Two mouse models of Alzheimer's disease accumulate amyloid at different rates and have distinct Aß oligomer profiles unaltered by ablation of cellular prion protein.

Oligomers formed from monomers of the amyloid ß-protein (Aß) are thought to be central to the pathogenesis of Alzheimer's disease (AD). Unsurprisingly for a complex disease, current mouse models of AD fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproduced in a different model. Cellular prion protein (PrPC) is now an established receptor for Aß oligomers. However, studies of the Aß-PrPC interaction in different mouse models have yielded contradictory results. Here we performed a longitudinal study assessing a range of biochemical and histological features in the commonly used J20 and APP-PS1 mouse models. Our analysis demonstrated that PrPC ablation had no effect on amyloid accumulation or oligomer production. However, we found that APP-PS1 mice had higher levels of oligomers, that these could bind to recombinant PrPC, and were recognised by the OC antibody which distinguishes parallel, in register fibrils. On the other hand, J20 mice had a lower level of Aß oligomers, which did not interact with PrPC when tested in vitro and were OC-negative. These results suggest the two mouse models produce diverse Aß assemblies that could interact with different targets, highlighting the necessity to characterise the conformation of the Aß oligomers concomitantly with the toxic cascade elicited by them. Our results provide an explanation for the apparent contradictory results found in APP-PS1 mice and the J20 mouse line in regards to Aß toxicity mediated by PrPC.

A Review of the COVID-19 Mental Health Impact in Post-Conflict Settings: Bridging the Mental Health Gap with Case Exemplars from an Implementation Science Lens.

The COVID-19 pandemic has further aggravated the burden of mental health and presents an opportunity for public health research to focus on evidence-based interventions appropriate for populations residing in resource-constrained, post-conflict settings. Post-conflict settings have a higher service gap in mental health and fewer protective factors, such as economic and domestic security. Post-conflict settings are defined as locations where open warfare has ended but resulting challenges have remained for years. A strong emphasis on the engagement of diverse stakeholders is needed to arrive at sustainable and scalable solutions to mental health service delivery. This review discusses mental health service delivery gaps in post-conflict settings, highlights the urgency of the matter in the context of the COVID-19 pandemic, and provides recommendations for service gaps from evidence-based case study exemplars with an implementation science lens using the Consolidated Framework for Implementation Research (CFIR) as guide to improving adaptation and uptake.

Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study.

PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS: SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.

Improving Cohort-Hospital Matching Accuracy through Standardization and Validation of Participant Identifiable Information.

Linking very large, consented birth cohorts to birthing hospitals clinical data could elucidate the lifecourse outcomes of health care and exposures during the pregnancy, birth and newborn periods. Unfortunately, cohort personally identifiable information (PII) often does not include unique identifier numbers, presenting matching challenges. To develop optimized cohort matching to birthing hospital clinical records, this pilot drew on a one-year (December 2020-December 2021) cohort for a single Australian birthing hospital participating in the whole-of-state Generation Victoria (GenV) study. For 1819 consented mother-baby pairs and 58 additional babies (whose mothers were not themselves participating), we tested the accuracy and effort of various approaches to matching. We selected demographic variables drawn from names, DOB, sex, telephone, address (and birth order for multiple births). After variable standardization and validation, accuracy rose from 10% to 99% using a deterministic-rule-based approach in 10 steps. Using cohort-specific modifications of the Australian Statistical Linkage Key (SLK-581), it took only 3 steps to reach 97% (SLK-5881) and 98% (SLK-5881.1) accuracy. We conclude that our SLK-5881 process could safely and efficiently achieve high accuracy at the population level for future birth cohort-birth hospital matching in the absence of unique identifier numbers.

Polarization-based smoke removal method for surgical images.

Smoke generated during surgery affects tissue visibility and degrades image quality, affecting surgical decisions and limiting further image processing and analysis. Polarization is a fundamental property of light and polarization-resolved imaging has been studied and applied to general visibility restoration scenarios such as for smog or mist removal or in underwater environments. However, there is no related research or application for surgical smoke removal. Due to differences between surgical smoke and general haze scenarios, we propose an alternative imaging degradation model by redefining the form of the transmission parameters. The analysis of the propagation of polarized light interacting with the mixed medium of smoke and tissue is proposed to realize polarization-based smoke removal (visibility restoration). Theoretical analysis and observation of experimental data shows that the cross-polarized channel data generated by multiple scattering is less affected by smoke compared to the co-polarized channel. The polarization difference calculation for different color channels can estimate the model transmission parameters and reconstruct the image with restored visibility. Qualitative and quantitative comparison with alternative methods show that the polarization-based image smoke-removal method can effectively reduce the degradation of biomedical images caused by surgical smoke and partially restore the original degree of polarization of the samples.

