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Context-Public education campaigns about organ donation are common, but their association to actual attitudes, beliefs, and decisions about organ donation among family members of donation-eligible individuals is unknown. Objective-To examine the sources of organ donation information identified by donor and nondonor families who participated in a large-scale study to examine factors that influence organ donation decisions. Design-Semistructured telephone survey conducted after a passive recruitment strategy. Setting and Participants-Participants were 285 next of kin of donor-eligible individuals (147 donors, 138 nondonors) from one organ procurement organization. Results-Most (85.6%) of next of kin were exposed to at least 1 source of donation information that was important to them, although the types of donation information they were exposed to varied widely. White and educated adults were more likely to have been exposed to more donation information than had minorities and persons with less education. Favorable attitudes and beliefs about organ donation, donor designation, and sharing donation intentions with others were all associated with more exposure to different types of donation information. Donation consent was more likely when next of kin had been exposed to more donation information in the months preceding the family member's death. Conclusions-When examined in the context of other recent research, these findings argue for continued development and implementation of public education campaigns for organ donation, with an emphasis on repeated exposure over time. [ABSTRACT FROM AUTHOR]

Context -- Information about the relationship between family disagreement and donation decisions may facilitate development of strategies to help families resolve conflict and possibly increase donation consent rates. Objective -- To assess how family interactions influence next-of-kin decisions about organ donation. Design -- Semistructured survey. Setting and Participants-Next of kin of potential donors (147 donors, 138 non-donors) from 1 organ procurement organization participated in a semistructured telephone interview, answering questions about the presence and influence of others during decision making related to organ donation. Results -- When others were actively involved in the donation decision (68%), disagreement about the donation decision occurred in 32% of cases. Compared with families initially in agreement, families not in agreement were less likely to donate (P< .001), took longer to make a decision (P< .001), and were less likely to make the same decision now (P< .001). Family disagreement was significantly associated with having more family members involved in the discussion, characteristics of the deceased (younger age, not married, nonwhite race, fewer days in the hospital, trauma-related death), next-of-kin characteristics (less education, less favorable organ donation beliefs), not knowing the deceased's donation intentions, less satisfaction with the health care team, and perceptions of a less compassionate donation requester. Conclusions -- Family disagreement occurred in one-third of donation approaches when other family members were present. Such disagreement is most likely to contribute to donation refusal when the deceased's donation intentions are unknown. Recognizing and assessing the nature of family disagreement may increase donation consent. [ABSTRACT FROM AUTHOR]

