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C32H28N4, monoclinic, P21/c (no. 14), a = 17.7218(4) Å, b = 20.7769(5) Å, c = 14.9434(3) Å, β = 113.598(3)° $113.598(3){}^{\circ}$ , V = 5042.1(2) Å3, Z = 8, R gt(F) = 0.0519, wR ref(F 2) = 0.1544, T = 294 K.

Abstract The coronavirus disease (COVID‐19), which the World Health Organization classified as the Sixth Public Health Emergency Of International Concern (PHEIC) on January 30, 2020, is no longer a PHEIC. Millions were affected due to unawareness. The increase in fatalities and shortage of medicine was the first outrage of COVID‐19. As per the Johns Hopkins COVID‐19 resource center database, it was observed that the disease has spread dynamically across 200+ nations worldwide affecting more than 600 million people from 2019 to 2023, and over thousands of people were victimized regularly at a 2% mortality rate (approx.). In the midway, the mutant variants of concern like omicron, and delta have also created havoc and caused significant impact on public health, global economy, and lifestyle. Since 2019, 3 years now passed and the dynamic disease statistics seem decelerated; moreover, the prevalence of COVID‐19 is also fading. The Johns Hopkins resource center has also stopped recording the data of the global pandemic recently from March 10, 2023. Hence, based on the facts, we are presenting a concise report on the pandemic from 2019 to 2023, which includes a brief discussion of the global pandemic. We have highlighted global epidemiology, emphasizing the Indian COVID scenario, vaccination across the globe, and the psychosocial and geopolitical consequences of COVID‐19 with a brief background to pathology, clinical management, and the worldwide response against triage. A lot has changed and still needs to change after three tough years of COVID‐19. Even though science has progressed and advanced research in medicine is pointing toward future generations, there is no standard care supplied for COVID‐19‐like calamities. COVID‐19 cases might have declined but its influence on the society is still stagnant. This COVID experience has taught us that, despite our bleak beginnings, there is always hope for the future and that we must act with foresight to improve things for future generations.

With increasing cost and use of energy in agriculture, the traditional practice of mono-cropping of rice in upland is neither sustainable nor eco-friendly. It is necessary to identify crop diversification options with high energy efficiency, productivity, and low global warming potential (GWP). In this experiment, an inclusive system analysis was accomplished for 3 years (2016–2019) of five mono-cropping production (MCP) systems namely rice (R), finger millet (FM), black gram (BG), horse gram (HG), pigeon pea (PP), and four intercropped systems viz. R+BG, R+HG, FM+ BG, and FM + HG. The key objective was to evaluate the flow of energy, carbon balance, and GWP of these varied production systems. Puddled rice was recorded as an energy-exhaustive crop (27,803 MJ ha−1), while horse gram was noted to have the lowest energy use (26,537 MJ ha−1). The total energy output from pigeon pea (130,312 MJ ha−1) and diversified intercropped systems (142,135 MJ ha−1) was 65.3% and 80.3% higher than mono-cultured systems, respectively. Rice and rice-based intercropping production systems showed higher carbon footprints (1,264–1,392 kg CO2 eq. ha−1). Results showed that R+BG and R+HG were the most energy-efficient production systems, having higher energy ratio (5.8 and 6.0), higher carbon efficiency (7.41 and 8.24), and carbon sustainability index (6.41 and 7.24) as against 3.30, 3.61, and 2.61 observed under sole cropping production systems. On average, rice and rice-based production systems had 7.4 times higher GWP than other production systems. In productivity terms, pigeon pea and FM+HG had higher rice equivalent yields of 8.81 and 5.79 t ha−1 and benefit-cost ratios of 2.29 and 1.87, respectively. Thus, the present study suggests that pigeon pea and finger millet-based intercropping systems were the most appropriate crop diversification options for the rainfed upland agro-ecosystem of the eastern region of India.

This study investigated the relationship between autistic traits, expressiveness, readability (both actual and perceived), social favourability, and likability. Sixty participants designated as 'targets' were video recorded in a range of social scenarios and their autistic traits were measured using the Autism Spectrum Quotient. The videos were then shown to 106 new participants designated 'perceivers', who were split into three groups to make judgments related to readability, expressiveness, and social favourability respectively. Mediation analyses revealed that autistic traits negatively impacted both perceived likeability and social favourability, mediated by lowered expressiveness. Autistic traits also directly impacted readability, which was not mediated by expressiveness. The findings show how the level of autistic traits of a target can influence how they are socially perceived by others.

Mosquitoes are the best-known disease vectors for most vector-borne diseases that significantly impact global health in terms of morbidity and mortality. In a geographical area, mosquito faunal diversity often alters with changing climatic factors and variable breeding habitats that differ across seasons. Using biodiversity indicators as tools, a study was conducted in rural, peri-urban, and urban areas of district Ganjam, Odisha state, to determine mosquito faunal diversity as an approach to forecast the possible risk of disease transmission in the three representative topographies. A two-year study was undertaken to assess the alpha diversity of mosquito species by the numerical strength of the species using various eco-diversity indices. Species richness and abundance of mosquito species are significantly higher in peri-urban areas compared to urban and rural areas. The species dominance of Culex quinquefasciatus was observed in all three topographies, while Aedes aegypti, Aedes albopictus, and Anopheles stephensi were in urban areas. Species richness may dilute the risk of disease in an area, but increased species dominance, mostly vector species, in a new habitat often allows pathogens to infect newer communities at risk, leading to the emergence of new diseases. The current study indicates the possible risk of lymphatic filariasis (LF) infection in all three topographies. On the other hand, the risk of malaria and dengue/chikungunya transmission is higher in urban areas. With routine entomological monitoring, including vector incrimination, the biodiversity indicators will be the best tool to forecast the risk of vector-borne diseases in an area; accordingly, judicious vector control strategies can be adopted.

