The complete sequence and comparative analysis of ape sex chromosomes.

Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.

Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer (PRAGMATIC): quality of life and service use results.

PURPOSE: To describe trends and explore factors associated with quality of life (QoL) and psychological morbidity and assess breast cancer (BC) health service use over a 12-month period for patients joining the supported self-management (SSM)/patient-initiated follow-up (PIFU) pathway. METHODS: Participants completed questionnaires at baseline, 3, 6, 9 and 12 months that measured QoL (FACT-B, EQ 5D-5L), self-efficacy (GSE), psychological morbidity (GHQ-12), roles and responsibilities (PRRS) and service use (cost diary). RESULTS: 99/110 patients completed all timepoints; 32% (35/110) had received chemotherapy. The chemotherapy group had poorer QoL; FACT-B total score mean differences were 8.53 (95% CI: 3.42 to 13.64), 5.38 (95% CI: 0.17 to 10.58) and 8.00 (95% CI: 2.76 to 13.24) at 6, 9 and 12 months, respectively. The odds of psychological morbidity (GHQ12 >4) were 5.5-fold greater for those treated with chemotherapy. Financial and caring burdens (PRRS) were worse for this group (mean difference in change at 9 months 3.25 (95% CI: 0.42 to 6.07)). GSE and GHQ-12 scores impacted FACT-B total scores, indicating QoL decline for those with high baseline psychological morbidity. Chemotherapy patients or those with high psychological morbidity or were unable to carry out normal activities had the highest service costs. Over the 12 months, 68.2% participants phoned/emailed breast care nurses, and 53.3% visited a hospital breast clinician. CONCLUSION: The data suggest that chemotherapy patients and/or those with heightened psychological morbidity might benefit from closer monitoring and/or supportive interventions whilst on the SSM/PIFU pathway. Reduced access due to COVID-19 could have affected service use.

Designing a mHealth clinical decision support system for Parkinson's disease: a theoretically grounded user needs approach.

BACKGROUND: Despite the established evidence and theoretical advances explaining human judgments under uncertainty, developments of mobile health (mHealth) Clinical Decision Support Systems (CDSS) have not explicitly applied the psychology of decision making to the study of user needs. We report on a user needs approach to develop a prototype of a mHealth CDSS for Parkinson's disease (PD), which is theoretically grounded in the psychological literature about expert decision making and judgement under uncertainty. METHODS: A suite of user needs studies was conducted in 4 European countries (Greece, Italy, Slovenia, the UK) prior to the development of PD_Manager, a mHealth-based CDSS designed for Parkinson's disease, using wireless technology. Study 1 undertook Hierarchical Task Analysis (HTA) including elicitation of user needs, cognitive demands and perceived risks/benefits (ethical considerations) associated with the proposed CDSS, through structured interviews of prescribing clinicians (N = 47). Study 2 carried out computational modelling of prescribing clinicians' (N = 12) decision strategies based on social judgment theory. Study 3 was a vignette study of prescribing clinicians' (N = 18) willingness to change treatment based on either self-reported symptoms data, devices-generated symptoms data or combinations of both. RESULTS: Study 1 indicated that system development should move away from the traditional silos of 'motor' and 'non-motor' symptom evaluations and suggest that presenting data on symptoms according to goal-based domains would be the most beneficial approach, the most important being patients' overall Quality of Life (QoL). The computational modelling in Study 2 extrapolated different factor combinations when making judgements about different questions. Study 3 indicated that the clinicians were equally likely to change the care plan based on information about the change in the patient's condition from the patient's self-report and the wearable devices. CONCLUSIONS: Based on our approach, we could formulate the following principles of mHealth design: 1) enabling shared decision making between the clinician, patient and the carer; 2) flexibility that accounts for diagnostic and treatment variation among clinicians; 3) monitoring of information integration from multiple sources. Our approach highlighted the central importance of the patient-clinician relationship in clinical decision making and the relevance of theoretical as opposed to algorithm (technology)-based modelling of human judgment.