BACKGROUND: Blacks are disproportionately affected by chronic kidney disease, but are far less likely to undergo live donor kidney transplantation (LDKT) than whites. We assessed the differential effectiveness in blacks and whites of a home-based (HB) LDKT educational approach. STUDY DESIGN: A planned secondary analysis of a previously published randomized trial. SETTING & PARTICIPANTS: 132 patients (60 black, 72 white) approved for kidney transplantation at 1 kidney transplant center in the southeastern United States. INTERVENTION: Assignment to receive either standard clinic-based (CB) transplant education (n = 69) or CB plus an HB (CB + HB) LDKT education program (n = 63). The HB education program was culturally sensitive for blacks, including using a minority health educator, brochures that highlight minority transplant recipients and donors, and discussion of race-specific outcome data. OUTCOMES: Primary outcomes were proportions of patients with live donor inquiries, evaluations, and transplants 1 year after study participation. MEASUREMENTS: Medical record and questionnaire data. RESULTS: 69 patients were assigned to the CB group, and 63 to the CB + HB group. After 1 year, there were 96 living donor inquiries (72.7%), 62 living donor evaluations (47.0%), and 54 LDKTs (40.9%). Patients assigned to the CB + HB group were more likely to have had living donor inquiries (odds ratio [OR], 1.7; confidence interval [CI], 1.2 to 3.0), a living donor evaluated (OR, 2.7; CI, 1.4 to 5.4), and LDKT (OR, 3.0; CI, 1.5 to 5.9). The effect was greater in blacks than whites for living donor evaluations and LDKT, but not for living donor inquiries (treatment-by-race interaction, P < 0.001, P < 0.001, and P = 0.8, respectively). Blacks in the CB + HB group were more likely to have had at least 1 living donor inquiry (51.7% versus 77.4%), at least 1 living donor evaluated (17.2% versus 48.4%), and LDKT (13.8% versus 45.2%) than those in the CB group. By comparison, whites in the CB + HB group were more likely to have had at least 1 living donor inquiry (72.5% versus 87.5%), at least 1 living donor evaluated (47.5% versus 71.9%), and LDKT (42.5% versus 59.4%) than those in the CB group. LIMITATIONS: Single-center study with greater dropout rate in the CB + HB group. CONCLUSIONS: These results suggest that a culturally sensitive LDKT education program that reaches out to blacks and their social support network can overcome some barriers to LDKT in this population. Copyright © 2008 by the National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Signed donor cards clearly demonstrate the donor's intention to donate organs after death. In many states, this donation cannot be rescinded by the next of kin, and organs can be recovered from the donor even if the family objects. The family usually does not object if the donor has signed an organ donor card, especially if the donor had discussed the issue with the family. In some situations, however, the family objects to donation despite the signed organ donor card. If the organ procurement organization pursues donation, adverse publicity and even legal action are possible. It can be a challenge for organ procurement personnel to deal with families who object to donation in the face of a signed organ donor card in a manner that will lead to successful organ recovery without adverse consequences. This article describes 4 cases where the donor had a signed organ donor card but the family initially objected to donation. Ultimately organs were recovered from 3 of these donors. [ABSTRACT FROM AUTHOR]

Background: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear.Methods: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks.Results: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change.Conclusions: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

OBJECTIVE: Cognitive models propose that the symptoms and psychological impairments associated with schizophrenia arise as a consequence of impaired communication between brain regions, especially the prefrontal cortex and the temporal and parietal lobes. Functional imaging and electrophysiological data have provided evidence of functional dysconnectivity, but it is unclear whether this reflects an underlying problem with anatomical connectivity. This study used diffusion tensor imaging to examine the integrity of the major white matter fasciculi, which connects the frontal and temporal-parietal cortices, and the corpus callosum in patients with schizophrenia. METHOD: A 1.5-T magnetic resonance scanner was used to acquire diffusion tensor images giving whole brain coverage at an isotropic 2.5-mm voxel size. Fractional anisotropy was measured in 33 patients with schizophrenia and 40 healthy comparison subjects with an automated voxel-based method of analysis. RESULTS: There was reduced fractional anisotropy in patients with schizophrenia in regions corresponding to the superior longitudinal fasciculi bilaterally and in the genu of the corpus callosum. However, within the patient group, the propensity to experience auditory hallucinations was associated with relatively increased fractional anisotropy in superior longitudinal fasciculi and in the anterior cingulum. CONCLUSIONS: Schizophrenia is associated with altered white matter integrity in the tracts connecting the frontal cortex with the temporal and parietal cortices and with the contralateral frontal and temporal lobes. The severity of these changes may vary with the pattern of symptoms associated with the disorder. [ABSTRACT FROM AUTHOR]

Background--Rates of living kidney donation have increased dramatically in recent years, in large part because of improved surgical techniques such as laparoscopic nephrectomy.Objective--To compare patient-reported outcomes of laparoscopic nephrectomy versus open donor nephrectomy in 84 adult live kidney donors.Outcome Measures--Outcomes included perceptions of pain and surgical scarring, number of surgical/medical complications, hospital length of stay, physical health problems related to donation, return to work, fmancial impact, health-related quality of life, and satisfaction with the donation experience.Results and Conclusion--The 2 groups did not differ significantly in pain perceptions, number of surgical/medical complications, physical health problems, financial impact, health-related quality of life, or overall satisfaction. However, laparoscopic nephrectomy donors had significantly fewer hospital days and faster return to work time than open donor nephrectomy donors. The majority of donors report excellent health-related quality of life and no complications in the months following surgery. In addition, it appears that laparoscopic nephrectomy, in comparison to open donor nephrectomy, may reduce barriers to living kidney donation by reducing hospital length of stay and time away from work. Being able to return to work much sooner after surgery may significantly reduce the indirect costs (ie, lost wages) associated with living donation. (Progress in Transplantation. 2006;16:162-169) [ABSTRACT FROM AUTHOR]