C22H42N6, triclinic, P 1‾ $\overline{1}$ (no. 2), a = 8.3115(2) Å, b = 8.8263(2) Å, c = 9.7688(2) Å, α = 111.490(2)° $111.490(2){}^{\circ}$ , β = 115.056(2)° $115.056(2){}^{\circ}$ , γ = 93.681(2)° $93.681(2){}^{\circ}$ , V = 583.25(3) Å3, Z = 1, R gt(F) = 0.0465, wR ref(F 2) = 0.1351, T = 294 K.

C22H46N6O2, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 8.5777(3) Å, b = 9.0205(4) Å, c = 9.9270(3) Å, α = 67.899(3)° $67.899(3){}^{\circ}$ , β = 71.106(3)° $71.106(3){}^{\circ}$ , γ = 63.774(4)° $63.774(4){}^{\circ}$ , V = 626.83(5) Å3, Z = 1, Rgt ${R}_{\mathit{g}\mathit{t}}$ (F) = 0.0400, wRref $w{R}_{\mathit{r}\mathit{e}\mathit{f}}$ (F 2) = 0.1162, T = 298(2) K.

C24H36ClN4NaNi2O8, monoclinic, C2/c (no. 15), a = 19.5909(11) Å, b = 10.8023(6) Å, c = 14.5722(8) Å, β = 112.032(1)°, V = 2858.7(3) Å3, Z = 4, R gt(F) = 0.0260, wR ref(F 2) = 0.0701, T = 93(2) K.

Abstract Central nervous system high‐grade glioma (HGG) occurring in an infratentorial midline location is not commonly found in the pediatric population. Though pediatric HGGs appear similar to their adult counterparts histopathologically, they differ in molecular, genetic, and clinical characteristics. Evidence for the management of HGG is sparse in the literature. Surgery in the form of maximum safe resection is the backbone of management and has been variably supplemented with external beam radiotherapy and cytotoxic chemotherapy. The outcome, though largely dismal, has some positive surprises too. As shown in the presented case, the combined modality of management in a 5‐year‐old female child has resulted in a disease‐free survival of 3.5 years.

Local communities are an important stakeholder in any carnivore translocation programme and therefore, their acceptance of the translocation and support are essential to ensure its viability. Recent tiger augmentation efforts in Satkosia Tiger Reserve, India received mixed responses from the local communities, causing a stalemate in its progress. As a part of the adaptive management strategy, it was required to assess the concerns and issues to provide a practical solution. Hence, we analyzed the attitude of the people toward conservation in general and tiger specifically. We used structured questionnaire surveys and interviewed 1,932 households from 43 villages located in and around the reserve. We tested the influence of several variables representing four categories- (1) socio-economic, (2) ecosystem values and dependence, (3) relationship with the forest department and (4) losses and fear, on the attitude toward tiger conservation. The villages were clustered based on the responses received under these categories. While conserving forest was important to 91% of respondents, 71% of respondents supported wildlife conservation and only 35% felt important to conserve tiger. The logistic binary regression predicted that at the household level attitude toward tiger conservation is influenced positively by economic well-being, sense of forest ecosystem services, resource dependence and negatively influenced by restrictions from the forest department, and previous experience of loss due to wildlife. At the village level, literacy, resource dependence, access to clean cooking fuel and cooperation from the forest department predicted a positive attitude toward tiger conservation. Restriction from the forest department, fear for livestock, and experience of losses due to wildlife had a negative influence on attitude. We recommend that the villages in the landscape are prioritized based on their needs and accordingly, specific interventions are made to address their concerns. Future augmentation programme must give importance to intangible factors such as fear and perceived restrictions and opt for the involvement of the local community in the decision-making process.

Identifying cellular reservoirs of human immunodeficiency virus type 1 (HIV-1) in patients on antiretroviral therapy (ART) is critical to finding a cure for HIV-1. In addition to resting CD4(+) T cells, CD34(+) hematopoietic progenitor cells have been proposed as another reservoir. We obtained bone marrow aspirates from 11 patients on ART who had undetectable plasma HIV-1 RNA. HIV-1 DNA was detected in CD4(+) T cells from peripheral blood in all patients and from bone marrow cellular fractions containing T cells in most patients. We did not find HIV-1 DNA in highly purified CD34(+) populations using either a sensitive real-time polymerase chain reaction assay or a coculture assay for replication-competent HIV-1. [ABSTRACT FROM AUTHOR]

Green parks and open spaces are indispensable parts of an urban environment as they play important roles in promoting public health, protecting natural ecosystems and improving socioeconomic conditions of the city dwellers. Hence, the information of green and open spaces in a city needs to be provided to its governing authority and people for better management and utilisation. WebGIS technology is capable of maintaining and disseminating green park information among its users over the web. The availability of open source geospatial software and tools made this technology more cost effective and acceptable to the user community. In present study an interactive and user friendly WebGIS enabled solution is developed for green parks of Kolkata city that facilitates city dwellers and decision makers to search and visualise green parks both on map and satellite image along with park information and ground photo. It is an easy deployable solution that helps in urban planning for creating new as well as preserving the existing green spaces.

Spinal meningiomas are mostly intradural in location although at times these are associated with some extradural extensions. Purely extradural spinal meningiomas (EDSMs) are however, extremely rare and when present, may cause diagnostic dilemma preoperatively. Only seven cases of pure EDSM have been reported till date. In this paper, we describe two cases of EDSM affecting the cervical spine and present their clinical profiles, radiological findings, operative management, and follow-up data, along with a review of the literature.

