Researchers could benefit from methodological advancements to advance uptake of new treatments while also reducing healthcare disparities. A comprehensive determinants framework for healthcare ...disparity implementation challenges is essential to accurately understand an implementation problem and select implementation strategies.
We integrated and modified two conceptual frameworks-one from implementation science and one from healthcare disparities research to develop the Health Equity Implementation Framework. We applied the Health Equity Implementation Framework to a historical healthcare disparity challenge-hepatitis C virus (HCV) and its treatment among Black patients seeking care in the US Department of Veterans Affairs (VA). A specific implementation assessment at the patient level was needed to understand any barriers to increasing uptake of HCV treatment, independent of cost. We conducted a preliminary study to assess how feasible it was for researchers to use the Health Equity Implementation Framework. We applied the framework to design the qualitative interview guide and interpret results. Using quantitative data to screen potential participants, this preliminary study consisted of semi-structured interviews with a purposively selected sample of Black, rural-dwelling, older adult VA patients (N = 12), living with HCV, from VA medical clinics in the Southern part of the USA.
The Health Equity Implementation Framework was feasible for implementation researchers. Barriers and facilitators were identified at all levels including the patient, provider (recipients), patient-provider interaction (clinical encounter), characteristics of treatment (innovation), and healthcare system (inner and outer context). Some barriers reflected general implementation issues (e.g., poor care coordination after testing positive for HCV). Other barriers were related to healthcare disparities and likely unique to racial minority patients (e.g., testimonials from Black peers about racial discrimination at VA). We identified several facilitators, including patient enthusiasm to obtain treatment because of its high cure rates, and VA clinics that offset HCV stigma by protecting patient confidentiality.
The Health Equity Implementation Framework showcases one way to modify an implementation framework to better assess health equity determinants as well. Researchers may be able to optimize the scientific yield of research inquiries by identifying and addressing factors that promote or impede implementation of novel treatments in addition to eliminating healthcare disparities.
Resting-state networks in schizophrenia Karbasforoushan, H; Woodward, N D
Current topics in medicinal chemistry,
11/2012, Letnik:
12, Številka:
21
Journal Article
Recenzirano
Schizophrenia has been conceptualized as a disorder of altered brain connectivity (i.e. dysconnectivity). Until relatively recently, it was not feasible to test dysconnectivity hypotheses of ...schizophrenia in vivo. Resting-state functional magnetic resonance imaging (fMRI) is a powerful tool for mapping functional networks of the brain, such as the default mode network (DMN), and investigating the systems-level pathology of neurological and psychiatric disorders. In this article, we review the latest findings from resting-state fMRI studies on schizophrenia. Despite the wide array of methods used and heterogeneity of patient samples, several tentative conclusions may be drawn from the existing literature. 1) Connectivity of the DMN is altered in schizophrenia. Findings vary across studies; however, a majority of investigations reported hyper-connectivity of the DMN. 2) Resting-state connectivity of the prefrontal cortex (PFC) is reduced in schizophrenia, particularly intra-PFC connectivity. 3) Cortical-subcortical networks, including thalamocortical, frontolimbic, and cortico-cerebellar networks are altered in schizophrenia. 4) Preliminary findings indicate that functional connectivity within auditory/language networks and the basal ganglia is related to specific clinical symptoms, including auditory- verbal hallucinations and delusions. 5) Whole-brain network topology measures based on graph theory indicate that functional brain networks in schizophrenia are characterized by reduced small-worldness, lower degree connectivity of brain hubs, and decreased modularity. 6) Some of the alterations in functional connectivity observed in probands are present in unaffected relatives, raising the possibility that functional dysconnectivity is an endophenotype related to genetic risk for schizophrenia. Combined, these findings provide broad support for dysconnectivity theories of schizophrenia. We conclude our review with a discussion of the limitations of the existing literature and potentially important areas of future research.
