There was 1 death from multisystem failure. There were 3 episodes of right VAD thrombus (thrombosis or clot ingestion); 1 managed medically, 1 recognized intraoperatively treated with clot retrieval, and 1 requiring pump exchange. There were 3 driveline infections. At 18 months after the procedure, 5 patients (41.7%) had undergone cardiac transplantation, 5 patients (41.7%) were alive and on biventricular support, 1 patient had died (8.3%), and 1 patient had VAD explantation for myocardial recovery (8.3%). Actuarial survival at 18 months was 91.7%., Conclusions: In this small study, HM3 BiVAD in these critically ill patients was used with low mortality. This suggests that the timely deployment of biventricular support with HM3 can be associated with favorable outcomes., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk., Summary: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions., (© 2016 International Society on Thrombosis and Haemostasis.)

Emergence of SIV and HIV specific CD8 T cells has been shown to correlate with control of in vivo replication. Poor correlation between IFN-γ ELISPOT responses and in vivo control of the virus has triggered the development of more relevant assays to assess functional HIV-1 specific CD8 T-cell responses for the evaluation and prioritization of new HIV-1 vaccine candidates. We previously established a viral inhibition assay (VIA) that measures the ability of vaccine-induced CD8 T-cell responses to inhibit viral replication in autologous CD4 T cells. In this assay, viral replication is determined by measuring p24 in the culture supernatant. Here we describe the development of a novel VIA, referred to as IMC LucR VIA that exploits replication-competent HIV-1 infectious molecular clones (IMCs) in which the complete proviral genome is strain-specific and which express the Renilla luciferase (LucR) gene to determine viral growth and inhibition. The introduction of the luciferase readout does provide significant improvement of the read out time. In addition to switching to the LucR read out, changes made to the overall protocol resulted in the miniaturization of the assay from a 48 to a 96-well plate format, which preserved sample and allowed for the introduction of replicates. The overall assay time was reduced from 13 to 8 days. The assay has a high degree of specificity, and the previously observed non-specific background inhibition in cells from HIV-1 negative volunteers has been reduced dramatically. Importantly, we observed an increase in positive responses, indicating an improvement in sensitivity compared to the original VIA. Currently, only a limited number of "whole-genome" IMC-LucR viruses are available and our efforts will focus on expanding the panel to better evaluate anti-viral breadth. Overall, we believe the IMC LucR VIA provides a platform to assess functional CD8 T-cell responses in large-scale clinical trial testing, which will enhance the ability to select the most promising HIV-1 vaccine candidates capable of controlling HIV-1 replication in vivo., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

The next generation of candidate HIV vaccines include replicating vectors selected for tropism to mucosal sites, where an efficacious T cell response will be required to limit T cell replication and HIV associated CD4 T cell loss. To fully assess immunogenicity of such candidates, there is a need to develop robust quality controlled analysis of gut derived HIV specific CD8+ T-cell responses. Despite obvious challenges in obtaining sufficient amounts of tissue, the highly compartmentalised nature of the mucosal immune responses, requires the assessment of CD8 T cells isolated directly from local tissue before any conclusions regarding the induction of mucosal responses are made. Here we describe the optimisation and subsequent qualification of a qualitative and quantitative polychromatic flow cytometry assay to assess antigen specific CD8+ T cells isolated from the gut, using samples from HIV positive and negative volunteers. Internal quality controls monitored over time, combined with the use of quality gating and standard operating procedures were used to demonstrate the generation of robust and reliable data., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The aim of this review was to analyze our results with extracorporeal membrane oxygenation (ECMO) support for primary graft failure (PGF) in heart transplant recipients., Methods: A retrospective review of 239 consecutive patients who underwent heart transplantation between January 2000 and August 2009 was performed. Orthotopic, heterotopic, and heart lung transplants were included in this analysis. Over that time period, 54 patients developed PGF, of whom 39 patients required ECMO support. These 39 patients form the basis of this review., Results: Thirty-four patients (87%) were successfully weaned from ECMO and 29 (74.3%) survived to hospital discharge. There were no significant differences in wean rates or complications between central and peripheral ECMO. Comparison of survival in the 39 ECMO patients to the non-PGF patients (n = 185) showed a significantly worse survival in the ECMO group (p = 0.007). When those patients who died in the first 30 days were excluded, there was no difference in overall survival between groups (p = 0.73)., Conclusions: Extracorporeal membrane oxygenation provides excellent circulatory support for patients with PGF after heart transplantation with good wean and survival to discharge rates., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We report the clinical course of a 16-year-old girl in remission from non-Hodgkin's lymphoma who presented in cardiogenic shock due to a severe anthracycline cardiomyopathy. The patient was initially stabilized using central extracorporeal membrane oxygenation support, followed by conversion to a left ventricular assist device. Unexpected evidence of cardiac recovery 9 months after implant enabled device weaning during a 3-month period, culminating in successful device explantation 1 year after implant. The patient survives 18 months after explant in New York Heart Association class I, on conventional heart failure medical management and metabolic therapy.

