Mortality and morbidity after combined heart and liver transplantation in the failing Fontan: An updated dual center retrospective study.

INTRODUCTION: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation. METHODS: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022. RESULTS: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis. CONCLUSION: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted.

Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease.

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Scedosporiosis and lomentosporiosis: modern perspectives on these difficult-to-treat rare mold infections.

SUMMARYAlthough Scedosporium species and Lomentospora prolificans are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different Scedosporium species. L. prolificans is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.

Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Chronic Epstein-Barr viral load carriage after pediatric organ transplantation.

Epstein-Barr virus (EBV) infection and EBV-associated post-transplant lymphoproliferative disorder (EBV/PTLD) is one of the most devastating complications occurring in pediatric solid organ transplant (SOT) recipients. Observations of SOT recipients undergoing serial EBV monitoring to inform reduction of immune suppression to prevent EBV-/PTLD has identified patients who maintain chronic high EBV load (CHL) in their blood. The CHL carrier state has been seen more commonly in pediatric compared to adult transplant recipients. Some but not all CHL may progress to EBV/PTLD. However, little is known regarding the biology of this CHL carrier state and the optimal clinical approach to CHL has not been established. This review summarizes the current knowledge and evidence of chronic high EBV load and introduces commonly adopted approaches from experts in this field.

Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Costs associated with invasive Scedosporium and Lomentospora prolificans infections: a case-control study.

BACKGROUND: Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. METHODS: A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. RESULTS: Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. CONCLUSIONS: The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial.

Rose bengal-encapsulated chitosan nanoparticles for the photodynamic treatment of Trichophyton species.

Rose bengal (RB) solutions coupled with a green laser have proven to be efficient in clearing resilient nail infections caused by Trichophyton rubrum in a human pilot study and in extensive in vitro experiments. Nonetheless, the RB solution can become diluted or dispersed over the tissue and prevented from penetrating the nail plate to reach the subungual area where fungal infection proliferates. Nanoparticles carrying RB can mitigate the problem of dilution and are reported to effectively penetrate through the nail. For this reason, we have synthesized RB-encapsulated chitosan nanoparticles with a peak distribution size of ~200 nm and high reactive oxygen species (ROS) production. The RB-encapsulated chitosan nanoparticles aPDT were shown to kill more than 99% of T. rubrum, T. mentagrophytes, and T. interdigitale spores, which are the common clinically relevant pathogens in onychomycosis. These nanoparticles are not cytotoxic against human fibroblasts, which promotes their safe application in clinical translation.

An integrated program to expand donor utilization in pediatric heart transplantation: Case report of successful transplant with multiple donor risk factors.

BACKGROUND: Pediatric heart transplantation (HT) continues to be limited by the shortage of donor organs, distance constraints, and the number of potential donor offers that are declined due to the presence of multiple risk factors. METHODS: We report a case of successful pediatric HT in which multiple risk factors were mitigated through a combination of innovative donor utilization improvement strategies. RESULTS: An 11-year-old, 25-kilogram child with cardiomyopathy and pulmonary hypertension, on chronic milrinone therapy and anticoagulated with apixaban, was transplanted with a heart from a Hepatitis C virus positive donor and an increased donor-to-recipient weight ratio. Due to extended geographic distance, an extracorporeal heart preservation system (TransMedics™ OCS Heart) was used for procurement. No significant bleeding was observed post-operatively, and she was discharged by post-operative day 15 with normal biventricular systolic function. Post-transplant Hepatitis C virus seroconversion was successfully treated. CONCLUSIONS: Heart transplantation in donors with multiple risk factor can be achieved with an integrative team approach and should be taken into consideration when evaluating marginal donors in order to expand the current limited donor pool in pediatric patients.

Emergence of multiple fluconazole-resistant Candida parapsilosis sensu stricto clones with persistence and transmission in China.