To enable reliable quantification of natamycin in rabbit and human plasma, a validated, sensitive and selective liquid chromatographyâtandem mass spectrometry assay was developed. The chromatographic separation was achieved isocratically on a Cyano column using methanol: aqueous 3.5Â mM ammonium acetate (pH 4) (90:10Â v/v). The assay was validated over a concentration range of 6.25â400Â ng/mL with lower limit of detection of 3.12Â ng/mL. Quantification was performed using the transitions 664.5â137.2m/z for natamycin and 923.5â183.4m/z for the IS. The method was validated with respect to linearity, accuracy, precision, recovery and stability. This assay has been successfully applied to a pharmacokinetic study of natamycin in NZ rabbit and plasma protein binding in human plasma. Keywords: Natamycin, LCâMS/MS, Pharmacokinetics, Protein binding

Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters. Present study in male Sprague-Dawley rat was performed to evaluate the effect of memory enhancing standardized extract of BM on hepatic and intestinal cytochrome P450 3A and P-glycoprotein expression and activity. The BM (31 mg/kg/day) was orally administered for one week in BM pre-treated group while the control group received the same amount of vehicle for the same time period. The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control. Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp. To investigate whether this BM pretreatment mediated decrease in activity of CYP3A and Pgp would account for the alteration of respective substrate or not, pharmacokinetic study with carbamazepine and digoxin was performed in BM pre-treated rats and vehicle treated rats. Carbamazepine and digoxin were used as CYP3A and Pgp probe drugs, respectively. Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

Alveolar soft-part sarcoma (ASPS) is an extremely rare disease arising from connective tissues with a propensity for recurrence and metastasis. Clinically, it can be confused with hemangioma or arterio-venous malformations. Thus, a high index of suspicion and histopathological examination are required to make a definitive diagnosis. We report a case of recurrent ASPS in a young female with multiple sites involvement without any features of metastasis who has been treated with excision of the symptomatic lesions followed by chemotherapy.

Measuring virus in biofluids is complicated by confounding biomolecules coisolated with viral nucleic acids. To address this, we developed an affinity-based microfluidic device for specific capture of intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our approach used an engineered angiotensin-converting enzyme 2 to capture intact virus from plasma and other complex biofluids. Our device leverages a staggered herringbone pattern, nanoparticle surface coating, and processing conditions to achieve detection of as few as 3 viral copies per milliliter. We further validated our microfluidic assay on 103 plasma, 36 saliva, and 29 stool samples collected from unique patients with COVID-19, showing SARS-CoV-2 detection in 72% of plasma samples. Longitudinal monitoring in the plasma revealed our device's capacity for ultrasensitive detection of active viral infections over time. Our technology can be adapted to target other viruses using relevant cell entry molecules for affinity capture. This versatility underscores the potential for widespread application in viral load monitoring and disease management.

This case report describes the management of a 30-year-old male patient with a history of an advanced nonseminomatous germ cell tumor, hip fracture complicated by extensive deep vein thrombosis and pulmonary embolism, and on apixaban presenting with asymptomatic intracardiac teratoma and abdominopelvic metastases. Multidisciplinary intervention, including successful surgical excision of the intracardiac mass, highlights the importance of coordinated care and vigilant follow-up in optimizing patient outcomes and preventing life-threatening complications., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: The impact of duration of ex-vivo heart perfusion (EVHP) on patient outcomes following donation after circulatory death (DCD) heart transplantation has not been established., Methods: Adult first-time DCD heart transplants using EVHP were identified in the Organ Procurement & Transplant Network database (12/2019-09/2023). Total out of body time (OBT) was dichotomized based on perfusion duration exceeding the 90th percentile of EVHP hearts in the study. The primary outcome of 6-month mortality was assessed using Kaplan Meier curves and multivariable Cox regression. 30-day, 1-year, and 3-year mortality were also assessed. Secondary postoperative outcomes of index hospitalization length of stay, acute rejection, dialysis, and stroke were assessed using univariable linear or logistic regression., Results: Among 575 recipients of DCD transplantations using EVHP, 58 hearts had extended perfusion times based on an OBT cutoff of 8.3 hours which identified OBT greater than the 90th percentile. Extended perfusion heart recipients had worse overall mortality at 6 months compared to standard perfusion hearts after adjusting for critical donor and recipient factors [aHR = 2.48(1.25,4.93),p = 0.009]. Early 30-day mortality was comparable between the groups (p = 0.592). However, 1-year and 3-year outcomes showed worse mortality in recipients of extended perfusion hearts (both p < 0.05). Post-transplant dialysis requirement and increased length of stay was more likely in the extended perfusion group (both p < 0.05). There was no difference in acute rejection (p = 0.163), and stroke (p = 0.170)., Conclusions: There is a potential detrimental effect of extended EVHP duration on DCD heart recipient survival. Future work will explore the identified opportunity to improve organ preservation during EVHP., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Transplantation using hearts obtained through donation after circulatory death (DCD) is increasing, but data on recipient renal outcomes are limited., Methods and Results: Patients at a single institution who underwent heart transplantation using organs procured through DCD or donation after brain death (DBD) from April 2016 to August 2022 were included in this retrospective cohort study. Hemodynamic measures were collected via right heart catheterization performed 1 week after transplantation. Posttransplantation renal outcomes included estimated glomerular filtration rate at 1 week, 4 weeks, and 16 weeks, and the incidence of acute kidney injury (AKI) and renal replacement therapy within 1 week. The analysis included 225 patients (55 recipients of DCD). Baseline characteristics were comparable between recipients of DCD and DBD. Renal outcomes within 1 week posttransplantation in recipients of DCD were similar to recipients of DBD, including percent change in estimated glomerular filtration rate (-37.9% [-58.6 to -6.2] versus -31.9% [-52.4 to -9.9]; P =0.91), incidence of AKI (47.3% versus 46.5%; P >0.99) and incidence of renal replacement therapy (3.6% versus 4.7%; P >0.99). Recipients of DCD with AKI within 1 week ("early AKI") did not recover to baseline estimated glomerular filtration rate (75.8 [60.2-91.3] mL/min per 1.73 m 2 ) by week 16 (59.3 [46.9-73.6] mL/min per 1.73 m 2 ; P =0.002), whereas recipients without early AKI exhibited comparable estimated glomerular filtration rate to baseline by week 4 (84.5 [70.8-98.5] mL/min per 1.73 m 2 ; P =0.084). Similar trends were observed in recipients of DBD., Conclusions: Recipients of DCD demonstrated similar renal outcomes compared with recipients of DBD, supporting the ongoing use of DCD transplantation. Early AKI was associated with persistent renal dysfunction for recipients of both DCD and DBD.

