Living donor kidney transplantation is the optimal treatment for end-stage kidney disease (ESKD) but confers a risk upon the donor, both in the short term and many years after donation. While ...perioperative mortality is low and longevity does not appear to be adversely affected, there are small increases in the risk of other important morbidities. The overall risk of ESKD among donors is low but appears to be three- to five-fold higher than among healthy non-donors, and this relative risk is even higher among donors of African ancestry. For these individuals, apolipoprotein L1 genotyping may be helpful. Kidney donors also have an increased risk of developing hypertension post-donation and a modestly increased risk of developing gout. Living kidney donation also increases the risk of gestational hypertension and preeclampsia while not affecting other important pregnancy outcomes. As our understanding of donor risk grows, it is important to counsel prospective donors according to their individual risk and so obtain better informed donor consent. As knowledge advances, it is also important that all clinicians who manage kidney transplant candidates have an up to date understanding of donor risk to inform shared decision making.
Cancer transmission is a known risk for recipients of organ transplants. Many people wait a long time for a suitable transplant; some never receive one. Although patients with brain tumors may donate ...their organs, opinions vary on the risks involved.
To determine the risk of cancer transmission associated with organ transplants from deceased donors with primary brain tumors. Key secondary objectives were to investigate the association that donor brain tumors have with organ usage and posttransplant survival.
This was a cohort study in England and Scotland, conducted from January 1, 2000, to December 31, 2016, with follow-up to December 31, 2020. This study used linked data on deceased donors and solid organ transplant recipients with valid national patient identifier numbers from the UK Transplant Registry, the National Cancer Registration and Analysis Service (England), and the Scottish Cancer Registry. For secondary analyses, comparators were matched on factors that may influence the likelihood of organ usage or transplant failure. Statistical analysis of study data took place from October 1, 2021, to May 31, 2022.
A history of primary brain tumor in the organ donor, identified from all 3 data sources using disease codes.
Transmission of brain tumor from the organ donor into the transplant recipient. Secondary outcomes were organ utilization (ie, transplant of an offered organ) and survival of kidney, liver, heart, and lung transplants and their recipients. Key covariates in donors with brain tumors were tumor grade and treatment history.
This study included a total of 282 donors (median IQR age, 42 33-54 years; 154 females 55%) with primary brain tumors and 887 transplants from them, 778 (88%) of which were analyzed for the primary outcome. There were 262 transplants from donors with high-grade tumors and 494 from donors with prior neurosurgical intervention or radiotherapy. Median (IQR) recipient age was 48 (35-58) years, and 476 (61%) were male. Among 83 posttransplant malignancies (excluding NMSC) that occurred over a median (IQR) of 6 (3-9) years in 79 recipients of transplants from donors with brain tumors, none were of a histological type matching the donor brain tumor. Transplant survival was equivalent to that of matched controls. Kidney, liver, and lung utilization were lower in donors with high-grade brain tumors compared with matched controls.
Results of this cohort study suggest that the risk of cancer transmission in transplants from deceased donors with primary brain tumors was lower than previously thought, even in the context of donors that are considered as higher risk. Long-term transplant outcomes are favorable. These results suggest that it may be possible to safely expand organ usage from this donor group.
Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children
, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously ...described differential screening method to analyse the proteome of blood-stage P. falciparum parasites
, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.
Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). ...However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy objective response rate (ORR) of molibresib combined with fulvestrant in women with HR+/HER2- mBC.
In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor.
The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% 95% confidence interval (CI), 8-20, not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73-4.83; P < 0.0001).
Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.
Patient and public involvement aims to create a partnership between healthcare users and researchers, so that the methods and outcomes of research are more appropriate to research participants and ...patients. This means doing research with rather than to, for, or about patients and the public. This report summarizes a workshop held in London to explore research participation from the patients' perspective, focusing on why patients participate in research and how clinical researchers can actively engage healthcare users in research planning and execution to enhance outcomes.
Background. Human immunodeficiency virus (HIV)—associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the ...epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. Methods. We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. Results. From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P<.001), and an index of chronic damage score >75 was associated with shorter renal survival (P<.001). Conclusions. Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.
The cellular basis for essential hypertension remains obscure. Abnormal ion transport has been demonstrated in both experimental and essential hypertension, raised levels of sodium-lithium ...(Na(+)-Li+) and sodium-proton (Na(+)-H+) exchange in blood cells being a consistent feature. However, Na(+)-H+ exchange is not the main regulator of intracellular pH at resting pH, while the importance of the contribution of bicarbonate to cellular pH regulation is now increasingly appreciated. Serum and serum-derived growth factors are known to affect intracellular pH and the activity of the Na(+)-H+ antiporter. This study was designed to investigate the activity of Na(+)-H+ exchange in the leucocytes of patients with essential hypertension in the presence of bicarbonate in vitro and to measure the effect of autologous serum on intracellular pH and Na(+)-H+ exchange. Paired serum samples from essential hypertensives and their controls were used on leucocytes from other (unrelated, normotensive) donors to investigate the same parameters. In a study of 30 patients with untreated essential hypertension and 30 controls matched for age, sex, race and body habitus we found no difference in resting pH or buffering capacity (pH 7.28 +/- 0.01 and 32.0 +/- 1.6 mmol/l per pH, hypertensives, versus 7.27 +/- 0.02 and 34.5 +/- 1.8 mmol/l per pH, controls) but a marked difference in the maximal rate of Na(+)-H+ exchange in response to intracellular acidification (57.8 +/- 3.2 mmol/l per min versus 47.2 +/- 1.4 mmol/l per min, P = 0.004).