Chronic Δ9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability.

Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of such deficits remain unclear. Adult male rhesus monkeys (N = 6) responded in the morning on tasks designed to assess different cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ9-tetrahydrocannabinol (THC; 0.01-0.56 mg/kg, i.v.) on cognitive performance, FR responding, and body temperature were determined. Next, THC (1.0-2.0 mg/kg, s.c.) was administered daily after FR 10 sessions for 12 weeks, during which the residual effects of THC (i.e., 22 hours after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared with drug-naive controls using positron emission tomography and [11C]-raclopride (N = 4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, and impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared with controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes.

Follow-up after curative treatment for colorectal cancer: longitudinal evaluation of patient initiated follow-up in the first 12 months.

PURPOSE: To compare patient-triggered follow-up (PTFU) for curatively treated colorectal cancer against traditional outpatient follow-up (OPFU). METHODS: Questionnaires were mailed at four time points over one-year post-treatment to two prospectively-recruited cohorts: A, patients entering follow-up and receiving OPFU pre-implementation of PTFU; B, patients entering follow-up (FU) and receiving either OPFU (B1) or PTFU (B2) post-implementation of PTFU. Bi-variate tests were used to compare patient characteristics and outcomes eight months after entering follow-up (generic and cancer-specific quality of life (QoL), satisfaction). Regression analysis explored associations between follow-up model and outcomes. Resource implications and costs of models were compared. RESULTS: Patients in Cohort B1 were significantly more likely to have received chemotherapy (p < 0.001), radiotherapy (p < 0.05), and reported poorer QoL (p = 0.001). Having a longstanding co-morbid condition was the most important determinant of QoL (p < 0.001); model of care was not significant. Patients were satisfied with their follow-up care regardless of model. Health service costs were higher in PTFU over the first year CONCLUSIONS: PTFU is acceptable to patients with colorectal cancer and can be considered to be a realistic alternative to OPFU for clinically suitable patients. The initial costs are higher due to provision of a self-management (SM) programme and remote surveillance. Further research is needed to establish long-term outcomes and costs.

Post-diagnostic dietary changes in prostate cancer: associations with patients' wellbeing and the perceptions of GPs.

This article aims to investigate associations between perceived control and health-related quality of life (HRQOL) with dietary changes after prostate cancer diagnosis and to explore General Practitioners' (GPs) perceptions on the role of diet in prostate cancer post-diagnosis. Ninety-five prostate cancer patients completed measures of dietary change, one for after diagnosis and another for after therapy. They also scored their HRQOL and perceived control. There were discrepancies in dietary changes reported between a general question (28.4% no dietary changes) and a specific (42.1%-51.5% range of no change for various food items). Most patients initiated healthy changes. Patients who changed their diet after diagnosis had lower cognitive functioning and external locus of control (doctors). Patients who changed their diet after therapy had lower cognitive and emotional functioning, quality of life and external locus of control (doctors). Then, fourty-four GPs responded to an online survey. Their open-ended responses were analysed using Content Analysis. They reported interest in the role of diet in cancer but also lack of relevant knowledge. They were skeptical on providing information. Clinical interventions should consider patients' cognitive ability, their relationship with their health professional and their wellbeing. Also, GPs' confidence to provide dietary advice needs to be addressed.

Structural polymorphism and diversity of human segmental duplications.

Segmental duplications (SDs) contribute significantly to human disease, evolution, and diversity yet have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies where the majority of SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms, we identify 173.2 Mbp of duplicated sequence (47.4 Mbp not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy number when compared to non-African samples. A comparison to a resource of 563 million full-length Iso-Seq reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs.

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.

Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (~3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.

Complete sequencing of ape genomes.

