Disseminated Blastomycosis in an Immunocompetent Patient.

Blastomycoses dermatitidis is a dimorphic fungus that can cause disseminated blastomycosis with varying clinical manifestations and multiorgan involvement. While blastomycosis commonly causes pulmonary disease, extrapulmonary spread can result in skin, bone, and central nervous system involvement. Cutaneous blastomycosis can present as pustular lesions that evolve into ulcerative or verrucous plaques. We present a case of disseminated blastomycosis in an immunocompetent patient with both pulmonary and cutaneous features. The patient developed hypoxic respiratory failure and was subsequently diagnosed with disseminated blastomycosis after undergoing bronchoscopy with bronchial washing. He was found to have ulcerative nasal lesions as part of his disseminated disease. He was successfully treated with amphotericin B and ultimately discharged from the hospital.

Equivalent-accuracy accelerated neural-network training using analogue memory.

Neural-network training can be slow and energy intensive, owing to the need to transfer the weight data for the network between conventional digital memory chips and processor chips. Analogue non-volatile memory can accelerate the neural-network training algorithm known as backpropagation by performing parallelized multiply-accumulate operations in the analogue domain at the location of the weight data. However, the classification accuracies of such in situ training using non-volatile-memory hardware have generally been less than those of software-based training, owing to insufficient dynamic range and excessive weight-update asymmetry. Here we demonstrate mixed hardware-software neural-network implementations that involve up to 204,900 synapses and that combine long-term storage in phase-change memory, near-linear updates of volatile capacitors and weight-data transfer with 'polarity inversion' to cancel out inherent device-to-device variations. We achieve generalization accuracies (on previously unseen data) equivalent to those of software-based training on various commonly used machine-learning test datasets (MNIST, MNIST-backrand, CIFAR-10 and CIFAR-100). The computational energy efficiency of 28,065 billion operations per second per watt and throughput per area of 3.6 trillion operations per second per square millimetre that we calculate for our implementation exceed those of today's graphical processing units by two orders of magnitude. This work provides a path towards hardware accelerators that are both fast and energy efficient, particularly on fully connected neural-network layers.

Health literacy and older adults: Findings from a national population-based survey.

ISSUE ADDRESSED: With an ageing population and growing complexity and fragmentation of health care systems, health literacy is increasingly important in managing health. This study investigated health literacy strengths and challenges reported by older Australians (people aged 65 or over) and identified how socio-demographic and health factors related to their health literacy profiles. METHODS: The sample comprised 1578 individuals responding to the Australian Government's 2018 Health Literacy Survey, conducted between January and August. Regression modelling was used to estimate the association between each of nine domains of the Health Literacy Questionnaire (HLQ) and individual socio-demographic and health characteristics. The model allowed for correlation between HLQ scores that was linked to unobserved characteristics of individuals. RESULTS: Across the health literacy domains, few individuals received mean scores in the lowest score range. Key individual characteristics associated with higher health literacy were increasing age, English proficiency, higher education levels, better self-assessed health and having certain chronic conditions (cancer, hypertension and arthritis). CONCLUSIONS: Our findings suggest that, among those aged 65 or over, being older or living with chronic illnesses were associated with greater confidence in engaging with providers, accessing information and navigating health services compared to individuals aged 65-69 and those older individuals without chronic illness. Lower health literacy was associated with psychological distress and low English proficiency. SO WHAT?: Interventions to improve individual health literacy and organisation health literacy responsiveness to minimise complexity of the Australian health system are required. This may enhance uptake and use of health information and services for the underserviced members of the community.

Validity Evidence of the eHealth Literacy Questionnaire (eHLQ) Part 2: Mixed Methods Approach to Evaluate Test Content, Response Process, and Internal Structure in the Australian Community Health Setting.

BACKGROUND: Digital technologies have changed how we manage our health, and eHealth literacy is needed to engage with health technologies. Any eHealth strategy would be ineffective if users' eHealth literacy needs are not addressed. A robust measure of eHealth literacy is essential for understanding these needs. On the basis of the eHealth Literacy Framework, which identified 7 dimensions of eHealth literacy, the eHealth Literacy Questionnaire (eHLQ) was developed. The tool has demonstrated robust psychometric properties in the Danish setting, but validity testing should be an ongoing and accumulative process. OBJECTIVE: This study aims to evaluate validity evidence based on test content, response process, and internal structure of the eHLQ in the Australian community health setting. METHODS: A mixed methods approach was used with cognitive interviewing conducted to examine evidence on test content and response process, whereas a cross-sectional survey was undertaken for evidence on internal structure. Data were collected at 3 diverse community health sites in Victoria, Australia. Psychometric testing included both the classical test theory and item response theory approaches. Methods included Bayesian structural equation modeling for confirmatory factor analysis, internal consistency and test-retest for reliability, and the Bayesian multiple-indicators, multiple-causes model for testing of differential item functioning. RESULTS: Cognitive interviewing identified only 1 confusing term, which was clarified. All items were easy to read and understood as intended. A total of 525 questionnaires were included for psychometric analysis. All scales were homogenous with composite scale reliability ranging from 0.73 to 0.90. The intraclass correlation coefficient for test-retest reliability for the 7 scales ranged from 0.72 to 0.95. A 7-factor Bayesian structural equation modeling using small variance priors for cross-loadings and residual covariances was fitted to the data, and the model of interest produced a satisfactory fit (posterior productive P=.49, 95% CI for the difference between observed and replicated chi-square values -101.40 to 108.83, prior-posterior productive P=.92). All items loaded on the relevant factor, with loadings ranging from 0.36 to 0.94. No significant cross-loading was found. There was no evidence of differential item functioning for administration format, site area, and health setting. However, discriminant validity was not well established for scales 1, 3, 5, 6, and 7. Item response theory analysis found that all items provided precise information at different trait levels, except for 1 item. All items demonstrated different sensitivity to different trait levels and represented a range of difficulty levels. CONCLUSIONS: The evidence suggests that the eHLQ is a tool with robust psychometric properties and further investigation of discriminant validity is recommended. It is ready to be used to identify eHealth literacy strengths and challenges and assist the development of digital health interventions to ensure that people with limited digital access and skills are not left behind.