OBJECTIVES: We explored the epidemiological and molecular characteristics of Candida parapsilosis sensu stricto isolates in China, and their mechanisms of azole resistance. METHODS: Azole susceptibilities of 2318 non-duplicate isolates were determined using CLSI broth microdilution. Isolates were genotyped by a microsatellite typing method. Molecular resistance mechanisms were also studied and functionally validated by CRISPR/Cas9-based genetic alterations. RESULTS: Fluconazole resistance occurred in 2.4% (n = 56) of isolates, and these isolates showed a higher frequency of distribution in ICU inpatients compared with susceptible isolates (48.2%, n = 27/56 versus 27.8%, 613/2208; P = 0.019). Microsatellite-genotyping analysis yielded 29 genotypes among 56 fluconazole-resistant isolates, of which 10 genotypes, including 37 isolates, belonged to clusters, persisting and transmitting in Chinese hospitals for 1-29 months. Clusters harbouring Erg11Y132F (5/10; 50%) were predominant in China. Among these, the second most dominant cluster MT07, including seven isolates, characteristically harbouring Erg11Y132F and Mrr1Q625K, lent its carriage to being one of the strongest associations with cross-resistance and high MICs of fluconazole (>256 mg/L) and voriconazole (2-8 mg/L), causing transmission across two hospitals. Among mutations tested, Mrr1Q625K led to the highest-level increase of fluconazole MIC (32-fold), while mutations located within or near the predicted transcription factor domain of Tac1 (D440Y, T492M and L518F) conferred cross-resistance to azoles. CONCLUSIONS: This study is the first Chinese report of persistence and transmissions of multiple fluconazole-resistant C. parapsilosis sensu stricto clones harbouring Erg11Y132F, and the first demonstration of the mutations Erg11G307A, Mrr1Q625K, Tac1L263S, Tac1D440Y and Tac1T492M as conferring resistance to azoles.

Beliefs about depression relate to active and avoidant coping in high-symptom adolescents.

BACKGROUND: Perceptions of personal attributes as less malleable are associated with more severe depression symptoms and less active coping in youth. Perceptions of depression itself as relatively fixed have been linked to more severe depression symptoms; however, it is not known how beliefs about depression relate to active and avoidant coping behaviors in particular. METHODS: We gathered information about beliefs about depression and activation and avoidance behaviors among 104 adolescents with high depression symptoms. The primary depression belief examined was prognostic pessimism, or the belief that depression is relatively permanent. We calculated correlations between this belief and activation and avoidance/rumination behaviors. RESULTS: Prognostic pessimism was negatively correlated with behavioral activation scores (r = -0.31; p = .001), and was positively correlated with behavioral avoidance/rumination scores (r = 0.30; p = .002). LIMITATIONS: This data was cross-sectional, and relied on self-report measures of depression beliefs and behaviors. CONCLUSIONS: Adolescents who believe that depression is relatively permanent might feel less motivated to engage in effortful activation behaviors, instead favoring avoidance. These results may help elucidate the ways in which malleability beliefs relate to mental health outcomes among adolescents, and highlight prognostic pessimism as a potential treatment target for reducing depressogenic behaviors.

Textbook outcomes after oesophagectomy: a single-centre observational study.

BACKGROUND: Textbook outcomes is a composite quality assurance tool assessing the ideal perioperative and postoperative course as a unified measure. Currently, its definition and application in the context of oesophagectomy in Australia is unknown. The aim of this study was to assess the textbook outcomes after oesophagectomy in a single referral centre of Australia and investigate the association between textbook outcomes and patient, tumour, and treatment characteristics. METHODS: An observational study was retrospectively performed on patients undergoing open, laparoscopic, or hybrid oesophagectomy between January 2010 and December 2019 in a single cancer referral centre. A textbook outcome was defined as the fulfillment of 10 criteria: R0 resection, retrieval of at least 15 lymph nodes, no intraoperative complications, no postoperative complications greater than Clavien-Dindo grade III, no anastomotic leak, no readmission to the ICU, no hospital stay beyond 21 days, no mortality within 90 days, no readmission related to the surgical procedure within 30 days from admission and no reintervention related to the surgical procedure. The proportion of patients who met each criterion for textbook outcome was calculated and compared. Selected patient-related parameters (age, gender, BMI, ASA score, CCI score), tumour-related factors (tumour location, tumour histology, AJCC clinical T and N stage and treatment-related factor [neoadjuvant chemotherapy and surgical approach]) were assessed. Disease recurrence and one year survival were also evaluated. RESULTS: 110 patients who underwent oesophagectomy were included. The overall textbook outcome rate was 24%. The difference in rates across the years was not statistically significant. The most achieved textbook outcome parameters were 'no mortality in 90 days' (96%) and 'R0 resection' (89%). The least frequently met textbook outcome parameter was 'no severe postoperative complications' (58%), followed by 'no hospital stays over 21 days' (61%). No significant association was found between patient, tumour and treatment characteristics and the rate of textbook outcome. Tumour recurrence rate and overall long term survival was similar between textbook outcome and non-textbook outcome groups. Patients with R0 resection, no intraoperative complication and a hospital stay less than 21 days had reduced mortality rates. CONCLUSIONS: Textbook outcome is a clinically relevant indicator and was achieved in 24% of patients. Severe complications and a prolonged hospital stay were the key criteria that limited the achievement of a textbook outcome. These findings provide meticulous evaluation of oesophagectomy perioperative care and provide a direction for the utilisation of this concept in identifying and improving surgical and oncological care across multiple healthcare levels.