Background: Donation after circulatory death (DCD) and ex-vivo lung perfusion (EVLP) have been adopted to expand the donor pool in lung transplantation, but outcomes data have been conflicting. This study explores outcomes of DCD and EVLP lung transplantation in the modern era., Methods: The United Network for Organ Sharing database was queried for adult lung transplants from January 1, 2015 to March 1, 2023. Loss to follow-up, multiorgan, and prior lung transplants were excluded. DCD versus donation after brain death (DBD) lung transplants were compared with subgroup analysis +/- EVLP. Outcomes were survival and postoperative complications., Results: The study included 1,103 DCD (221 with EVLP and 882 without) and 17,973 DBD lung transplants (524 with EVLP and 17,449 without). Median follow-up was 3 years. DCD donors were less likely to be CDC high risk (19.3% vs 24.1%, p < 0.001), have purulence on bronchoscopy (13.3% vs 18.3%, p < 0.001), or infiltrates on chest X-ray (66.7% vs 67.8%, p = 0.013). EVLP was more likely to be used for DCD transplants (20.0% vs 2.9%, p < 0.001). After transplant, DCD recipients were more likely to be reintubated (24.3% vs 18.5%, p < 0.001) and require ECMO within 72 hours (14.9% vs 7.8%, p < 0.001), and DCD donation was an independent risk factor for these complications on multivariable logistic regression. Overall survival did not differ significantly between DCD and DBD transplants on adjusted survival analysis in the early or modern era (p = 0.774 and p = 0.468, respectively). On subgroup analysis, the DCD+EVLP cohort had significantly worse survival in the modern era, which remained significant after adjusting for donor and recipient factors (p = 0.005). EVLP was an independent risk factor for graft failure in the DCD cohort (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.00-1.77, p = 0.047) but did not significantly affect DBD graft survival (p = 0.870). Risk factors for graft failure and mortality in the DCD+EVLP cohort included pulmonary hypertension (HR 77.5, 95% CI 6.15-979, p < 0.001), transfusion before transplant (HR 2.60, 95% CI 1.07-6.31, p = 0.035), elevated creatinine (HR 2.82, 95% CI 1.34-5.90, p = 0.006), and higher allocation score (HR 1.02, 95% CI 1.00-1.04, p = 0.017) CONCLUSIONS: Study findings suggest increased risks of mortality and perioperative complications following transplantation with DCD lungs that have undergone EVLP. DCD lung transplantation without EVLP confers equivalent survival but with some increase in perioperative complications. Further investigation and careful recipient selection are warranted to optimize the use of these extended criteria donors in the modern era., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The number of patients waiting for heart transplant far exceeds the number of hearts available. Donation after circulatory death (DCD) combined with machine perfusion can increase the number of transplantable hearts by as much as 48%. Emerging studies also suggest machine perfusion could enable allograft "reconditioning" to optimize outcomes. However, a detailed understanding of the energetic substrates and metabolic changes during perfusion is lacking., Methods: Metabolites were analyzed using 1-dimensional 1 H and 2-dimensional 13 C- 1 H heteronuclear spectrum quantum correlation nuclear magnetic resonance spectroscopy on serial perfusate samples (N = 98) from 32 DCD hearts that were successfully transplanted. Wilcoxon signed-rank and Kruskal-Wallis tests were used to test for significant differences in metabolite resonances during perfusion and network analysis was used to uncover altered metabolic pathways., Results: Metabolite differences were observed comparing baseline perfusate to samples from hearts at time points 1-2, 3-4, and 5-6 h of perfusion and all pairwise combinations. Among the most significant changes observed were a steady decrease in fatty acids and succinate and an increase in amino acids, especially alanine, glutamine, and glycine. This core set of metabolites was also altered in a DCD porcine model perfused with a nonblood-based perfusate., Conclusions: Temporal metabolic changes were identified during ex vivo perfusion of DCD hearts. Fatty acids, which are normally the predominant myocardial energy source, are rapidly depleted, while amino acids such as alanine, glutamine, and glycine increase. We also noted depletion of ketone, β-hydroxybutyric acid, which is known to have cardioprotective properties. Collectively, these results suggest a shift in energy substrates and provide a basis to design optimal preservation techniques during perfusion., Competing Interests: A.T., J.Z., and E.M.O. are employees of Olaris, Inc and have ownership and salary interest in the company. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Ex vivo machine perfusion or normothermic machine perfusion is a preservation method that has gained great importance in the transplantation field. Despite the immense opportunity for assessment due to the beating state of the heart, current clinical practice depends on limited metabolic trends for graft evaluation. Hemodynamic measurements obtained from left ventricular loading have garnered significant attention within the field due to their potential as objective assessment parameters. In effect, this protocol provides an easy and effective manner of incorporating loading capabilities to established Langendorff perfusion systems through the simple addition of an extra reservoir. Furthermore, it demonstrates the feasibility of employing passive left atrial pressurization for loading, an approach that, to our knowledge, has not been previously demonstrated. This approach is complemented by a passive Windkessel base afterload, which acts as a compliance chamber to maximize myocardial perfusion during diastole. Lastly, it highlights the capability of capturing functional metrics during cardiac loading, including left ventricular pulse pressure, contractility, and relaxation, to uncover deficiencies in cardiac graft function after extended periods of preservation times (˃6 h).

