Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

Combined islet and kidney xenotransplantation for diabetic nephropathy: an update in ongoing research for a clinically relevant application of porcine islet transplantation.

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial.

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

National UK guidelines for the management of paediatric craniopharyngioma.

Although rare, craniopharyngiomas constitute up to 80% of tumours in the hypothalamic-pituitary region in childhood. Despite being benign, the close proximity of these tumours to the visual pathways, hypothalamus, and pituitary gland means that both treatment of the tumour and the tumour itself can cause pronounced long-term neuroendocrine morbidity against a background of high overall survival. To date, the optimal management strategy for these tumours remains undefined, with practice varying between centres. In light of these discrepancies, as part of a national endeavour to create evidence-based and consensus-based guidance for the management of rare paediatric endocrine tumours in the UK, we aimed to develop guidelines, which are presented in this Review. These guidelines were developed under the auspices of the UK Children's Cancer and Leukaemia Group and the British Society for Paediatric Endocrinology and Diabetes, with the oversight and endorsement of the Royal College of Paediatrics and Child Health using Appraisal of Guidelines for Research & Evaluation II methodology to standardise care for children and young people with craniopharyngiomas.

Histopathological screening of Pontogammarus robustoides (Amphipoda), an invader on route to the United Kingdom.

Biological invasions may act as conduits for pathogen introduction. To determine which invasive non-native species pose the biggest threat, we must first determine the symbionts (pathogens, parasites, commensals, mutualists) they carry, via pathological surveys that can be conducted in multiple ways (i.e., molecular, pathological, and histological). Whole animal histopathology allows for the observation of pathogenic agents (virus to Metazoa), based on their pathological effect upon host tissue. Where the technique cannot accurately predict pathogen taxonomy, it does highlight pathogen groups of importance. This study provides a histopathological survey of Pontogammarus robustoides (invasive amphipod in Europe) as a baseline for symbiont groups that may translocate to other areas/hosts in future invasions. Pontogammarus robustoides (n = 1,141) collected throughout Poland (seven sites), were noted to include a total of 13 symbiotic groups: a putative gut epithelia virus (overall prevalence = 0.6%), a putative hepatopancreatic cytoplasmic virus (1.4%), a hepatopancreatic bacilliform virus (15.7%), systemic bacteria (0.7%), fouling ciliates (62.0%), gut gregarines (39.5%), hepatopancreatic gregarines (0.4%), haplosporidians (0.4%), muscle infecting microsporidians (6.4%), digeneans (3.5%), external rotifers (3.0%), an endoparasitic arthropod (putatively: Isopoda) (0.1%), and Gregarines with putative microsporidian infections (1.4%). Parasite assemblages partially differed across collection sites. Co-infection patterns revealed strong positive and negative associations between five parasites. Microsporidians were common across sites and could easily spread to other areas following the invasion of P. robustoides. By providing this initial histopathological survey, we hope to provide a concise list of symbiont groups for risk-assessment in the case of a novel invasion by this highly invasive amphipod.

Biological Invasions Affect Resource Processing in Aquatic Ecosystems: The Invasive Amphipod Dikerogammarus villosus Impacts Detritus Processing through High Abundance Rather than Differential Response to Temperature.

Anthropogenic stressors such as climate warming and invasive species and natural stressors such as parasites exert pressures that can interact to impact the function of ecosystems. This study investigated how these stressors interact to impact the vital ecosystem process of shredding by keystone species in temperate freshwater ecosystems. We compared metabolic rates and rates of shredding at a range of temperatures up to extreme levels, from 5 °C to 30 °C, between invasive and native amphipods that were unparasitised or parasitised by a common acanthocephalan, Echinorhynchus truttae. Shredding results were compared using the relative impact potential (RIP) metric to investigate how they impacted the scale with a numerical response. Although per capita shredding was higher for the native amphipod at all temperatures, the higher abundance of the invader led to higher relative impact scores; hence, the replacement of the native by the invasive amphipod is predicted to drive an increase in shredding. This could be interpreted as a positive effect on the ecosystem function, leading to a faster accumulation of amphipod biomass and a greater rate of fine particulate organic matter (FPOM) provisioning for the ecosystem. However, the high density of invaders compared with natives may lead to the exhaustion of the resource in sites with relatively low leaf detritus levels.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Neutralizing activity and 3-month durability of tixagevimab and cilgavimab prophylaxis against Omicron sublineages in transplant recipients.