The synthesis, electrochemical, and photophysical characterization of N,N′-dialkylated and N,N′-dibenzylated dipyridinium thiazolo5,4-dthiazole derivatives are reported. The thiazolothiazole ...viologens exhibit strong blue fluorescence with high quantum yields between 0.8–0.96. The dioctyl, dimethyl, and dibenzyl derivatives also show distinctive and reversible yellow to dark blue electrochromism at low reduction potentials. The fused bicyclic thiazolo5,4-dthiazole heterocycle allows the alkylated pyridinium groups to remain planar, strongly affecting their electrochemical properties. The singlet quantum yield is greatly enhanced with quaternarization of the peripheral 4-pyridyl groups (ΦF increases from 0.22 to 0.96) while long-lived fluorescence lifetimes were observed between 1.8–2.4 ns. The thiazolothiazole viologens have been characterized using cyclic voltammetry, UV–visible absorbance and fluorescence spectroscopy, spectroelectrochemistry, and time-resolved photoluminescence. The electrochromic properties observed in solution, in addition to their strong fluorescent emission properties, which can be suppressed upon 2 e– reduction, make these materials attractive for multifunctional optoelectronic, electron transfer sensing, and other photochemical applications.
Standardized donor‐derived cell‐free DNA (dd‐cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this ...dd‐cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single‐center cohort of 33 patients at high risk for antibody‐mediated rejection (AMR). Plasma dd‐cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd‐cfDNA levels were correlated to paired events of biopsy‐based diagnosis of rejection. The median dd‐cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd‐cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd‐cfDNA levels were elevated 3‐fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd‐cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd‐cfDNA assay.
A large multicenter study in a broad heart transplant surveillance population demonstrates the ability of standardized donor‐ derived cell‐free DNA testing to identify both T cell–mediated and antibody‐mediated acute rejection with a high negative predictive value.
Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a ...noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection ABMR) and controls (no rejection histologically),
<0.001 (receiver operating characteristic area under the curve AUC, 0.74; 95% confidence interval 95% CI, 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (
=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.
Osteohistology, the study of bone microstructure, provides an important avenue for assessing extinct and extant vertebrate growth and life history. Cortical vascularity and collagen fibre ...organization are direct reflections of growth rate, while bone growth marks are indicative of absolute age. However, each skeletal element has its own ontogenetic trajectory and microstructure of certain bones may not be a true representation of whole body growth. Extensive comparative study of modern taxa is required to resolve intraskeletal discrepancies among age, vascularity and tissue organization in extinct vertebrates. Despite their comparative utility, studies of bone microstructure in modern taxa are severely lacking. Here, we add to a growing comparative osteohistological database by describing (1) bone tissue organization, (2) growth mark count, (3) sexually dimorphic bone (e.g. medullary bone) and (4) secondary cortical reconstruction in the bone microstructure of a 14‐year‐old male and 5‐year‐old female North Island Brown Kiwi (Apteryx mantelli). Transverse and longitudinal histological ground sections were processed and described for femora, tibiotarsi, tarsometatarsi, humeri, ulnae and radii in both kiwis. Cortical bone can generally be described as parallel‐fibered tissue, interrupted by cyclical growth marks, with vascular canals oriented longitudinally within primary and secondary osteons. Tissue morphologically resembling medullary bone is present in the hindlimbs of the female, and coarse compacted cancellous bone (CCCB) is found sporadically in the male and female hindlimbs. Lines of arrested growth (LAGs) are present in all hindlimb bones of both kiwi, but remodelling has obliterated all LAGs in the male ulnae and radii. LAG count varies intraskeletally, but large weight bearing elements such as femora and tibiotarsi have less remodelling and, thus, higher number of LAGs. LAG count did not match absolute age in any skeletal element; a maximum of seven LAGs are present in the male kiwi and a maximum of seven LAGs in the female kiwi. The tissue organization within the forelimbs and hindlimbs is reflective of the protracted growth strategy of the North Island Brown Kiwi and congruent with previous studies of the kiwi. LAGs were highly variable throughout the skeleton of the kiwi and a decoupling of age and LAG deposition is apparent from the male kiwi samples. Excess LAGs in the 5‐year‐old female kiwi may be a product of hatching, egg laying or captivity. Regardless, LAG count variation in the kiwi stresses the importance of intraskeletal sampling when assessing growth patterns of extinct taxa. An extensive ontogenetic sampling of kiwi is necessary for future investigations of bone growth patterns, CCCB formation, medullary bone and LAG deposition and obliteration in these elusive birds.