Despite important advancements in the diagnosis and treatment of cardiovascular diseases (CVDs), the field is in urgent need of increased research and scientific advancement. As a result, innovation, improvement and/or repurposing of the available research toolset can provide improved testbeds for research advancement. Langendorff perfusion is an extremely valuable research technique for the field of CVD research that can be modified to accommodate a wide array of experimental needs. This tailoring can be achieved by personalizing a large number of perfusion parameters, including perfusion pressure, flow, perfusate, temperature, etc. This protocol demonstrates the versatility of Langendorff perfusion and the feasibility of achieving longer perfusion times (4 h) without graft function loss by utilizing lower perfusion pressures (30-35 mmHg). Achieving extended perfusion times without graft damage and/or function loss caused by the technique itself has the potential to eliminate confounding elements from experimental results. In effect, in scientific circumstances where longer perfusion times are relevant to the experimental needs (i.e., drug treatments, immunological response analysis, gene editing, graft preservation, etc.), lower perfusion pressures can be key for scientific success.

Static ice storage has long been the standard-of-care for lung preservation, although freezing injury limits ischemic time (IT). Controlled hypothermic storage (CHS) at elevated temperature could safely extend IT. This retrospective analysis assesses feasibility and safety of CHS with IT > 15 hours. Three lung transplant (LuTx) centers (April-October 2023) included demographics, storage details, IT, and short-term outcome from 13 LuTx recipients (8 male, 59 years old). Donor lungs were preserved in a portable CHS device at 7 (5-9.3)°C. Indication was overnight bridging and/or long-distance transport. IT of second-implanted lung was 17.3 (15.1-22) hours. LuTx were successful, 4/13 exhibited primary graft dysfunction grade 3 within 72 hours and 0/13 at 72 hours. Post-LuTx mechanical ventilation was 29 (7-442) hours. Intensive care unit stay was 9 (5-28) and hospital stay 30 (16-90) days. Four patients needed postoperative extracorporeal membrane oxygenation (ECMO). One patient died (day 7) following malpositioning of an ECMO cannula. This multicenter experience demonstrates the possibility of safely extending IT > 15 hours by CHS., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The current understanding of the safety of heart transplantation from COVID-19+ donors is uncertain. Preliminary studies suggest that heart transplants from these donors may be feasible. We analyzed 1-year outcomes in COVID-19+ donor heart recipients using 1:3 propensity matching. The OPTN database was queried for adult heart transplant recipients between 1 January 2020 and 30 September 2022. COVID-19+ donors were defined as those who tested positive on NATs or antigen tests within 21 days prior to procurement. Multiorgan transplants, retransplants, donors without COVID-19 testing, and recipients allocated under the old heart allocation system were excluded. A total of 7211 heart transplant recipients met the inclusion criteria, including 316 COVID-19+ donor heart recipients. Further, 290 COVID-19+ donor heart recipients were matched to 870 COVID-19- donor heart recipients. Survival was similar between the groups at 30 days ( p = 0.46), 6 months ( p = 0.17), and 1 year ( p = 0.07). Recipients from COVID-19+ donors in the matched cohort were less likely to experience postoperative acute rejection prior to discharge ( p = 0.01). National COVID-19+ donor heart usage varied by region: region 11 transplanted the most COVID-19+ hearts (15.8%), and region 6 transplanted the fewest (3.2%). Our findings indicate that COVID-19+ heart transplantation can be performed with safe early outcomes. Further analyses are needed to determine if long-term outcomes are equivalent between groups.