We present haplotype-resolved reference genomes and comparative analyses of six ape species, namely: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan, and siamang. We achieve chromosome-level contiguity with unparalleled sequence accuracy (<1 error in 500,000 base pairs), completely sequencing 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, providing more in-depth evolutionary insights. Comparative analyses, including human, allow us to investigate the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference. This includes newly minted gene families within lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes, and subterminal heterochromatin. This resource should serve as a definitive baseline for all future evolutionary studies of humans and our closest living ape relatives.

PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration.

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.

The Complete Sequence and Comparative Analysis of Ape Sex Chromosomes.

Apes possess two sex chromosomes-the male-specific Y and the X shared by males and females. The Y chromosome is crucial for male reproduction, with deletions linked to infertility. The X chromosome carries genes vital for reproduction and cognition. Variation in mating patterns and brain function among great apes suggests corresponding differences in their sex chromosome structure and evolution. However, due to their highly repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the state-of-the-art experimental and computational methods developed for the telomere-to-telomere (T2T) human genome, we produced gapless, complete assemblies of the X and Y chromosomes for five great apes (chimpanzee, bonobo, gorilla, Bornean and Sumatran orangutans) and a lesser ape, the siamang gibbon. These assemblies completely resolved ampliconic, palindromic, and satellite sequences, including the entire centromeres, allowing us to untangle the intricacies of ape sex chromosome evolution. We found that, compared to the X, ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements. This divergence on the Y arises from the accumulation of lineage-specific ampliconic regions and palindromes (which are shared more broadly among species on the X) and from the abundance of transposable elements and satellites (which have a lower representation on the X). Our analysis of Y chromosome genes revealed lineage-specific expansions of multi-copy gene families and signatures of purifying selection. In summary, the Y exhibits dynamic evolution, while the X is more stable. Finally, mapping short-read sequencing data from >100 great ape individuals revealed the patterns of diversity and selection on their sex chromosomes, demonstrating the utility of these reference assemblies for studies of great ape evolution. These complete sex chromosome assemblies are expected to further inform conservation genetics of nonhuman apes, all of which are endangered species.

Laparoscopic and open colorectal surgery: a prospective cost analysis.

AIM: Cost has been perceived to be a factor limiting the development of laparoscopic colorectal surgery. This study aimed to compare the costs of laparoscopic and open colorectal surgery. METHOD: Patients undergoing laparoscopic or open elective colorectal surgery were recruited into a prospective study to evaluate the healthcare costs of each operative procedure in a district general hospital in England. All healthcare resources used (operation, hospital and community) were recorded and converted to costs in British pounds, 2006-2007. Costs of laparoscopic and open surgery were compared. RESULTS: In all, 201 consecutive patients consented and were recruited (131 laparoscopic, 70 open). Operative costs were greater in the laparoscopic group (£2049 vs£1263, P < 0.001) due to the costs of disposable instruments, but the hospital costs were less (£1807 vs£3468, P < 0.001) due to longer lengths of stay in the open group. Community costs were similar in the two groups and had little impact on the overall costs, which were not significantly different (£3875 laparoscopic vs£4383 open, P = 0.308). In the subgroup of patients with a stoma, overall costs in the laparoscopic group are higher (not significant). CONCLUSION: The costs of laparoscopic and open colorectal surgery are broadly equivalent. If there is an associated improvement in patient benefit, then laparoscopic colorectal surgery may be considered to be cost effective compared with open surgery.

Foraging ecology of critically endangered Eastern Pacific hawksbill sea turtles (Eretmochelys imbricata) in the Gulf of California, Mexico.

The Eastern Pacific hawksbill sea turtle population is one of the most endangered of all sea turtle species. Here, we examine the foraging ecology of 47 hawksbill turtles (40.5-90.3 cm CCL, mean = 54.1 ± 10.1 cm) around Isla San José, Gulf of California, Mexico by integrating information from passive acoustic telemetry, behavior recordings, fecal analysis, and habitat surveys. Tagged hawkbill turtles exhibited high site fidelity over months and years (tracking duration 1-1490 days, mean = 255 ± 373 days) to the location and benthic habitat where individuals were initially caught. Diet was dominated by benthic invertebrates and algae including sponges, algae, tunicates, and mangrove roots. The mean percent cover of these benthic food items was significantly greater in the mangrove estuary than in adjacent rocky and sandy reef habitats. The Isla San José foraging ground is a high-use area for hawksbills and should be granted national protection status.

PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys.

Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15-20% within 1 week of initiating self-administration and remained reduced by approximately 20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.

Field courses narrow demographic achievement gaps in ecology and evolutionary biology.

Disparities remain in the representation of marginalized students in STEM. Classroom-based experiential learning opportunities can increase student confidence and academic success; however, the effectiveness of extending learning to outdoor settings is unknown. Our objectives were to examine (a) demographic gaps in ecology and evolutionary biology (EEB) major completion, college graduation, and GPAs for students who did and did not enroll in field courses, (b) whether under-represented demographic groups were less likely to enroll in field courses, and (c) whether under-represented demographic groups were more likely to feel increased competency in science-related tasks (hereafter, self-efficacy) after participating in field courses. We compared the relationships among academic success measures and demographic data (race/ethnicity, socioeconomic status, first-generation, and gender) for UC Santa Cruz undergraduate students admitted between 2008 and 2019 who participated in field courses (N = 941 students) and who did not (N = 28,215 students). Additionally, we administered longitudinal surveys to evaluate self-efficacy gains during field-based versus classroom-based courses (N = 570 students). We found no differences in the proportion of students matriculating at the university as undecided, proposed EEB, or proposed other majors across demographic groups. However, five years later, under-represented students were significantly less likely to graduate with EEB degrees, indicating retention rather than recruitment drives disparities in representation. This retention gap is partly due to a lower rate of college completion and partly through attrition to other majors. Although under-represented students were less likely to enroll in field courses, field courses were associated with higher self-efficacy gains, higher college graduation rates, higher EEB major retention, and higher GPAs at graduation. All demographic groups experienced significant increases in self-efficacy during field-based but not lecture-based courses. Together, our findings suggest that increasing the number of field courses and actively facilitating access to students from under-represented groups can be a powerful tool for increasing STEM diversity.

Behavioral and neurobiological characteristics influencing social hierarchy formation in female cynomolgus monkeys.

Socially housed monkeys have been used as a model to study human diseases. The present study examined behavioral, physiological and neurochemical measures as predictors of social rank in 16 experimentally naïve, individually housed female cynomolgus monkeys (Macaca fascicularis). The two behavioral measures examined were novel object reactivity (NOR), as determined by latency to touch an opaque acrylic box placed in the home cage, and locomotor activity assessed in a novel open-field apparatus. Serum cortisol concentrations were evaluated three times per week for four consecutive weeks, and stress reactivity was assessed on one occasion by evaluating the cortisol response to adrenocorticotropic hormone (ACTH) following dexamethasone suppression. Measures of serotonin (5-HT) function included whole blood 5-HT (WBS) concentrations, cerebrospinal fluid (CSF) concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) and brain 5-HT transporter (SERT) availability obtained using positron emission tomography (PET). After baseline measures were obtained, monkeys were assigned to four social groups of four monkeys per group. The two measures that correlated with eventual social rank were CSF 5-HIAA concentrations, which were significantly higher in the animals who eventually became subordinate, and latency to touch the novel object, which was significantly lower in eventual subordinate monkeys. Measures of 5-HT function did not change as a consequence of social rank. These data suggest that levels of central 5-HIAA and measures of novel object reactivity may be trait markers that influence eventual social rank in female macaques.

Enhanced cholinergic response in pancreata of nonhuman primates with impaired glucose tolerance shown on [18F]fluorobenzyltrozamicol positron emission tomography.