The Occurrence of Ophidiomyces ophiodiicola in Northern Georgia Wild and Captive Snake Populations.

Ophidiomycosis, or snake fungal disease, is an emerging wildlife disease caused by the Ophidiomyces ophiodiicola fungus. The fungus can result in high mortality rates among infected snakes and has been documented across much of the eastern US, including southern Georgia. However, little is known about ophidiomycosis in northern Georgia. We surveyed wild snake populations in five counties of northern Georgia between March 2019 and March 2020 and swabbed captured snakes (n=27) for the presence of O. ophiodiicola DNA. We followed similar sampling protocols with a group of captive snakes (n=6) at the Elachee Nature Center in Hall County, Georgia. Quantitative PCR confirmed the presence of O. ophiodiicola DNA in 33% (11/33) of snakes. Eight of the confirmed positive samples were collected from wild snakes (30%, 8/27) across our sample region, while three were from our captive group (50%, 3/6). Our results indicated that O. ophiodiicola is present in wild snake populations in northern Georgia, and the pathogen is present in seemingly healthy captive snakes. This knowledge is critical for conservation and management efforts, but more research is needed to fully understand ophidiomycosis and its effect on snake populations in the region.

Cerebral oxygenation is stable in preterm infants transitioning to heated humidified high-flow nasal cannula therapy.

AIM: To assess cerebral oxygenation in premature infants who are transitioning from nasal continuous positive airway pressure (nCPAP) to heated humidified high-flow nasal cannula therapy (HFNC). METHODS: A prospective observational study done in a single-centre neonatal intensive care unit (NICU). Regional cerebral oxygen saturations (RcSO2 ) were measured using frequency-domain near-infrared spectroscopy (FD-NIRS) in very low birthweight (VLBW) premature infants born at <32 weeks transitioning from nCPAP to HFNC. RESULTS: Median gestational age was 27 weeks and median birthweight was 924 g. Recordings were performed at a median gestational age of 30 weeks and a median postnatal age of 10 days. Median weight at study entry was 1111 g. Cerebral oxygenation was not significantly different in infants transitioning from nCPAP to HFNC (66% vs 66%). CONCLUSION: No difference in cerebral oxygenation in premature infants transitioning from nCPAP to HFNC was observed. This finding is reassuring and further supports the use of HFNC in preterm infants.

In vivo label-free mapping of the effect of a photosystem II inhibiting herbicide in plants using chlorophyll fluorescence lifetime.

BACKGROUND: In order to better understand and improve the mode of action of agrochemicals, it is useful to be able to visualize their uptake and distribution in vivo, non-invasively and, ideally, in the field. Here we explore the potential of plant autofluorescence (specifically chlorophyll fluorescence) to provide a readout of herbicide action across the scales utilising multiphoton-excited fluorescence lifetime imaging, wide-field single-photon excited fluorescence lifetime imaging and single point fluorescence lifetime measurements via a fibre-optic probe. RESULTS: Our studies indicate that changes in chlorophyll fluorescence lifetime can be utilised as an indirect readout of a photosystem II inhibiting herbicide activity in living plant leaves at three different scales: cellular (~µm), single point (~1 mm2) and macroscopic (~8 × 6 mm2 of a leaf). Multiphoton excited fluorescence lifetime imaging of Triticum aestivum leaves indicated that there is an increase in the spatially averaged chlorophyll fluorescence lifetime of leaves treated with Flagon EC-a photosystem II inhibiting herbicide. The untreated leaf exhibited an average lifetime of 560 ± 30 ps while the leaf imaged 2 h post treatment exhibited an increased lifetime of 2000 ± 440 ps in different fields of view. The results from in vivo wide-field single-photon excited fluorescence lifetime imaging excited at 440 nm indicated an increase in chlorophyll fluorescence lifetime from 521 ps in an untreated leaf to 1000 ps, just 3 min after treating the same leaf with Flagon EC, and to 2150 ps after 27 min. In vivo single point fluorescence lifetime measurements demonstrated a similar increase in chlorophyll fluorescence lifetime. Untreated leaf presented a fluorescence lifetime of 435 ps in the 440 nm excited chlorophyll channel, CH4 (620-710 nm). In the first 5 min after treatment, mean fluorescence lifetime is observed to have increased to 1 ns and then to 1.3 ns after 60 min. For all these in vivo plant autofluorescence lifetime measurements, the plants were not dark-adapted. CONCLUSIONS: We demonstrate that the local impact of a photosystem II herbicide on living plant leaves can be conveniently mapped in space and time via changes in autofluorescence lifetime, which we attribute to changes in chlorophyll fluorescence. Using portable fibre-optic probe instrumentation originally designed for label-free biomedical applications, this capability could be deployed outside the laboratory for monitoring the distribution of herbicides in growing plants.