Renal impairment at the time of heart transplantation complicates the choice of subsequent immunosuppressive therapy. Calcineurin (CNI)-free regimens utilizing proliferation signal inhibitors (PSI) may mitigate against nephrotoxicity in this group; however, their effectiveness remains unclear. We present our 7-year experience with de novo CNI-free, PSI-based immunosuppression after heart transplantation. Of the 152 patients transplanted between July 1999 and July 2006, de novo immunosuppression regimens were 49 CNI-free, PSI-based, 88 CNI, 15 combination of CNI+PSI. Pretransplant creatinine clearance improved within 6 months in the PSI group (0.69 +/- 0.34 mL/s vs. 1.00 +/- 0.54 mL/s, p < 0.05) but not the CNI (1.32 +/- 0.54 mL/s vs. 1.36 +/- 0.53 mL/s, p = ns) or CNI+PSI (1.20 +/- 0.24 mL/s vs. 1.20 +/- 0.41 mL/s, p = ns) groups. The PSI group had more episodes of early (

Background: The purpose of this study was to determine the incidence and type of malignancies in heart and/or lung transplant recipients at a single institution in Victoria, Australia, and to compare these findings with the non-transplant general Victorian population., Methods: Recipients of heart and/or lung transplants at the Alfred Hospital between February 1989 and January 2004 were cross-referenced with the Victorian Cancer Registry. The medical records of all patients with a cancer diagnosis by January 1, 2005 were reviewed. Data were collected on baseline demographics, including cancer type, stage, treatment and survival. Cancer incidence was then compared with rates found in the Victorian population., Results: There were 907 transplants (Tx) conducted between February 1989 and January 1, 2004 on 905 patients, which included 424 heart (HTx), 56 heart-lung (HLTx), 200 single-lung (SLTx), and 227 double-lung (DLTx) procedures. Of these patients, 606 (67%) were male and 299 (33%) were female. Mean age at transplantation was 46.4 years (range 12.6 to 70.4 years). Four hundred twenty-four (47%) deaths have occurred. Median survival for all patients after transplantation was 8.6 years. One hundred two cancers were confirmed, translating to a 7.1-fold increased incidence compared with the non-transplant population. The most common cancer diagnoses were lymphoproliferative disorders (692 per 100,000 person-years), head and neck cancer (336 per 100,000 person-years) and lung cancer (251 per 100,000 person-years). Compared with the non-transplant population this translates into a 26.2-, 21.0- and 9.3-fold increased risk for developing these cancers, respectively, after cardio-pulmonary transplantation., Conclusions: Certain malignancies are more common after heart and/or lung transplantation. The most predominant in our cohort were lymphoproliferative disorders, head and neck cancer and lung cancer.

Matrix metalloproteinases constitute a family of structurally related endopeptidases that are crucial for the normal turnover of the extracellular matrix. Elevated levels of MMP-9 have been demonstrated in synovial fluids of rheumatoid arthritis patients, and a correlation with the severity of the disease has been described. The aim of this study was to explore the impact of MMP-9 expression on joint inflammation and destruction in a model of bacterially induced septic arthritis. MMP-9 knock-out mice and C57Bl6 congenic controls were inoculated intravenously or intra-articularly with Staphylococcus aureus. Arthritis was evaluated clinically and by means of histology. Zymographic analyses were performed to study ex vivo induction of MMP-9 following exposure to S. aureus. The MMP-9 knock-out mice displayed a significantly higher frequency and severity, but not destructivity, of arthritis than did the wild-type mice. The knock-out mice also proved to harbour an increased number of bacteria locally in joints and systemically in kidneys, possibly by impaired extravasation and recruitment of leukocytes and a deficient early defence against infection. Our findings indicate that deficiency in MMP-9 increases the degree of joint inflammation due to decreased bacterial clearance.