Objective: To assess the effects of the 2020 United States Public Health Service (PHS) "Increased Risk" Guidelines update., Background: Donors labeled as "Increased Risk" for transmission of infectious diseases have been found to have decreased organ utilization rates despite no significant impact on recipient survival. Recently, the PHS provided an updated guideline focused on "Increased Risk" organ donors, which included the removal of the "Increased Risk" label and the elimination of the separate informed consent form, although the actual increased risk status of donors is still ultimately transmitted to transplant physicians. We sought to analyze the effect of this update on organ utilization rates., Methods: This was a retrospective analysis of the Organ Procurement and Transplantation Network database which compared donor organ utilization in the 2 years before the June 2020 PHS Guideline update for increased-risk donor organs (June 2018-May 2020) versus the 2 years after the update (August 2020-July 2022). The organ utilization rate for each donor was determined by dividing the number of organs transplanted by the total number of organs available for procurement. Student t test and multivariable logistic regression models were used for analysis., Results: There were 17,272 donors in the preupdate cohort and 17,922 donors in the postupdate cohort; of these, 4,977 (28.8%) and 3,893 (21.7%) donors were considered "Increased Risk", respectively. There was a 2% decrease in overall organ utilization rates after the update, driven by a 3% decrease in liver utilization rates and a 2% decrease in lung utilization rates. After multivariable adjustment, donors in the postupdate cohort had 10% decreased odds of having all organs transplanted., Conclusions: The 2020 PHS "Increased Risk" Donor Guideline update was not associated with an increase in organ utilization rates in the first 2 years after its implementation, despite a decrease in the proportion of donors considered to be at higher risk. Further efforts to educate the community on the safe usage of high-risk organs are needed and may increase organ utilization., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Donation after circulatory death (DCD) heart transplantation has promising early survival, but the effects on rejection remain unclear., Methods: The United Network for Organ Sharing database was queried for adult heart transplants from December 1, 2019, to December 31, 2021. Multiorgan transplants and loss to follow-up were excluded. The primary outcome was acute rejection, comparing DCD and donation after brain death (DBD) transplants., Results: A total of 292 DCD and 5,582 DBD transplants met study criteria. Most DCD transplants were transplanted at status 3-4 (61.0%) compared to 58.6% of DBD recipients at status 1-2. DCD recipients were less likely to be hospitalized at transplant (26.7% vs 58.3%, p < 0.001) and to require intra-aortic balloon pumping (IABP; 9.6% vs 28.9%, p < 0.001), extracorporeal membrane oxygenation (ECMO; 0.3% vs 5.9%, p < 0.001) or temporary left ventricular assist device (LVAD; 1.0% vs 2.7%, p < 0.001). DCD recipients were more likely to have acute rejection prior to discharge (23.3% vs 18.4%, p = 0.044) and to be hospitalized for rejection (23.4% vs 11.4%, p = 0.003) at a median follow-up of 15 months; the latter remained significant after propensity matching. On multivariable logistic regression, DCD donation was an independent predictor of acute rejection (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.00-2.15, p = 0.048) and hospitalization for rejection (OR 2.03, 95% CI 1.06-3.70, p = 0.026). On center-specific subgroup analysis, DCD recipients continued to have higher rates of hospitalization for rejection (23.4% vs 13.8%, p = 0.043)., Conclusions: DCD recipients are more likely to experience acute rejection. Early survival is similar between DCD and DBD recipients, but long-term implications of increased early rejection in DCD recipients require further investigation., (Published by Elsevier Inc.)

Donation after circulatory death (DCD) donor hearts recovered using the direct procurement and perfusion method experience variable durations of warm ischemia at the time of procurement (WIP). We used the Organ Procurement and Transplantation Network database to assess the effect of WIP on 30-day mortality after DCD heart transplantation. The analysis evaluated outcomes in 237 recipients of DCD heart transplantation, demonstrating an optimal WIP cut point of <36 minutes. Multivariable logistic regression modeling identified donor left ventricular ejection fraction (LVEF) <60% as an independent predictor of 30-day mortality. The area under the receiver operating characteristic curve for predicting 30-day mortality based on WIP ≥36 minutes and donor LVEF <60% was 0.90. Based on these findings, we do not recommend proceeding with DCD heart transplantation for patients with WIP ≥36 minutes, particularly in donors with LVEF <60%., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Since the beginning of the pandemic, coronavirus disease 2019 (COVID-19) has caused debilitating lung failure in many patients. Practitioners have understandably been hesitant to use lungs from donors with COVID-19 for transplantation. This study aimed to analyze the characteristics and short-term outcomes of lung transplantation from donors with recent positive COVID-19 testing results., Methods: Lung transplantations performed between January 2020 and June 2022 were queried from the United Network for Organ Sharing database. Pediatric, multiorgan, and repeat lung transplantations were excluded. Propensity scoring matched recipients of lungs from donors with recent positive COVID-19 testing results to recipients of lungs from donors with negative COVID-19 testing results, and comparisons of 30-day mortality, 3-month mortality, and perioperative outcomes were performed., Results: A total of 5270 patients underwent lung transplantation during the study dates, including 51 patients who received lungs from donors with recent positive COVID-19 testing results. Forty-five recipients of lungs from donors with recent positive COVID-19 testing results were matched with 135 recipients of lungs from donors with negative COVID-19 testing results. After matching, there was no difference in 30-day (log-rank P = .42) and 3-month (log-rank P = .42) mortality. The incidence of other perioperative complications was similar between the groups., Conclusions: The 30-day and 3-month survival outcomes were similar between recipients of lungs from donors with recent positive COVID-19 testing results and recipients of lungs from donors with negative COVID-19 testing results. This finding suggests that highly selected COVID-19-positive donors without evidence of active infection may be safely considered for lung transplantation. Further studies should explore long-term outcomes to provide reassurance about the safety of this practice., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose of the Review: The current lack of objective and quantitative assessment techniques to determine cardiac graft relative viability results in risk-averse decision-making, which negatively impact the utilization of cardiac grafts. The purpose of this review is to highlight the current deficiencies in cardiac allograft assessment before focusing on novel cardiac assessment techniques that exploit conventional and emerging imaging modalities, including ultrasound, magnetic resonance, and spectroscopy., Recent Findings: Extensive work is ongoing by the scientific community to identify improved objective metrics and tools for cardiac graft assessment, with the goal to safely increasing the number and proportion of hearts accepted for transplantation., Summary: This review briefly discusses the in situ and ex vivo tools currently available for clinical organ assessment, before focusing on the individual capabilities of ultrasound, magnetic resonance, and spectroscopy to provide insightful, non-invasive information regarding cardiac graft functional and metabolic status that may be used to predict outcome after transplantation., Competing Interests: Competing Interests Dr. Tessier has patent applications relevant to this study. The remaining authors declare no competing interests.