The scale and drivers of marine biodiversity loss are being revealed by the International Union for Conservation of Nature (IUCN) Red List assessment process. We present the first global reassessment ...of 1,199 species in Class Chondrichthyes—sharks, rays, and chimeras. The first global assessment (in 2014) concluded that one-quarter (24%) of species were threatened. Now, 391 (32.6%) species are threatened with extinction. When this percentage of threat is applied to Data Deficient species, more than one-third (37.5%) of chondrichthyans are estimated to be threatened, with much of this change resulting from new information. Three species are Critically Endangered (Possibly Extinct), representing possibly the first global marine fish extinctions due to overfishing. Consequently, the chondrichthyan extinction rate is potentially 25 extinctions per million species years, comparable to that of terrestrial vertebrates. Overfishing is the universal threat affecting all 391 threatened species and is the sole threat for 67.3% of species and interacts with three other threats for the remaining third: loss and degradation of habitat (31.2% of threatened species), climate change (10.2%), and pollution (6.9%). Species are disproportionately threatened in tropical and subtropical coastal waters. Science-based limits on fishing, effective marine protected areas, and approaches that reduce or eliminate fishing mortality are urgently needed to minimize mortality of threatened species and ensure sustainable catch and trade of others. Immediate action is essential to prevent further extinctions and protect the potential for food security and ecosystem functions provided by this iconic lineage of predators.
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•More than one-third of chondrichthyan fish species are threatened by overfishing•Disproportionate threat in tropics risk loss of ecosystem functions and services•Three species not seen in >80 years are Critically Endangered (Possibly Extinct)•The depletion of these species has been driven by continuing demand for human food
The IUCN Red List of Threatened Species is increasingly used to reveal the health of ocean biodiversity. Dulvy et al. assess 1,199 chondrichthyans and demonstrate the need for fishing limits on target and incidental catch and spatial protection to avoid further extinctions and allow for food security and ecosystem functions.
An essential foundation of any science is a standard lexicon. Any given conservation project can be described in terms of the biodiversity targets, direct threats, contributing factors at the project ...site, and the conservation actions that the project team is employing to change the situation. These common elements can be linked in a causal chain, which represents a theory of change about how the conservation actions are intended to bring about desired project outcomes. If project teams want to describe and share their work and learn from one another, they need a standard and precise lexicon to specifically describe each node along this chain. To date, there have been several independent efforts to develop standard classifications for the direct threats that affect biodiversity and the conservation actions required to counteract these threats. Recognizing that it is far more effective to have only one accepted global scheme, we merged these separate efforts into unified classifications of threats and actions, which we present here. Each classification is a hierarchical listing of terms and associated definitions. The classifications are comprehensive and exclusive at the upper levels of the hierarchy, expandable at the lower levels, and simple, consistent, and scalable at all levels. We tested these classifications by applying them post hoc to 1191 threatened bird species and 737 conservation projects. Almost all threats and actions could be assigned to the new classification systems, save for some cases lacking detailed information. Furthermore, the new classification systems provided an improved way of analyzing and comparing information across projects when compared with earlier systems. We believe that widespread adoption of these classifications will help practitioners more systematically identify threats and appropriate actions, managers to more efficiently set priorities and allocate resources, and most important, facilitate cross-project learning and the development of a systematic science of conservation.
Governments have committed to conserving ≥17% of terrestrial and ≥10% of marine environments globally, especially “areas of particular importance for biodiversity” through “ecologically ...representative” Protected Area (PA) systems or other “area‐based conservation measures”, while individual countries have committed to conserve 3–50% of their land area. We estimate that PAs currently cover 14.6% of terrestrial and 2.8% of marine extent, but 59–68% of ecoregions, 77–78% of important sites for biodiversity, and 57% of 25,380 species have inadequate coverage. The existing 19.7 million km² terrestrial PA network needs only 3.3 million km² to be added to achieve 17% terrestrial coverage. However, it would require nearly doubling to achieve, cost‐efficiently, coverage targets for all countries, ecoregions, important sites, and species. Poorer countries have the largest relative shortfalls. Such extensive and rapid expansion of formal PAs is unlikely to be achievable. Greater focus is therefore needed on alternative approaches, including community‐ and privately managed sites and other effective area‐based conservation measures.
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