IMPORTANCE: The present strategy to identify infants needing treatment for retinopathy of prematurity (ROP) requires repeated examinations of at-risk infants by physicians. However, less than 10% ...ultimately require treatment. Retinal imaging by nonphysicians with remote image interpretation by nonphysicians may provide a more efficient strategy. OBJECTIVE: To evaluate the validity of a telemedicine system to identify infants who have sufficiently severe ROP to require evaluation by an ophthalmologist. DESIGN, SETTING, AND PARTICIPANTS: An observational study of premature infants starting at 32 weeks’ postmenstrual age was conducted. This study involved 1257 infants with birth weight less than 1251 g in neonatal intensive care units in 13 North American centers enrolled from May 25, 2011, through October 31, 2013. INTERVENTIONS: Infants underwent regularly scheduled diagnostic examinations by an ophthalmologist and digital imaging by nonphysician staff using a wide-field digital camera. Ophthalmologists documented findings consistent with referral-warranted (RW) ROP (ie, zone I ROP, stage 3 ROP or worse, or plus disease). A standard 6-image set per eye was sent to a central server and graded by 2 trained, masked, nonphysician readers. A reading supervisor adjudicated disagreements. MAIN OUTCOMES AND MEASURES: The validity of grading retinal image sets was based on the sensitivity and specificity for detecting RW-ROP compared with the criterion standard diagnostic examination. RESULTS: A total of 1257 infants (mean birth weight, 864 g; mean gestational age, 27 weeks) underwent a median of 3 sessions of examinations and imaging. Diagnostic examination identified characteristics of RW-ROP in 18.2% of eyes (19.4% of infants). Remote grading of images of an eye at a single session had sensitivity of 81.9% (95% CI, 77.4-85.6) and specificity of 90.1% (95% CI, 87.9-91.8). When both eyes were considered for the presence of RW-ROP, as would routinely be done in a screening, the sensitivity was 90.0% (95% CI, 85.4-93.5), with specificity of 87.0% (95% CI, 84.0-89.5), negative predictive value of 97.3%, and positive predictive value of 62.5% at the observed RW-ROP rate of 19.4%. CONCLUSIONS AND RELEVANCE: When compared with the criterion standard diagnostic examination, these results provide strong support for the validity of remote evaluation by trained nonphysician readers of digital retinal images taken by trained nonphysician imagers from infants at risk for RW-ROP. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01264276
Pathogenic sequence variants (PSV) in
or
(
) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in
were associated with risk of overall prostate cancer or ...high grade (Gleason 8+) prostate cancer using an international sample of 65
and 171
male PSV carriers with prostate cancer, and 3,388
and 2,880
male PSV carriers without prostate cancer. PSVs in the 3' region of
(c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 HR = 1.78; 95% confidence interval (CI), 1.25-2.52;
= 0.001, as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95;
= 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68;
= 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54;
= 0.0002). No genotype-phenotype associations were detected for PSVs in
. These results demonstrate that specific
PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Cancer for adolescents and young adults (AYA) differs from younger and older patients; AYA face medical challenges while navigating social and developmental transitions. Research suggests that these ...patients are under or inadequately served by current support services, which may affect health-related quality of life (HRQOL).
We examined unmet service needs and HRQOL in the National Cancer Institute's Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study, a population-based cohort (n = 484), age 15-39, diagnosed with cancer 6-14 months prior, in 2007-2009. Unmet service needs were psychosocial, physical, spiritual, and financial services where respondents endorsed that they needed, but did not receive, a listed service. Linear regression models tested associations between any or specific unmet service needs and HRQOL, adjusting for demographic, medical, and health insurance variables.
Over one-third of respondents reported at least one unmet service need. The most common were financial (16%), mental health (15%), and support group (14%) services. Adjusted models showed that having any unmet service need was associated with worse overall HRQOL, fatigue, physical, emotional, social, and school/work functioning, and mental health (p's < 0.0001). Specific unmet services were related to particular outcomes e.g., needing pain management was associated with worse overall HRQOL, physical and social functioning (p's < 0.001). Needing mental health services had the strongest associations with worse HRQOL outcomes; needing physical/occupational therapy was most consistently associated with poorer functioning across domains.
Unmet service needs in AYAs recently diagnosed with cancer are associated with worse HRQOL. Research should examine developmentally appropriate, relevant practices to improve access to services demonstrated to adversely impact HRQOL, particularly physical therapy and mental health services.