BACKGROUND: Islet cell adaptation to insulin resistance in type 2 diabetes mellitus may be due in part to increased stimulation of beta cells by the autonomic nervous system. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor correlates with cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. In this study, we utilize [18F]FBT PET to demonstrate pancreatic cholinergic activity before and after dextrose infusion in nonhuman primates with normal (NGT) and impaired (IGT) glucose tolerance. METHODS: Seven adult female vervet (Chlorocebus aethiops) monkeys were maintained on an atherogenic Western diet. They were divided into two groups: four with NGT and three with IGT. Each subject underwent [18F]FBT PET twice: first, a baseline PET under fasting conditions; and second, PET under fasting conditions but after intravenous infusion of dextrose solution. Quantitative analysis of pancreatic uptake at 60 min post-injection was performed. RESULTS: There was no difference in pancreatic uptake of [18F]FBT on baseline scans between the two groups. Pancreatic uptake of [18F]FBT increased in every subject after dextrose infusion (P = 0.03). On post-dextrose PET scans, pancreatic uptake of [18F]FBT was significantly higher in IGT subjects compared with NGT subjects (P = 0.03). The post-dextrose to pre-dextrose uptake ratios were higher in IGT subjects (P = 0.08). CONCLUSIONS: Acute increases in pancreatic cholinergic activity in vivo were detected in the pancreata of nonhuman primates with NGT and IGT after intravenous dextrose infusion on [18F]FBT PET. In subjects with IGT, this activity was significantly higher, suggesting increased autonomic nervous system stimulation of the pancreatic islets in insulin-resistant subjects.

Dual radiotracer analysis of cholinergic neuronal changes in prediabetic mouse pancreas.

BACKGROUND: Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state. METHODS: Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods. RESULTS: [(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01). CONCLUSIONS: These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.

Effects of cocaine and MDMA self-administration on serotonin transporter availability in monkeys.

Although serotonin (5-HT) can interact with dopamine (DA) systems to modulate the subjective and reinforcing effects of psychostimulants such as cocaine and 3,4-methyldioxymethamphetamine (MDMA, ecstasy), the long-term effects of exposure to psychostimulants on brain 5-HT systems are not well characterized. The present study assessed 5-HT transporter (SERT) availability using positron emission tomography (PET) in rhesus monkeys with the SERT-specific radioligand [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB). SERT availability was assessed in regions of interest including the caudate nucleus, putamen, anterior cingulate cortex, and cerebellum. [(11)C]DASB distribution volume ratios (DVRs) were calculated using the cerebellum as the reference region. DVRs were calculated in control monkeys and in cocaine or MDMA self-administering monkeys approximately 24 h after the last self-administration (SA) session. SERT availability did not differ between monkeys with a history of MDMA SA and control monkeys in any region examined. In contrast, monkeys with a history of cocaine SA showed significantly higher levels of SERT availability in the caudate nucleus and putamen compared to control subjects. These results suggest that chronic SA of cocaine, but not MDMA, leads to alterations in serotonergic function in brain areas relevant to drug abuse. The higher level of SERT availability in cocaine-experienced monkeys may lead to a reduced inhibitory tone of 5-HT on the DA system, which may explain, in part, differences in the abuse liability between cocaine and MDMA.

Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product designs.