Smell and Taste to Improve Nutrition in Very Preterm Infants: A Randomized Controlled Pilot Trial.

BACKGROUND: The perception of smell and taste, though present early in development, is not routinely considered in the care of preterm infants. Smell and taste are known to increase gut motility, insulin secretion, and the release of appetite, digestive and metabolic hormones. OBJECTIVE: We aimed to investigate the effect of regular smell and taste on the time from birth to full enteral feeds, and the feasibility of the study protocol in very preterm infants. METHODS: In a randomized controlled trial, infants <29 weeks' postmenstrual age (PA) were assigned to receive either the smell and taste of milk before each feed or to have no exposure to the smell and taste of milk (control). RESULTS: Infants in the treatment group (n = 28) and control group (n = 23) were born at a mean (SD) PA of 26.7 (1.5) and 27.2 (1.4) weeks, respectively. They reached full enteral feeds at a median (IQR) of 13.5 (10.0-19.0) and 15.5 (11.0-22.0) days, respectively. Survival analysis showed an adjusted hazard ratio of 1.63 (95% confidence interval 0.91-2.91; p = 0.10) for the effect on the time to establish full enteral feeds. Repeated-measures analysis indicated significant group differences in weight z scores at 36 weeks' PA and at discharge in favor of the intervention (p < 0.05). CONCLUSION: These data indicate that the smell and taste of milk may improve milk tolerance and weight in preterm infants. The role of regular smell and taste in promoting enteral nutrition and growth in preterm infants merits a larger trial powered to detect important outcomes.

Amyloid-ß Receptors: The Good, the Bad, and the Prion Protein.

Several different receptor proteins have been identified that bind monomeric, oligomeric, or fibrillar forms of amyloid-ß (Aß). "Good" receptors internalize Aß or promote its transcytosis out of the brain, whereas "bad" receptors bind oligomeric forms of Aß that are largely responsible for the synapticloss, memory impairments, and neurotoxicity that underlie Alzheimer disease. The prion protein both removes Aß from the brain and transduces the toxic actions of Aß. The clustering of distinct receptors in cell surface signaling platforms likely underlies the actions of distinct oligomeric species of Aß. These Aß receptor-signaling platforms provide opportunities for therapeutic intervention in Alzheimer disease.

Changes in medical errors after implementation of a handoff program.

BACKGROUND: Miscommunications are a leading cause of serious medical errors. Data from multicenter studies assessing programs designed to improve handoff of information about patient care are lacking. METHODS: We conducted a prospective intervention study of a resident handoff-improvement program in nine hospitals, measuring rates of medical errors, preventable adverse events, and miscommunications, as well as resident workflow. The intervention included a mnemonic to standardize oral and written handoffs, handoff and communication training, a faculty development and observation program, and a sustainability campaign. Error rates were measured through active surveillance. Handoffs were assessed by means of evaluation of printed handoff documents and audio recordings. Workflow was assessed through time-motion observations. The primary outcome had two components: medical errors and preventable adverse events. RESULTS: In 10,740 patient admissions, the medical-error rate decreased by 23% from the preintervention period to the postintervention period (24.5 vs. 18.8 per 100 admissions, P<0.001), and the rate of preventable adverse events decreased by 30% (4.7 vs. 3.3 events per 100 admissions, P<0.001). The rate of nonpreventable adverse events did not change significantly (3.0 and 2.8 events per 100 admissions, P=0.79). Site-level analyses showed significant error reductions at six of nine sites. Across sites, significant increases were observed in the inclusion of all prespecified key elements in written documents and oral communication during handoff (nine written and five oral elements; P<0.001 for all 14 comparisons). There were no significant changes from the preintervention period to the postintervention period in the duration of oral handoffs (2.4 and 2.5 minutes per patient, respectively; P=0.55) or in resident workflow, including patient-family contact and computer time. CONCLUSIONS: Implementation of the handoff program was associated with reductions in medical errors and in preventable adverse events and with improvements in communication, without a negative effect on workflow. (Funded by the Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services, and others.).