The soybean-derived isoflavone genistein has been shown to exert beneficial effects on many disorders, including cancer and cardiovascular diseases. The effects of genistein on mammalian cells are mediated by its abilities to inhibit topoisomerase II and protein tyrosine kinase. In order to examine the potential antibacterial activities of genistein, we incubated the bacteria with various concentrations of this compound for different periods of time and assessed the viable counts. Exposure to genistein exhibited an inhibitory effect on all staphylococcal strains tested, including methicillin-resistant strains. Furthermore, the growth of Streptococcus pasteurianus, Bacillus cereus, and Helicobacter pylori was clearly inhibited by genistein, whereas Escherichia coli growth was not suppressed. Daidzein, which is structurally similar to genistein, but deficient in topoisomerase II inhibitory activity, also inhibited the growth of Staphylococcus aureus, albeit with lower potency than genistein. Our results indicate that genistein exerts potent antibacterial properties in vitro, which are possibly mediated by the stabilization of the covalent topoisomerase II-DNA cleavage complex.

Study Objective: Central sleep apnea (CSA) associated with Cheyne-Stokes respiration in patients with congestive heart failure (CHF) is thought to be an acquired pattern of respiratory control instability related, at least in part, to elevated sympathetic nervous system activity. The effect of restoring heart function to normal with heart transplantation in patients with CHF and CSA has only been reported within weeks of the transplant and with varying results. The purpose of the study was to evaluate the impact of successful heart transplant on sympathetic nervous system activity and CSA severity in patients with CHF., Design: Controlled prospective trial., Setting: University hospital., Patients: Twenty-two patients with CHF (13 patients with CSA, and 9 patients with no sleep-disordered breathing [SDB])., Interventions and Measurements: Polysomnography, left ventricular ejection fraction (LVEF), and overnight urinary norepinephrine excretion (UNE) were measured before and > 6 months after successful heart transplantation., Results: In the CSA group, there was a fall in apnea-hypopnea index (AHI) [mean +/- SD, 28 +/- 15 to 7 +/- 6/h; p < 0.001] and UNE (48.1 +/- 30.9 to 6.1 +/- 4.8 nmol/mmol creatinine, p < 0.001) associated with normalization of LVEF (19.2 +/- 9.3% to 53.7 +/- 6.1%, p < 0.001) at 13.2 +/- 8.3 months following heart transplantation. Of the CSA group following transplantation, seven patients had no SDB (AHI < 5/h), three patients had persistent CSA (AHI, 12.3 +/- 0.9/h) and four patients acquired obstructive sleep apnea (OSA) [AHI, 11.2 +/- 7.4/h]. In comparison, none of the control group acquired CSA or OSA after transplantation., Conclusions: We conclude that CSA may persist despite normalization of heart function and sympathetic nerve activity.

Objectives: To compare and establish the relevance of the relative degree of sympathetic nervous system activity (SNSA) in groups of patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA), and in a control group., Background: Elevated SNSA is a characteristic feature of CHF, as well as of OSA and nonhypercapnic central sleep apnea (CSA). OSA and CSA commonly occur with CHF; however, the relative contribution of apnea-related hypoxemia and sleep fragmentation to the SNSA of patients with CHF is not known., Methods: This was a prospective, controlled, observational trial in which the overnight urinary norepinephrine (UNE) level, which is a measure of integrated overnight SNSA while asleep, was measured in 15 healthy male volunteers, 15 male OSA patients who did not have CHF, and 90 CHF patients (77 men). CHF patients also had right heart pressure measurements and then were grouped by the presence of sleep apnea., Results: Compared with healthy individuals, the mean (+/- SD) UNE level was significantly elevated in the OSA group and was even further elevated in the CHF group (13.4 +/- 5.6 vs 19.7 +/- 12.3 vs 32.2 +/- 20.2 nmol/mmol creatinine, respectively; p < 0.001 [by analysis of variance]). Within the CHF group, the mean UNE levels were greatest in the CHF-CSA group compared with the CHF-OSA group and the CHF nonapnea group (43.9 +/- 24.1 vs 24.0 +/- 10.8 vs 22.4 +/- 8.9 nmol/mmol creatinine, respectively; p < 0.001). Using a multivariate regression model, the variance of the UNE level in the CHF group was predicted, in descending order, by pulmonary capillary wedge pressure (14% variance), rapid eye movement sleep (8%), and the mean sleep pulse oximetry level (7%)., Conclusions: Overnight SNSA is significantly greater in CHF patients than in OSA patients. Moreover, the hemodynamic severity of CHF contributes to the elevation of SNSA in CHF patients to a greater degree than apnea-related hypoxemia.