A laboratory framework for ongoing optimization of amplification-based genomic surveillance programs.

IMPORTANCE: This study provides a laboratory framework to ensure ongoing relevance and performance of amplification-based whole genome sequencing to strengthen public health surveillance during extended outbreaks or pandemics. The framework integrates regular reviews of the performance of a genomic surveillance system and highlights the importance of ongoing monitoring and the identification and implementation of improvements to whole genome sequencing methods to enhance public health responses to pathogen outbreaks.

Outcomes after initial heart failure consultation in Fontan patients.

BACKGROUND: Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care. METHODS: This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as "too late" (death or declined for transplant due to being too sick) and/or "care escalation" (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. "Late referral" was defined as those referred too late and/or had care escalation. RESULTS: Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8-21.5, p=0.004). CONCLUSIONS: Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.

Outbreaks of Fungal Infections in Hospitals: Epidemiology, Detection, and Management.

Nosocomial clusters of fungal infections, whilst uncommon, cannot be predicted and are associated with significant morbidity and mortality. Here, we review reports of nosocomial outbreaks of invasive fungal disease to glean insight into their epidemiology, risks for infection, methods employed in outbreak detection including genomic testing to confirm the outbreak, and approaches to clinical and infection control management. Both yeasts and filamentous fungi cause outbreaks, with each having general and specific risks. The early detection and confirmation of the outbreak are essential for diagnosis, treatment of affected patients, and termination of the outbreak. Environmental sampling, including the air in mould outbreaks, for the pathogen may be indicated. The genetic analysis of epidemiologically linked isolates is strongly recommended through a sufficiently discriminatory approach such as whole genome sequencing or a method that is acceptably discriminatory for that pathogen. An analysis of both linked isolates and epidemiologically unrelated strains is required to enable genetic similarity comparisons. The management of the outbreak encompasses input from a multi-disciplinary team with epidemiological investigation and infection control measures, including screening for additional cases, patient cohorting, and strict hygiene and cleaning procedures. Automated methods for fungal infection surveillance would greatly aid earlier outbreak detection and should be a focus of research.

Maternal Diabetes and Cardiovascular Health in the Offspring.

Pulse wave velocity (PWV) has been explored to predict cardiovascular health in adults. Less is known about neonatal PWV. We evaluated the association between arterial stiffness of neonates of mothers (NoM) with diabetes and childhood health. Neonatal brachial-femoral PWV (bfPWV) was measured after birth and neonates followed for a median of 5.2 years [1 month-6.6 years]. 36 pregnant women with pregestational diabetes mellitus PGDM (n = 12), gestational diabetes mellitus (GDM) (n = 13), and controls (n = 11) were enrolled. Neonates were similar in weight, gestational age, and delivery mode. 26 neonates had follow-up data including weight, height and blood pressure. More mothers with PGDM had poor glycemic control compared to mothers with GDM (83% vs. 8%; p = 0.0002). PWV was higher in NoM with PGDM than controls (3.4 ± 0.5 vs. 2.6 ± 0.8 m/s; p = 0.04). At follow-up, children of mothers with diabetes (n = 16) had higher weight percentile (78.5 ± 27.9 vs 49.5 ± 34.6%; p = 0.02) and diastolic blood pressure (DBP) (68 ± 13.6 vs 57.3 ± 4.3 mmHg; p = 0.01) than controls (n = 10). No correlation emerged between neonatal PWV and childhood body mass index (BMI) or maternal HbA1c. Results suggest maternal diabetes affect neonatal arterial stiffness and childhood blood pressure; however, the mechanism is unclear. The long-term implications of these findings warrant further investigation.