Tobacco use adversely affects transplant outcomes such as graft survival, patient survival, and other conditions that alter transplant patient longevity. Especially concerning is tobacco's relationship to cardiovascular disease, the number 1 cause of death in kidney transplant recipients. Many authors conclude that tobacco interventions ought to be provided to patients and sometimes lament that there are no tobacco dependence interventions designed for kidney transplant recipients. European Best Practice Guidelines for Renal Transplantation also support tobacco dependence interventions. The purpose of this article is to describe one institution's experience in implementing the clinical practice guideline for treating tobacco use and dependence within a kidney and pancreas transplant program. [ABSTRACT FROM AUTHOR]

BACKGROUND: People with persecutory delusions regard ambiguous data in the social domain as self-relevant and selectively attend to threatening information. This study aimed to characterize these social cognitive biases in functional neuroanatomical terms. METHOD: Eight schizophrenic patients with active persecutory delusions and eight matched normal controls underwent functional magnetic resonance imaging while determining the self-relevance of ambiguous self-relevant or unambiguous other-relevant neutral and threatening statements. RESULTS: In determining self-relevance, the deluded subjects showed a marked absence of rostral-ventral anterior cingulate activation together with increased posterior cingulate gyrus activation in comparison to the normal subjects. The influence of threat on self-relevance determination did not yield statistically significant differences between deluded and normal subjects. CONCLUSIONS: Abnormalities of cingulate gyrus activation while determining self-relevance suggest impaired self-reflection in the persecutory deluded state. This may contribute to persecutory belief formation and maintenance. [ABSTRACT FROM AUTHOR]

α7 nicotinic acetylcholine receptors (nAChRs) are homopentameric ligand-gated ion channels with critical roles in the nervous system. Recent studies have resolved and functionally annotated closed, open, and desensitized states of these receptors, providing insight into ion permeation and lipid binding. However, the process by which α7 nAChRs transition between states remains unclear. To understand gating and lipid modulation, we generated two ensembles of molecular dynamics simulations of apo α7 nAChRs, with or without cholesterol. Using symmetry-adapted Markov state modeling, we developed a five-state gating model. Free energies recapitulated functional behavior, with the closed state dominating in absence of agonist. Open-to-nonconducting transition rates corresponded to experimental open durations. Cholesterol relatively stabilized the desensitized state, and reduced open-desensitized barriers. These results establish plausible asymmetric transition pathways between states, define lipid modulation effects on the α7 nAChR conformational cycle, and provide an ensemble of structural models applicable to rational design of lipidic pharmaceuticals., (© 2024. The Author(s).)

ρ-type γ-aminobutyric acid-A (GABA A ) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including β-estradiol and pregnenolone sulfate negatively modulate the function of ρ1 GABA A receptors, but their inhibitory mechanisms are not clear. By combining five cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of β-estradiol and pregnenolone sulfate at the human ρ1 GABA A receptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of ρ1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design., (© 2024. The Author(s).)

The rise of open science and the absence of a global dedicated data repository for molecular dynamics (MD) simulations has led to the accumulation of MD files in generalist data repositories, constituting the dark matter of MD - data that is technically accessible, but neither indexed, curated, or easily searchable. Leveraging an original search strategy, we found and indexed about 250,000 files and 2000 datasets from Zenodo, Figshare and Open Science Framework. With a focus on files produced by the Gromacs MD software, we illustrate the potential offered by the mining of publicly available MD data. We identified systems with specific molecular composition and were able to characterize essential parameters of MD simulation such as temperature and simulation length, and could identify model resolution, such as all-atom and coarse-grain. Based on this analysis, we inferred metadata to propose a search engine prototype to explore the MD data. To continue in this direction, we call on the community to pursue the effort of sharing MD data, and to report and standardize metadata to reuse this valuable matter., Competing Interests: JT, MS, LB, MO, SG, RH, EL, MB, KL, MC, PP No competing interests declared, LD Reviewing editor, eLife, (© 2023, Tiemann et al.)