Validity Testing and Cultural Adaptation of the eHealth Literacy Questionnaire (eHLQ) Among People With Chronic Diseases in Taiwan: Mixed Methods Study.

BACKGROUND: Advancements in digital technologies seek to promote health and access to services. However, people lacking abilities and confidence to use technology are likely to be left behind, leading to health disparities. In providing digital health services, health care providers need to be aware of users' diverse electronic health (eHealth) literacy to address their particular needs and ensure equitable uptake and use of digital services. To understand such needs, an instrument that captures users' knowledge, skills, trust, motivation, and experiences in relation to technology is required. The eHealth Literacy Questionnaire (eHLQ) is a multidimensional tool with 7 scales covering diverse dimensions of eHealth literacy. The tool was simultaneously developed in English and Danish using a grounded and validity-driven approach and has been shown to have strong psychometric properties. OBJECTIVE: This study aims to translate and culturally adapt the eHLQ for application among Mandarin-speaking people with chronic diseases in Taiwan and then undertake a rigorous set of validity-testing procedures. METHODS: The cross-cultural adaptation of the eHLQ included translation and evaluation of the translations. The measurement properties were assessed using classical test theory and item response theory (IRT) approaches. Content validity, known-group validity, and internal consistency were explored, as well as item characteristic curves (ICCs), item discrimination, and item location/difficulty. RESULTS: The adapted version was reviewed, and a recommended forward translation was confirmed through consensus. The tool exhibited good content validity. A total of 420 people with 1 or more chronic diseases participated in a validity-testing survey. The eHLQ showed good internal consistency (Cronbach α=.75-.95). For known-group validity, all 7 eHLQ scales showed strong associations with education. Unidimensionality and local independence assumptions were met except for scale 2. IRT analysis showed that all items demonstrated good discrimination (range 0.27-12.15) and a good range of difficulty (range 0.59-1.67) except for 2 items in scale 7. CONCLUSIONS: Using a rigorous process, the eHLQ was translated from English into a culturally appropriate tool for use in the Mandarin language. Validity testing provided evidence of satisfactory-to-strong psychometric properties of the eHLQ. The 7 scales are likely to be useful research tools for evaluating digital health interventions and for informing the development of health technology products and interventions that equitably suit diverse users' needs.

Digital Health Literacy as a Predictor of Awareness, Engagement, and Use of a National Web-Based Personal Health Record: Population-Based Survey Study.

BACKGROUND: Web-based personal health records (PHRs) have the potential to improve the quality, accuracy, and timeliness of health care. However, the international uptake of web-based PHRs has been slow. Populations experiencing disadvantages are less likely to use web-based PHRs, potentially widening health inequities within and among countries. OBJECTIVE: With limited understanding of the predictors of community uptake and use of web-based PHR, the aim of this study was to identify the predictors of awareness, engagement, and use of the Australian national web-based PHR, My Health Record (MyHR). METHODS: A population-based survey of adult participants residing in regional Victoria, Australia, was conducted in 2018 using telephone interviews. Logistic regression, adjusted for age, was used to assess the relationship among digital health literacy, health literacy, and demographic characteristics, and the 3 dependent variables of MyHR: awareness, engagement, and use. Digital health literacy and health literacy were measured using multidimensional tools, using all 7 scales of the eHealth Literacy Questionnaire and 4 out of the 9 scales of the Health Literacy Questionnaire. RESULTS: A total of 998 responses were analyzed. Many elements of digital health literacy were strongly associated with MyHR awareness, engagement, and use. A 1-unit increase in each of the 7 eHealth Literacy Questionnaire scales was associated with a 2- to 4-fold increase in the odds of using MyHR: using technology to process health information (odds ratio [OR] 4.14, 95% CI 2.34-7.31), understanding of health concepts and language (OR 2.25, 95% CI 1.08-4.69), ability to actively engage with digital services (OR 4.44, 95% CI 2.55-7.75), feel safe and in control (OR 2.36, 95% CI 1.43-3.88), motivated to engage with digital services (OR 4.24, 95% CI 2.36-7.61), access to digital services that work (OR 2.49, 95% CI 1.32-4.69), and digital services that suit individual needs (OR 3.48, 95% CI 1.97-6.15). The Health Literacy Questionnaire scales of health care support, actively managing health, and social support were also associated with a 1- to 2-fold increase in the odds of using MyHR. Using the internet to search for health information was another strong predictor; however, older people and those with less education were less likely to use MyHR. CONCLUSIONS: This study revealed strong and consistent patterns of association between digital health literacy and the use of a web-based PHR. The results indicate potential actions for promoting PHR uptake, including improving digital technology and skill experiences that may improve digital health literacy and willingness to engage in web-based PHR. Uptake may also be improved through more responsive digital services, strengthened health care, and better social support. A holistic approach, including targeted solutions, is needed to ensure that web-based PHR can realize its full potential to help reduce health inequities.