Hindlimb and forelimb bones of two captive raised Apteryx mantelli were histologically sampled to assess intraskeletal variation in tissue organization and growth mark count. Tissue organization agreed with previous findings, but growth mark counts varied between elements and differed from the known ages of the sampled individuals. Growth mark formation in the kiwi is subject to developmental plasticity, which has broad implications on osteohistological interpretations of modern and fossil tetrapods.
ABSTRACT
The whole‐body (tachymetabolic) endothermy seen in modern birds and mammals is long held to have evolved independently in each group, a reasonable assumption when it was believed that its ...earliest appearances in birds and mammals arose many millions of years apart. That assumption is consistent with current acceptance that the non‐shivering thermogenesis (NST) component of regulatory body heat originates differently in each group: from skeletal muscle in birds and from brown adipose tissue (BAT) in mammals. However, BAT is absent in monotremes, marsupials, and many eutherians, all whole‐body endotherms. Indeed, recent research implies that BAT‐driven NST originated more recently and that the biochemical processes driving muscle NST in birds, many modern mammals and the ancestors of both may be similar, deriving from controlled ‘slippage’ of Ca2+ from the sarcoplasmic reticulum Ca2+‐ATPase (SERCA) in skeletal muscle, similar to a process seen in some fishes. This similarity prompted our realisation that the capacity for whole‐body endothermy could even have pre‐dated the divergence of Amniota into Synapsida and Sauropsida, leading us to hypothesise the homology of whole‐body endothermy in birds and mammals, in contrast to the current assumption of their independent (convergent) evolution. To explore the extent of similarity between muscle NST in mammals and birds we undertook a detailed review of these processes and their control in each group. We found considerable but not complete similarity between them: in extant mammals the ‘slippage’ is controlled by the protein sarcolipin (SLN), in birds the SLN is slightly different structurally and its role in NST is not yet proved. However, considering the multi‐millions of years since the separation of synapsids and diapsids, we consider that the similarity between NST production in birds and mammals is consistent with their whole‐body endothermy being homologous. If so, we should expect to find evidence for it much earlier and more widespread among extinct amniotes than is currently recognised. Accordingly, we conducted an extensive survey of the palaeontological literature using established proxies. Fossil bone histology reveals evidence of sustained rapid growth rates indicating tachymetabolism. Large body size and erect stature indicate high systemic arterial blood pressures and four‐chambered hearts, characteristic of tachymetabolism. Large nutrient foramina in long bones are indicative of high bone perfusion for rapid somatic growth and for repair of microfractures caused by intense locomotion. Obligate bipedality appeared early and only in whole‐body endotherms. Isotopic profiles of fossil material indicate endothermic levels of body temperature. These proxies led us to compelling evidence for the widespread occurrence of whole‐body endothermy among numerous extinct synapsids and sauropsids, and very early in each clade's family tree. These results are consistent with and support our hypothesis that tachymetabolic endothermy is plesiomorphic in Amniota. A hypothetical structure for the heart of the earliest endothermic amniotes is proposed. We conclude that there is strong evidence for whole‐body endothermy being ancient and widespread among amniotes and that the similarity of biochemical processes driving muscle NST in extant birds and mammals strengthens the case for its plesiomorphy.
In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio HR 0.542 95% confidence interval (CI) 0.413-0.711; P < 0.0001) and improved patient-reported outcomes ...(PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS).
This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments.
A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan–Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses.
In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.