Objective: To study the clinical impact of gout treatment following cardiac transplantation., Methods: We performed an audit of all cardiac transplant recipients of the Alfred Hospital before August 1998 who lived in Victoria., Results: We studied 225 patients (81% men), with a mean post-transplant follow-up of 50.8 months (SD 36). Forty-three (19%) had pre-transplant gout, 19 recurring post-transplantation. Twenty-three patients developed gout de novo. Of the 24 patients who received allopurinol, 6 developed pancytopenia and required hospitalization. Fourteen received a change in immunosuppression: in 5 patients following pancytopenia, and in 9 to enable safe use of allopurinol. Thirty-two patients received colchicine; 5 developed neuromyopathy. Impaired renal function, diuretic use, and hypertension were more common in this sub-group. Non-steroidal anti-inflammatory agents, used in 16 patients, caused serious complications in 1 patient (life-threatening peptic ulceration and hemorrhage, precipitating dialysis-dependent chronic renal failure)., Conclusions: Cardiac transplant recipients, when treated for gout, are at high risk of therapeutic complications. Thus, gout treatment significantly affects care, health, and immunosuppression of these patients.

Acute fulminant myocarditis frequently causes circulatory collapse that is resistant to conventional therapy. We describe a case in which a patient with histologically confirmed viral myocarditis was supported by a left ventricular assist device (LVAD) as a bridge to recovery. The LVAD was successfully weaned 3 weeks later.

Background: The limited availability of cardiac allografts together with the increasing number of patients on the waiting list restricts treatment of this population with heart transplantation. An increase in the available donor pool has been facilitated by the use of allografts with prolonged ischemic time (> 240 minutes)., Methods: Short- and long-term outcomes were compared in 150 heart transplant recipients on the basis of allograft ischemic time (< 241 minutes, 241 to 300 minutes, and > 300 minutes)., Results: No difference was found in allograft functional capacity, the development of transplant-associated coronary disease, or actuarial survival in the short and long term., Conclusions: Improved population treatment with prolonged ischemic time cardiac allografts can be safely undertaken without long-term risk to heart transplant recipients.

Heart transplantation now provides an acceptable therapy for patients with severe end-stage heart disease. Although patient outcome has significantly improved both early and late after heart transplantation, early morbidity and mortality continues to affect overall survival and may be unpredictable. In an attempt to identify factors that may assist in predicting early outcome after orthotopic heart transplantation, we assessed allograft function in 16 patients in the immediate postoperative period, 30 minutes after weaning from cardiopulmonary bypass by measuring the fractional shortening of the left ventricle with transesophageal echocardiography. In addition, standard hemodynamic indexes of allograft function (arterial blood pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, and cardiac output) were obtained at this early time point. Early outcome was assessed by the duration and peak dose of inotrope support required after transplantation, requirement for mechanical support, and the duration of stay in the intensive care unit. Left ventricular fractional shortening 30 minutes after cardiopulmonary bypass was significantly lower in those patients requiring inotropic support (28.4% +/- 4.6% versus 43.7% +/- 3.5%, p < 0.05), whereas hemodynamic variables failed to distinguish these groups. In those patients requiring inotropes, there was a significant negative correlation of fractional shortening with the peak dose (r = -0.87, p < 0.01) and the duration of inotropic support (r = -0.62, p < 0.05). The total ischemic time of the allograft (206 +/- 22 minutes, range 77 to 359) did not correlate with the subsequent fractional shortening, but patients requiring inotrope support after the operation had significantly longer ischemic times (259 +/- 22 versus 138 +/- 22 minutes, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)