Background: Donor organ demand continues to outpace supply in heart transplantation. Utilization of donation after circulatory death (DCD) hearts could significantly increase heart donor availability for patients with advanced heart failure., Objectives: The purpose of this study was to describe hemodynamic and clinical profiles of DCD hearts in comparison to standard of care (SOC) hearts donated after brain death (DBD)., Methods: This single-center retrospective cohort study of consecutive heart transplant recipients analyzed right heart catheterization measurements, inotrope scores, echocardiograms, and clinical outcomes between DCD and DBD heart recipients., Results: Between April 2016 and February 2022, 47 DCD and 166 SOC hearts were transplanted. Median time from DCD consent to transplant was significantly shorter compared with SOC waiting list time (17 days [6-28 days] vs 70 days [23-240 days]; P < 0.001). Right heart function was significantly impaired in DCD recipients compared with SOC recipients 1 week post-transplant (higher median right atrial pressure (10 mm Hg [8-13 mm Hg] vs 7 mm Hg [5-11 mm Hg]; P < 0.001), higher right atrial pressure to pulmonary capillary wedge pressure ratio (0.64 [0.54-0.82] vs 0.57 [0.43-0.73]; P = 0.016), and lower pulmonary arterial pulsatility index (1.66 [1.27-2.50] vs 2.52 [1.63-3.82]; P < 0.001), but was similar between groups by 3 weeks post-transplant. DCD and SOC recipient mortality was similar at 30 days (DCD 0 vs SOC 2%; P = 0.29) and 1 year post-transplant (DCD 3% vs SOC 8%; P = 0.16)., Conclusions: DCD heart utilization is associated with transient post-transplant right heart dysfunction and short-term clinical outcomes otherwise similar to transplantation using DBD hearts., Competing Interests: Funding Support and Author Disclosures Dr Wolfe’s research fellowship is made possible by philanthropic support by the Martignetti family. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The catastrophic global effects of the SARS-CoV-2 pandemic highlight the need to develop novel therapeutics strategies to prevent and treat viral infections of the respiratory tract. To enable this work, we need scalable, affordable, and physiologically relevant models of the human lung, the primary organ involved in the pathogenesis of COVID-19. To date, most COVID-19 in vitro models rely on platforms such as cell lines and organoids. While 2D and 3D models have provided important insights, human distal lung models that can model epithelial viral uptake have yet to be established. We hypothesized that by leveraging techniques of whole organ engineering and directed differentiation of induced pluripotent stem cells (iPSC) we could model human distal lung epithelium, examine viral infection at the tissue level in real time, and establish a platform for COVID-19 related research ex vivo. In the present study, we used type 2 alveolar epithelial cells (AT2) derived from human iPSCs to repopulate whole rat lung acellular scaffolds and maintained them in extended biomimetic organ culture for 30 days to induce the maturation of distal lung epithelium. We observed emergence of a mixed type 1 and type 2 alveolar epithelial phenotype during tissue formation. When exposing our system to a pseudotyped lentivirus containing the spike of wildtype SARS-CoV-2 and the more virulent D614G, we observed progression of the infection in real time. We then found that the protease inhibitor Camostat Mesyalte significantly reduced viral transfection in distal lung epithelium. In summary, our data show that a mature human distal lung epithelium can serve as a novel moderate throughput research platform to examine viral infection and to evaluate novel therapeutics ex vivo., (Copyright © 2022. Published by Elsevier Ltd.)

The clinical significance of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) RNA in stool remains uncertain. We found that extrapulmonary dissemination of infection to the gastrointestinal tract, assessed by the presence of SARS-CoV-2 RNA in stool, is associated with decreased coronavirus disease 2019 (COVID-19) survival. Measurement of SARS-CoV-2 RNA in stool may have utility for clinical risk assessment., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Pregnant and lactating women were excluded from initial coronavirus disease 2019 vaccine trials; thus, data to guide vaccine decision making are lacking., Objective: This study aimed to evaluate the immunogenicity and reactogenicity of coronavirus disease 2019 messenger RNA vaccination in pregnant and lactating women compared with: (1) nonpregnant controls and (2) natural coronavirus disease 2019 infection in pregnancy., Study Design: A total of 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 nonpregnant women) were enrolled in a prospective cohort study at 2 academic medical centers. Titers of severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin G, immunoglobulin A, and immunoglobulin M were quantified in participant sera (n=131) and breastmilk (n=31) at baseline, at the second vaccine dose, at 2 to 6 weeks after the second vaccine, and at delivery by Luminex. Umbilical cord sera (n=10) titers were assessed at delivery. Titers were compared with those of pregnant women 4 to 12 weeks from the natural infection (n=37) by enzyme-linked immunosorbent assay. A pseudovirus neutralization assay was used to quantify neutralizing antibody titers for the subset of women who delivered during the study period. Postvaccination symptoms were assessed via questionnaire. Kruskal-Wallis tests and a mixed-effects model, with correction for multiple comparisons, were used to assess differences among groups., Results: Vaccine-induced antibody titers were equivalent in pregnant and lactating compared with nonpregnant women (pregnant, median, 5.59; interquartile range, 4.68-5.89; lactating, median, 5.74; interquartile range, 5.06-6.22; nonpregnant, median, 5.62; interquartile range, 4.77-5.98, P=.24). All titers were significantly higher than those induced by severe acute respiratory syndrome coronavirus 2 infection during pregnancy (P<.0001). Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. Neutralizing antibody titers were lower in umbilical cord than maternal sera, although this finding did not achieve statistical significance (maternal sera, median, 104.7; interquartile range, 61.2-188.2; cord sera, median, 52.3; interquartile range, 11.7-69.6; P=.05). The second vaccine dose (boost dose) increased severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G, but not immunoglobulin A, in maternal blood and breastmilk. No differences were noted in reactogenicity across the groups., Conclusion: Coronavirus disease 2019 messenger RNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in nonpregnant women. Vaccine-induced immune responses were statistically significantly greater than the response to natural infection. Immune transfer to neonates occurred via placenta and breastmilk., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pregnant and lactating women were excluded from initial COVID-19 vaccine trials; thus, data to guide vaccine decision-making are lacking. We sought to evaluate the immunogenicity and reactogenicity of COVID-19 mRNA vaccination in pregnant and lactating women., Methods: 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant) were enrolled in a prospective cohort study at two academic medical centers. Titers of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131), umbilical cord sera (N=10), and breastmilk (N=31) at baseline, 2nd vaccine dose, 2-6 weeks post 2nd vaccine, and delivery by Luminex, and confirmed by ELISA. Titers were compared to pregnant women 4-12 weeks from native infection (N=37). Post-vaccination symptoms were assessed. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups., Results: Vaccine-induced immune responses were equivalent in pregnant and lactating vs non-pregnant women. All titers were higher than those induced by SARS-CoV-2 infection during pregnancy. Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. SARS-CoV-2 specific IgG, but not IgA, increased in maternal blood and breastmilk with vaccine boost. No differences were noted in reactogenicity across the groups., Conclusions: COVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Vaccine-induced immune responses were significantly greater than the response to natural infection. Immune transfer to neonates occurred via placental and breastmilk.