Background The median survival for patients with newly diagnosed (ND) higher risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) remains poor. The potential curability of ...MDS and CMML with allogeneic hematopoietic stem cell transplantation supports the concept of anti-tumor immunity and has led to interest in evaluating immune-based therapeutic approaches in myeloid neoplasms. The immune checkpoint molecule TIM-3 (encoded by the gene HAVCR2) is a target of interest in myeloid neoplasms given its expression on leukemic stem cells as well as several subsets of immune cells including T cells, monocytes, dendritic cells and NK cells. Sabatolimab (MBG453) is an investigational IgG4 anti-TIM-3 antibody currently under evaluation for myeloid neoplasms. In this exploratory study, we sought to characterize the effects of sabatolimab combined with the hypomethylating agent (HMA), azacitidine, on the immune landscape using single cell sequencing of samples from subjects with MDS and CMML treated with the combination from a previously reported phase 1b study (NCT03066648; Brunner et al 2022). Methods Following IRB approval, single-cell RNA sequencing (scRNA-seq) and associated proteomic cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) was performed on both blood (BLD) and bone-marrow (BM) derived samples from subjects with: 1) MDS (n=3) or CMML (n=2) treated with HMA therapy alone as part of standard care; 2) ND MDS (n=5) or CMML (n=3) treated with azacitidine combined with sabatolimab; and 3) relapsed/refractory MDS (n=3) treated with sabatolimab alone. Paired BLD and BM samples as well as samples from serial treatment time points were selected whenever feasible (Fig 1). A total of 206,183 cells from BM and 172,421 cells from BLD post-quality control filtering were analyzed. Further, scRNAseq data from normal BLD(200,000 cells) and BM(240,650 cells) generated as part of the human cell atlas (https://data.humancellatlas.org/explore/projects/cc95ff89-2e68-4a08-a234-480eca21ce79) were integrated with this dataset to assist with immune cell subset characterization, enable downstream comparisons to healthy hematopoietic cells, and to help define cell subsets associated with disease states. Results In baseline samples from subjects with MDS treated with azacitidine-sabatolimab, we found that an increased baseline abundance of interferon-responsive CD8 T cells in both the BM and BLD (FDR<0.1) was associated with response to therapy. An increased baseline abundance of plasmacytoid dendritic cells and a granulocyte population also suggested an association with response to therapy. Differential gene expression analysis of baseline samples from responding versus non-responding subjects with MDS treated with azacitidine-sabatolimab showed a higher baseline expression of TNF and IFNG in BM CD8 T cells and up-regulated expression of MHC-II machinery ( HLA-DRB1, HLA-DPA1, CD74) in myeloid cell subsets in responding subjects (FDR <0.1), suggesting that pre-treatment ability of these cells to be involved in antigen-presentation may play a role in response. In subjects with CMML treated with azacitidine-sabatolimab, we observed dynamic changes in cellular abundances and gene expression when comparing baseline to post-therapy timepoints. Specifically, BM CD8 T cell subsets showed an up-regulation of cytotoxicity genes ( GZMA), interferon response genes ( IFIT2, IFITM1, IFITM2) and IL32 cytokine post-therapy (FDR <0.1). When evaluating myelomonocytic cell populations, we observed an increase in CD16 monocytes post-treatment. Additionally, dendritic cells and monocytes showed an up-regulation of interferon response genes ( IFIT1, OAS1, IFI27). Conversely, we observed a down-regulation of metallothionein genes ( MT1E, MT1G, MT2A) as well as a collection of transcription factors ( NR4A1, FOSL2, JUN, CEBPB, CEBPD), NF-κB inhibitors ( NFKBIZ, NFKBIA) and CXCL8 in the post-treatment samples (FDR <0.1). Conclusions Our study provides one of the most comprehensive evaluations of the cellular dynamics of anti-TIM3 immunotherapy in patients to date, allowing for the nomination of novel putative predictive biomarkers of response and identification of potential immunomodulatory mechanisms induced by the combination of sabatolimab with azacitidine in MDS and CMML for further future analysis.