Neutralizing antibody (nAb) responses are attenuated in solid organ transplant recipients (SOTRs) despite severe acute respiratory syndrome-coronavirus-2 vaccination. Preexposure prophylaxis (PrEP) with the antibody combination tixagevimab and cilgavimab (T+C) might augment immunoprotection, yet in vitro activity and durability against Omicron sublineages BA.4/5 in fully vaccinated SOTRs have not been delineated. Vaccinated SOTRs, who received 300 + 300 mg T+C (ie, full dose), within a prospective observational cohort submitted pre and postinjection samples between January 31, 2022, and July 6, 2022. The peak live virus nAb was measured against Omicron sublineages (BA.1, BA.2, BA.2.12.1, and BA.4), and surrogate neutralization (percent inhibition of angiotensin-converting enzyme 2 receptor binding to full length spike, validated vs live virus) was measured out to 3 months against sublineages, including BA.4/5. With live virus testing, the proportion of SOTRs with any nAb increased against BA.2 (47%-100%; P < .01), BA.2.12.1 (27%-80%; P < .01), and BA.4 (27%-93%; P < .01), but not against BA.1 (40%-33%; P = .6). The proportion of SOTRs with surrogate neutralizing inhibition against BA.5, however, fell to 15% by 3 months. Two participants developed mild severe acute respiratory syndrome-coronavirus-2 infection during follow-up. The majority of fully vaccinated SOTRs receiving T+C PrEP achieved BA.4/5 neutralization, yet nAb activity commonly waned by 3 months postinjection. It is critical to assess the optimal dose and interval of T+C PrEP to maximize protection in a changing variant climate.

Responses of the in vitro turtle brain to visual and auditory stimuli during severe hypoxia.

North American pond turtles (Emydidae) are renowned for their ability to survive extreme hypoxia and anoxia, which enables several species to overwinter in ice-locked, anoxic freshwater ponds and bogs for months. Centrally important for surviving these conditions is a profound metabolic suppression, which enables ATP demands to be met entirely with glycolysis. To better understand whether anoxia limits special sensory functions, we recorded evoked potentials in a reduced brain preparation, in vitro, that was perfused with severely hypoxic artificial cerebral spinal fluid (aCSF). For recordings of visual responses, an LED was flashed onto retinal eyecups while evoked potentials were recorded from the retina or the optic tectum. For recordings of auditory responses, a piezomotor-controlled glass actuator displaced the tympanic membrane while evoked potentials were recorded from the cochlear nuclei. We found that visual responses decreased when perfused with hypoxic perfusate (aCSF PO2<4.0 kPa). In contrast, the evoked response within the cochlear nuclei was unattenuated. These data provide further support that pond turtles have a limited ability to sense visual information in their environment even while moderately hypoxic, but that auditory input may become a principal avenue of sensory perception during extreme diving in this species such as occurs during anoxic submergence.

Head and Neck Sarcoma Tumor Board Survival Guide for Neuroradiologists: Imaging Findings, History, and Pathology.

Sarcomas of the head and neck carry a poor prognosis as diagnosis is often delayed until a late stage of the disease. Accordingly, it is essential to be familiar with the clinical and imaging features of sarcomas to suggest an appropriate differential diagnosis for collaborating surgeons and pathologists. However, as there are only 1000-1500 cases in the United States annually, many radiologists lack experience with pertinent imaging findings of sarcoma and lack knowledge of both treatment and necessary follow-up. In this review, a brief discussion of WHO definitions and histopathology is included to decode information provided by pathologists. Finally, staging and treatments are illuminated to aid the radiologist with initial imaging staging and follow-up care. This review aims to increase the comprehensive knowledge of a neuroradiologist and further their value to the multidisciplinary tumor board.

Patient-reported outcomes after Tixagevimab and Cilgavimab pre-exposure prophylaxis among solid organ transplant recipients: Safety, effectiveness, and perceptions of risk.