•In BRCA1/2-mutated advanced breast cancer, talazoparib did not significantly improve overall survival (OS) versus chemotherapy.•OS was generally consistent across subgroups including by prior platinum, hormone-receptor status, or line of treatment.•Most patients received subsequent systemic treatments, which may have confounded the survival outcome.•Toxicities were managed by supportive care medication/dose modifications; safety was consistent with previous observations.•Extended follow-up of patient-reported outcomes continued to favor talazoparib over chemotherapy.
Processing speed predicts functional outcome and is a potential endophenotype for schizophrenia. Establishing the neural basis of processing speed impairment may inform the treatment and etiology of ...schizophrenia. Neuroimaging investigations in healthy subjects have linked processing speed to brain anatomical connectivity. However, the relationship between processing speed impairment and white matter (WM) integrity in schizophrenia is unclear.
Individuals with schizophrenia and healthy subjects underwent diffusion tensor imaging (DTI) and completed a brief neuropsychological assessment that included measures of processing speed, verbal learning, working memory and executive functioning. Group differences in WM integrity, inferred from fractional anisotropy (FA), were examined throughout the brain and the hypothesis that processing speed impairment in schizophrenia is mediated by diminished WM integrity was tested.
WM integrity of the corpus callosum, cingulum, superior and inferior frontal gyri, and precuneus was reduced in schizophrenia. Average FA in these regions mediated group differences in processing speed but not in other cognitive domains. Diminished WM integrity in schizophrenia was accounted for, in large part, by individual differences in processing speed.
Cognitive impairment in schizophrenia was mediated by reduced WM integrity. This relationship was strongest for processing speed because deficits in working memory, verbal learning and executive functioning were not mediated by WM integrity. Larger sample sizes may be required to detect more subtle mediation effects in these domains. Interventions that preserve WM integrity or ameliorate WM disruption may enhance processing speed and functional outcome in schizophrenia.
A recent paradigm shift has led to an explicit focus on enhancing health equity through equity-oriented dissemination and implementation (D&I) research. However, the integration and bidirectional ...learning across these two fields is still in its infancy and siloed. This exploratory study aimed to examine participants' perceived capabilities, opportunities, and motivations to conduct equity-oriented D&I research.
We conducted an exploratory cross-sectional survey distributed online from December 2020 to April 2021. Participants were recruited at either D&I or health disparities-oriented conferences, meetings, through social media, or personal outreach via emails. Informed by the Capability, Opportunity, and Motivation Model (COM-B), the survey queried respondents about different aspects of engaging in and conducting equity-oriented D&I research. All analyses were conducted in SPSS Version 27.0.
A total of 180 participants responded to the survey. Most participants were women (81.7%), white (66.1%), academics (78.9%), and faculty members (53.9%). Many reported they were advanced (36.7%) or advanced beginners (27.8%) in the D&I field, and a substantial proportion (37.8%) reported being novice in D&I research that focused on health equity. Participants reported high motivation (e.g., 62.8% were motivated to apply theories, models, frameworks for promoting health equity in D&I research), but low capability to conduct equity-oriented D&I research (e.g., 5% had the information needed for promoting health equity in D&I research). Most participants (62.2%) reported not having used measures to examine equity in their D&I projects, and for those who did use measures, they mainly used individual-level measures (vs. organizational- or structural-level measures). When asked about factors that could influence their ability to conduct equity-oriented D&I research, 44.4% reported not having the skills necessary, and 32.2% stated difficulties in receiving funding for equity-oriented D&I research.
Study findings provide empirical insight into the perspectives of researchers from different backgrounds on what is needed to conduct equity-oriented D&I research. These data suggest the need for a multi-pronged approach to enhance the capability and opportunities for conducting equity-oriented D&I work, such as: training specifically in equity-oriented D&I, collaboration between D&I researchers with individuals with expertise and lived experience with health equity research, funding for equity-oriented D&I research, and recognition of the value of community engaged research in promotion packages.
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