Abstract Previous research has suggested that abnormalities within the amygdala and prefrontal cortex (PFC) may underlie major depressive disorder (MDD). The contribution of microstructural ...alterations within these regions in adult MDD is still equivocal. Therefore, seventeen middle-aged medication-free remitted MDD patients and 21 matched never-depressed control subjects underwent structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Despite comparable amygdala volumes, remitted MDD patients revealed decreased mean diffusivity (MD) and increased fractional anisotropy (FA) within the left amygdala, which may be interpreted as greater cell density and increased number of fibers, respectively. This last notion was supported by probabilistic tractography results, which revealed increased connectivity from the left amygdala to the hippocampus, the cerebellum and the brain stem. Further, altered microstructure as indicated by increased MD possibly reflecting decreased cell density within the medial PFC (mPFC) was found. Taken together, the current DTI study shows that abnormal microstructure and connectivity of the amygdala and mPFC might be key factors in the pathophysiology of MDD that may account for functional changes.
The paramagnetic complexes (TmtBu)CoX (X = Cl, Br, I) have been readily prepared and structurally characterized and provide a convenient entry into cobalt(II) tris(mercaptoimidazolyl)borate ...chemistry. A number of derivatives, including mononuclear triphenylphosphine adducts (TmtBu)Co(PPh3)X and dinuclear compounds Co2(TmtBu)2XY, have been prepared in order to ascertain whether cobalt is a reliable surrogate for zinc in biological systems, particularly in sulfur-rich coordination environments. The structure of the first cobaltaboratrane is also reported.
The National Academy of Medicine recently identified improving clinicians' serious illness communication skills as a necessary step in improving patient and family outcomes near the end of life, but ...there is not an accepted set of core communication skills for engaging with surrogate decision makers.
To determine the core serious illness communication skills clinicians should acquire to care for incapacitated, hospitalized patients with acute, life-threatening illness, including patients with Alzheimer's disease and related dementias.
From January 2019 to July 2020, we conducted a modified Delphi study with a panel of 79 experts in the field of serious illness communication. We developed a preliminary list of candidate communication skills through a structured literature review. We presented the candidate skills to the panelists in the context of three prototypical serious illness conversations. Over three rounds, panelists first augmented the list of candidate skills, then voted on the skills. The final set included skills deemed "very important" or "essential" by 70% of panelists. For external validation, we engaged 11 practicing clinicians and 7 community stakeholders for their perspectives on the expert-endorsed list of skills.
The panelists' ratings indicate the importance of a diverse set of communication skills related to providing clear information exchange as well as emotional and psychological support to surrogates. The final set included 33 skills, 12 of which were endorsed for all three prototypical serious illness conversations. Practicing clinicians and community stakeholders supported the expert-endorsed framework with only minor additions.
We generated a stakeholder-endorsed list of skills that can inform the content of communication skills training programs for clinicians who care for incapacitated patients in the inpatient setting. The skills go beyond those required to provide traditional cognitive decision support and suggest the need for a paradigm shift in curricular content for communication training.
Power and Conflict in Adaptive Management Arnold, Jennifer S.; Koro-Ljungberg, Mirka; Bartels, Wendy-Lin
Ecology and society,
01/2012, Letnik:
17, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Adaptive collaborative management emphasizes stakeholder engagement as a crucial component of resilient social-ecological systems. Collaboration among diverse stakeholders is expected to enhance ...learning, build social legitimacy for decision making, and establish relationships that support learning and adaptation in the long term. However, simply bringing together diverse stakeholders does not guarantee productive engagement. Using critical discourse analysis, we examined how diverse stakeholders negotiated knowledge and power in a workshop designed to inform adaptive management of riparian livestock grazing on a National Forest in the southwestern USA. Publicly recognized as a successful component of a larger collaborative effort, we found that the workshop effectively brought together diverse participants, yet still restricted dialogue in important ways. Notably, workshop facilitators took on the additional roles of riparian experts and instructors. As they guided workshop participants toward a consensus view of riparian conditions and management recommendations, they used their status as riparian experts to emphasize commonalities with stakeholders supportive of riparian grazing and accentuate differences with stakeholders skeptical of riparian grazing, including some Forest Service staff with power to influence management decisions. Ultimately, the management plan published one year later did not fully adopt the consensus view from the workshop, but rather included and acknowledged a broader diversity of stakeholder perspectives. Our findings suggest that leaders and facilitators of adaptive collaborative management can more effectively manage for productive stakeholder engagement and, thus, social-ecological resilience if they are more tentative in their convictions, more critical of the role of expert knowledge, and more attentive to the knowledge, interests, and power of diverse stakeholders.
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