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8 + T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The latent reservoir for HIV-1 in resting memory CD4 + T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4 + T cells undergoing effector-to-memory transition including temporary upregulation of CCR5 expression and rapid downregulation of cellular gene transcription. These cells allowed completion of steps in the HIV-1 life cycle through integration but suppressed HIV-1 gene transcription, thus allowing the establishment of latency. CD4 + T cells in this stage were substantially more permissive for HIV-1 latent infection than other CD4 + T cells. Establishment of latent HIV-1 infection in CD4 + T could be inhibited by viral-specific CD8 + T cells, a result with implications for elimination of latent HIV-1 infection by T cell-based vaccines., (Copyright © 2017. Published by Elsevier Inc.)

Objectives: Highly active antiretroviral therapy (HAART) is the mainstay of treatment for HIV-1 infection. While current HAART regimens have been extremely effective, issues of associated toxicity, cost and resistance remain and there is a need for novel antiretroviral compounds to complement the existing therapy. We sought to develop a novel high-throughput method for identifying compounds that block later steps in the life cycle not targeted by current therapy., Methods: We designed a high-throughput screen to identify inhibitors of post-integration steps in the HIV-1 life cycle. The screening method was applied to a library of compounds that included numerous FDA-approved small molecules., Results: Among the small molecules that inhibited late stages in HIV-1 replication were members of the cardiac glycoside family. We demonstrate that cardiac glycosides potently inhibit HIV-1 gene expression, thereby reducing the production of infectious HIV-1. We demonstrate that this inhibition is dependent upon the human Na(+)/K(+)-ATPase, but independent of cardiac glycoside-induced increases in intracellular Ca(2+)., Conclusions: We have validated a novel high-throughput screen to identify small molecule inhibitors of HIV-1 gene expression, virion assembly and budding. Using this screen, we have demonstrated that a number of FDA-approved compounds developed for other purposes potently inhibit HIV-1 replication, including the cardiac glycosides. Our work indicates that the entire cardiac glycoside family of drugs shows potential for antiretroviral drug development.

In about half of patients infected with HIV-1 subtype B, viral populations shift from utilizing the transmembrane protein CCR5 to CXCR4, as well as or instead of CCR5, during late stage progression of the disease. How the relative adhesion efficiency and fusion competency of the viral Env proteins relate to infection during this transition is not well understood. Using a virus-cell fusion assay and live-cell single-molecule force spectroscopy, we compare the entry competency of viral clones to tensile strengths of the individual Env-receptor bonds of Env proteins obtained from a HIV-1 infected patient prior to and during coreceptor switching. The results suggest that the genetic determinants of viral entry were predominantly enriched in the C3, HR1 and CD regions rather than V3. Env proteins can better mediate entry into cells after coreceptor switch; this effective entry capacity does not correlate with the bond strengths between viral Env and cellular receptors.

HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral drugs. They are characterized by highly cooperative dose-response curves that are not explained by current pharmacodynamic theory. An unresolved problem affecting the clinical use of PIs is that patients who fail PI-containing regimens often have virus that lacks protease mutations, in apparent violation of fundamental evolutionary theory. Here, we show that these unresolved issues can be explained through analysis of the effects of PIs on distinct steps in the viral life cycle. We found that PIs do not affect virion release from infected cells but block entry, reverse transcription, and post-reverse transcription steps. The overall dose-response curves could be reconstructed by combining the curves for each step using the Bliss independence principle, showing that independent inhibition of multiple distinct steps in the life cycle generates the highly cooperative dose-response curves that make these drugs uniquely effective. Approximately half of the inhibitory potential of PIs is manifest at the entry step, likely reflecting interactions between the uncleaved Gag and the cytoplasmic tail (CT) of the Env protein. Sequence changes in the CT alone, which are ignored in current clinical tests for PI resistance, conferred PI resistance, providing an explanation for PI failure without resistance.

Current assays for quantification of HIV-1 virions rely on real-time reverse transcriptase (RT)-PCR detection of conserved regions of HIV-1 RNA and can be limited by detection of contaminating viral or plasmid DNA. We developed a novel RT-PCR assay using a reverse primer that hybridizes with the poly(A) tail of HIV-1 mRNAs, anchored by conserved viral nucleotides at the most distal region of the transcript. This assay can detect and quantify HIV-1 RNA with high specificity and sensitivity.