OBJECTIVES: To compare the performance and cost-effectiveness of the key absorbent product designs to provide a more solid basis for guiding selection and purchase. Also to carry out the first stage in the development of a quality of life (QoL) instrument for measuring the impact of absorbent product use on users' lives. DESIGN: Three clinical trials focused on the three biggest market sectors. Each trial had a similar crossover design in which each participant tested all products within their group in random order. SETTING, PARTICIPANTS AND INTERVENTIONS: In Trial 1, 85 women with light urinary incontinence living in the community tested three products from each of the four design categories available (total of 12 test products): disposable inserts (pads); menstrual pads; washable pants with integral pad; and washable inserts. In Trial 2a, 85 moderate/heavily incontinent adults (urinary or urinary/faecal) living in the community (49 men and 36 women) tested three (or two) products from each of the five design categories available (total of 14 test products): disposable inserts (with mesh pants); disposable diapers (nappies); disposable pull-ups (similar to toddlers' trainer pants); disposable T-shaped diapers (nappies with waist-band); and washable diapers. All products were provided in a daytime and a (mostly more absorbent) night-time variant. In these first two trials, the test products were selected on the basis of data from pilot studies. In Trial 2b, 100 moderate/heavily incontinent adults (urinary or urinary/faecal) living in 10 nursing homes (27 men and 73 women) evaluated one product from each of the four disposable design categories from Trial 2a. Products were selected on the basis of product performance in Trial 2a and, again, day time and night-time variants were provided. The first phase of developing a QoL tool for measuring the impact of using different pad designs was carried out by interviewing participants from Trials 1 and 2a. MAIN OUTCOME MEASURES: Product performance (e.g. comfort, discreetness) was characterised using a weekly validated questionnaire. A daily pad change and leakage diary was used to record severity of leakage, numbers of laundry items and pads. Skin health changes were recorded weekly. At a final interview preferences were ranked, acceptability of each design recorded, and overall opinion marked on a visual analogue scale (VAS) of 0-100 points. This VAS score was used to estimate cost-effectiveness. In addition, a timed pad changing exercise was conducted with 10 women from Trial 2b to determine any differences between product designs. RESULTS: Disposable inserts are currently the mainstay of management for lightly incontinent women (Trial 1) and they were better for leakage and other variables (but not discreetness) and better overall than the other three designs. However, some women preferred menstrual pads (6/85) or washable pants (13/85), both of which are cheaper to use. Washable inserts were worse both overall and for leakage than the other three designs (72/85 found them unacceptable). For disposable inserts and disposable diapers, findings from the community (Trial 2a) and nursing home trials (Trial 2b) were broadly similar. Leakage performance of disposable inserts was worse than that of the other designs for day and night. Pull-ups were preferred over inserts for the daytime. The new T-shaped diaper was not better overall than the traditional disposable one. However, there were important differences in performance and preference findings for men and women from both trials. Pull-ups (the most expensive) were better overall than the other designs for women during the day and for community-dwelling women during the night. Although disposable diapers were better for leakage than disposable inserts (the cheapest), women did not prefer them (except in nursing homes at night), but for men the diapers were better both overall and for leakage and were the most cost-effective design. No firm conclusions could be drawn about the performance of designs for faecal incontinence. Nursing home carers found pull-ups and inserts easier to apply (in the standing position) and quicker (in the pad change experiment) than the diaper designs; the ability to stand was associated with preference for pull-ups or inserts. The T-shaped diaper was not easier or quicker to change than the diaper. The washable products (Trial 2a) gave diverse results: they were better for leakage at night, but were worse overall for daytime than the other designs. Three-quarters of the women (27/36) found them unacceptable, but nearly two-thirds of men (31/49) found them highly acceptable at night. Findings from the two community trials (Trials 1 and 2a) showed that there were many practical problems in dealing with washable products but, together with the less effective and less expensive products, such as menstrual pads, they were more acceptable at home (and, in the case of washables, at night). This suggests that cost-effective management may involve combining products by using more effective (for a given user) but more expensive designs (e.g. pull-ups) when out and less effective but less expensive designs when at home. The interviews examining the impact of pad use on QoL provided themes and domains that can be further developed into a tool for further evaluation of absorbent products. CONCLUSIONS: This study showed that there were significant and substantial differences between the designs of absorbent products and for moderate/heavy incontinence some designs are better for men/women than others. There was considerable individual variability in preferences and cost-effective management may best be achieved by allowing users to choose combinations of designs for different circumstances within a budget. Further research is needed into the feasibility of providing choice and combinations of designs to users, as well as into the development of more effective washables and of specifically male disposable products. QoL measurement tools are needed for users of absorbent products, as are clinical trials of designs for community-dwelling carer-dependent men and women with moderate/heavy incontinence.