Loss-of-function mutations of the CFTR gene cause the life-shortening genetic disease cystic fibrosis (CF), whereas overactivity of CFTR may lead to secretory diarrhea and polycystic kidney disease. While effective drugs targeting the CFTR protein have been developed for the treatment of CF, little progress has been made for diseases caused by hyper-activated CFTR. Here, we solve the cryo-EM structure of CFTR in complex with CFTRinh-172 (Inh-172), a CFTR gating inhibitor with promising potency and efficacy. We find that Inh-172 binds inside the pore of CFTR, interacting with amino acid residues from transmembrane segments (TMs) 1, 6, 8, 9, and 12 through mostly hydrophobic interactions and a salt bridge. Substitution of these residues lowers the apparent affinity of Inh-172. The inhibitor-bound structure reveals re-orientations of the extracellular segment of TMs 1, 8, and 12, supporting an allosteric modulation mechanism involving post-binding conformational changes. This allosteric inhibitory mechanism readily explains our observations that pig CFTR, which preserves all the amino acid residues involved in Inh-172 binding, exhibits a much-reduced sensitivity to Inh-172 and that the apparent affinity of Inh-172 is altered by the CF drug ivacaftor (i.e., VX-770) which enhances CFTR's activity through binding to a site also comprising TM8., (© 2024. The Author(s).)

Background: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life., Methods: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out., Results: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms., Conclusions: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO 2 activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization. The involvement of proton modulation sites for weak acid-sensitivity was supported by the identification of titratable extracellular (Glu495, Glu561) and intracellular (His521) residues on a cryo-EM structure of rat TRPV2 (rTRPV2) treated with acetic acid. Molecular dynamics simulations as well as patch clamp experiments on mutant rTRPV2 constructs confirmed that these residues are critical for weak acid-sensitivity. We also demonstrate that the pore residue Glu609 dictates an inhibition of weak acid-induced currents by extracellular calcium. Finally, TRPV2-expression in HEK293 cells is associated with an increased weak acid-induced cytotoxicity. Together, our data provide new insights into weak acids as endogenous modulators of TRPV2., (© 2024. The Author(s).)

Background: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease., Methods: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391)., Findings: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention., Interpretation: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services., Funding: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association., Competing Interests: Declaration of interests RLG, CJM, BJT, CVR, MBu, MBr, PK, EJT, DAW, MAS, CDG, LMM, LHG, AA-C, TY, VL, CC, PJS, and RJH declare institutional financial support from the grant for the submitted work (National Institute for Health and Care Research Health Technology Assessment 16/81/01). RLG, MAS, RJH, MBr, CC, TY, PJS, CJM, AA-C, VL, and LHG are supported by a public research body (National Institute for Health and Care Research Biomedical Research Centres). LHG has received royalties for books on psychology and neuropsychology and fees for lectures on neurology. AA-C and PJS receive payment for consultancy and advisory board participation from commercial organisations (Amylyx, Apellis, Biogen, Brainstorm, Clene Therapeutics, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, Sano, Sanofi, and Wave Pharmaceuticals), none of which are related to the content of this submitted work. RWO, LMM, and CF have received grants for research from public bodies. RWO has received grants for research and trials from commercial organisations (Amylyx Pharmaceuticals, Biogen, Orphazyme) and received payment for neurological medicolegal work. RWO and CF sit on safety monitoring or advisory boards for motor neuron disease. RWO, JE, and AH sit on boards in organisations associated with motor neuron disease. AH receives grant funding for his clinical role at Motor Neurone Disease Association. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)