Development, implementation, and dissemination of the I-PASS handoff curriculum: A multisite educational intervention to improve patient handoffs.

Patient handoffs are a key source of communication failures and adverse events in hospitals. Despite Accreditation Council for Graduate Medical Education requirements for residency training programs to provide formal handoff skills training and to monitor handoffs, well-established curricula and validated skills assessment tools are lacking. Developing a handoff curriculum is challenging because of the need for standardized processes and faculty development, cultural resistance to change, and diverse institution- and unit-level factors. In this article, the authors apply a logic model to describe the process they used from June 2010 to February 2014 to develop, implement, and disseminate an innovative, comprehensive handoff curriculum in pediatric residency training programs as a fundamental component of the multicenter Initiative for Innovation in Pediatric Education-Pediatric Research in Inpatient Settings Accelerating Safe Sign-outs (I-PASS) Study. They describe resources, activities, and outputs, and report preliminary learner outcomes using data from resident and faculty evaluations of the I-PASS Handoff Curriculum: 96% of residents and 97% of faculty agreed or strongly agreed that the curriculum promoted acquisition of relevant skills for patient care activities. They also share lessons learned that could be of value to others seeking to adopt a structured handoff curriculum or to develop large-scale curricular innovations that involve redesigning firmly established processes. These lessons include the importance of approaching curricular implementation as a transformational change effort, assembling a diverse team of junior and senior faculty to provide opportunities for mentoring and professional development, and linking the educational intervention with the direct measurement of patient outcomes.

Validity and reliability of portfolio assessment of competency in a baccalaureate dental hygiene program.

This study examined the validity and reliability of portfolio assessment using Messick's unified framework of construct validity. Theoretical and empirical evidence was sought for six aspects of construct validity. Seven faculty raters evaluated twenty student portfolios using a primary trait analysis scoring rubric. A significant relationship (r = .81-.95; p < .01) between the seven subscales in the scoring rubric demonstrates measurement of a common construct. There was a significant relationship between portfolios and GPA (r = .70; p < .01) and the NBDHE (r = .60; p < .01). The relationship between portfolios and the Central Regional Dental Testing Service (CRDTS) examination was both weak and nonsignificant (r = .19; p > .05). A fully crossed, two-facet generalizability (G) study design was used to examine reliability. ANOVA demonstrated that the greatest source of variance was the scoring rubric itself, accounting for 78 percent of the total variance. The smallest source of variance was the interaction between portfolio and rubric (1.15 percent). Faculty rater variance accounted for only 1.28 percent of total variance. A phi coefficient of .86, analogous to a reliability coefficient in classical test theory, was obtained in the decision study by increasing the subscales to fourteen and decreasing faculty raters to three. In conclusion, the pattern of findings from this study suggests that portfolios can serve as a valid and reliable measure for assessing student competency.

Effect of paramedic experience on orotracheal intubation success rates.

This study's objective was to determine the effect of paramedic experience on orotracheal intubation success in prehospital adult nontraumatic cardiac arrest patients. This retrospective study analyzed all attempted intubations of prehospital adult nontraumatic cardiac arrest patients between January 1, 1997 and April 30, 1997 in an urban, all ALS service. Data were abstracted from EMS reports and intubation data forms. Variables included months of experience, number of patients in whom intubation was attempted, number of intubation attempts, success per attempt, and success per patient. Ninety-eight paramedics performed 909 intubations on 1066 cardiac arrest patients, yielding an intubation success rate of 85.3%. The median months of experience was 59.5 (Range 5-223). The median number of patients in whom intubation was attempted per paramedic was 10 (Range 1-36). The mean intubation success rate per paramedic was 80.6% (+/- 22.4, 95% CI 76.1, 85.1). There was significant correlation between total number of patients in whom intubation was attempted and intubation success rate (p <.001, R = 0.32). There was no correlation between months of experience and intubation success rate. In conclusion, the number of patients in whom intubation was attempted per paramedic was significantly correlated with the intubation success rate. Months of experience per paramedic had no significant correlation with intubation success rate.