BACKGROUND: Tixagevimab and Cilgavimab (T + C) is authorized for pre-exposure prophylaxis (PrEP) against Coronavirus Disease 2019 (COVID-19) in solid organ transplant recipients (SOTRs), yet patient-reported outcomes after injection are not well described. Furthermore, changes in risk tolerance after T + C PrEP have not been reported, of interest given uncertain activity against emerging Omicron sublineages. METHODS: Within a national prospective observational study, SOTRs who reported receiving T + C were surveyed for 3 months to ascertain: (1) local and systemic reactogenicity, (2) severe adverse events with focus on cardiovascular and alloimmune complications, and (3) breakthrough COVID-19, contextualized through (4) changes in attitudes regarding COVID-19 risk and behaviors. RESULTS: At 7 days postinjection, the most common reactions were mild fatigue (29%), headache (20%), and pain at injection sites (18%). Severe adverse events were uncommon; over 3 months of follow-up, 4/392 (1%) reported acute rejection and one (.3%) reported a myocardial infarction. Breakthrough COVID-19 occurred in 9%, 16-129 days after receiving full dose (300/300 mg) T + C, including two non-ICU hospitalizations. Most surveyed SOTRs (65%) felt T + C PrEP was likely to reduce their COVID-19 risk, and 70% reported increased willingness to engage in social activities such as visiting friends. However, few felt safe to return to in-person work (20%) or cease public mask-wearing (15%). CONCLUSIONS: In this prospective study of patient-reported outcomes, T + C was well tolerated with few serious events. Several COVID-19 breakthroughs were reported, notable as most SOTRs reported changes in risk tolerance after T + C. These results aid counseling of SOTRs regarding real-world safety and effectiveness of T + C.

Patient, clinical, surgical, and institutional factors associated with length of stay in scheduled degenerative thoracolumbar spine surgery: National Multicenter Cohort Analysis from the Canadian Spine Outcomes and Research Network.

OBJECTIVE: Length of stay (LOS) is a contributor to costs and resource utilization. The primary goal of this study was to identify patient, clinical, surgical, and institutional variables that influence LOS after elective surgery for thoracolumbar degenerative pathology. The secondary objective was to examine variability in LOS and institutional strategies used to decrease LOS. METHODS: This is a retrospective study of prospectively collected data from a multicentric cohort enrolled in the Canadian Spine Outcomes and Research Network (CSORN) between January 2015 and October 2020 who underwent elective thoracolumbar surgery (discectomy [1 or 2 levels], laminectomy [1 or 2 levels], and posterior instrumented fusion [up to 5 levels]). Prolonged LOS was defined as LOS greater than the median. Logistic regression models were used to determine factors associated with prolonged LOS for each procedure. A survey was sent to the principal investigators of the participating healthcare institutions to understand institutional practices that are used to decrease LOS. RESULTS: A total of 3700 patients were included (967 discectomies, 1094 laminectomies, and 1639 fusions). The median LOSs for discectomy, laminectomy, and fusion were 0.0 (IQR 1.0), 1.0 (IQR 2.0), and 4.0 (IQR 2.0) days, respectively. On multivariable analysis, predictors of prolonged LOS for discectomy were having more leg pain, higher Oswestry Disability Index (ODI) scores, symptom duration more than 2 years, having undergone an open procedure, occurrence of an adverse event (AE), and treatment at an institution without protocols to reduce LOS (p < 0.05). Predictors of prolonged LOS for laminectomy were increased age, living alone, higher ODI scores, higher BMI, open procedures, longer operative time, AEs, and treatment at an institution without protocols to reduce LOS (p < 0.05). For posterior instrumented fusion, predictors of prolonged LOS were older age, living alone, more comorbidities, higher ODI scores, longer operative time, AEs, and treatment at an institution without protocols to reduce LOS (p < 0.05). The laminectomy group had the largest variability in LOS (SD 4.4 days, range 0-133 days). Three hundred fifty-four patients (22%) had an LOS above the 75th percentile. Ten institutions (53%) had either Enhanced Recovery After Surgery or standardized protocols in place. CONCLUSIONS: Among the factors identified in this study, worse baseline ODI scores, experiencing AEs, and treatment at an institution without protocols aimed at reducing LOS were predictive of prolonged LOS in all surgical groups. The laminectomy group had the largest variability in LOS.

Complications of Hip Hemiarthroplasty.

Hip hemiarthroplasty is a commonly performed orthopedic surgery, used to treat proximal femur fractures in the elderly population. Although hip hemiarthroplasty is frequently successful in addressing these injuries, complications can occur. Commonly seen complications include dislocation, periprosthetic fracture, acetabular erosion, and leg-length inequality. Less frequently seen complications include neurovascular injury and capsular interposition. This article presents a comprehensive review of the complications associated with the management of hip hemiarthroplasty. [Orthopedics. 2023;46(4):e199-e209.].

Predicting a Positive Antibody Response After 2 SARS-CoV-2 mRNA Vaccines in Transplant Recipients: A Machine Learning Approach With External Validation.

BACKGROUND: Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations. METHODS: Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital. RESULTS: Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ . CONCLUSIONS: Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.