Validity Evidence Based on Relations to Other Variables of the eHealth Literacy Questionnaire (eHLQ): Bayesian Approach to Test for Known-Groups Validity.

BACKGROUND: As health resources and services are increasingly delivered through digital platforms, eHealth literacy is becoming a set of essential capabilities to improve consumer health in the digital era. To understand eHealth literacy needs, a meaningful measure is required. Strong initial evidence for the reliability and construct validity of inferences drawn from the eHealth Literacy Questionnaire (eHLQ) was obtained during its development in Denmark, but validity testing for varying purposes is an ongoing and cumulative process. OBJECTIVE: This study aims to examine validity evidence based on relations to other variables-using data collected with the known-groups approach-to further explore if the eHLQ is a robust tool to understand eHealth literacy needs in different contexts. A priori hypotheses are set for the expected score differences among age, sex, education, and information and communication technology (ICT) use for each of the 7 eHealth literacy constructs represented by the 7 eHLQ scales. METHODS: A Bayesian mediated multiple indicators multiple causes model approach was used to simultaneously identify group differences and test measurement invariance through differential item functioning across the groups, with ICT use as a mediator. A sample size of 500 participants was estimated. Data were collected at 3 diverse health sites in Australia. RESULTS: Responses from 525 participants were included for analysis. Being older was significantly related to lower scores in 4 eHLQ scales, with 3. Ability to actively engage with digital services having the strongest effect (total effect -0.37; P<.001), followed by 1. Using technology to process health information (total effect -0.32; P<.001), 5. Motivated to engage with digital services (total effect -0.21; P=.01), and 7. Digital services that suit individual needs (total effect -0.21; P=.02). However, the effects were only partially mediated by ICT use. Higher education was associated with higher scores in 1. Using technology to process health information (total effect 0.22; P=.01) and 3. Ability to actively engage with digital services (total effect 0.25; P<.001), with the effects mostly mediated by ICT use. Higher ICT use was related to higher scores in all scales except 2. Understanding health concepts and language and 4. Feel safe and in control. Either no or ignorable cases of differential item functioning were found across the 4 groups. CONCLUSIONS: By using a Bayesian mediated multiple indicators multiple causes model, this study provides supportive validity evidence for the eHLQ based on relations to other variables as well as established evidence regarding internal structure related to measurement invariance across the groups for the 7 scales in the Australian community health context. This study also demonstrates that the eHLQ can be used to gain valuable insights into people's eHealth literacy needs to help optimize access and use of digital health and promote health equity.

Translation method is validity evidence for construct equivalence: analysis of secondary data routinely collected during translations of the Health Literacy Questionnaire (HLQ).

BACKGROUND: Cross-cultural research with patient-reported outcomes measures (PROMs) assumes that the PROM in the target language will measure the same construct in the same way as the PROM in the source language. Yet translation methods are rarely used to qualitatively maximise construct equivalence or to describe the intents of each item to support common understanding within translation teams. This study aimed to systematically investigate the utility of the Translation Integrity Procedure (TIP), in particular the use of item intent descriptions, to maximise construct equivalence during the translation process, and to demonstrate how documented data from the TIP contributes evidence to a validity argument for construct equivalence between translated and source language PROMs. METHODS: Analysis of secondary data was conducted on routinely collected data in TIP Management Grids of translations (n = 9) of the Health Literacy Questionnaire (HLQ) that took place between August 2014 and August 2015: Arabic, Czech, French (Canada), French (France), Hindi, Indonesian, Slovak, Somali and Spanish (Argentina). Two researchers initially independently deductively coded the data to nine common types of translation errors. Round two of coding included an identified 10th code. Coded data were compared for discrepancies, and checked when needed with a third researcher for final code allocation. RESULTS: Across the nine translations, 259 changes were made to provisional forward translations and were coded into 10 types of errors. Most frequently coded errors were Complex word or phrase (n = 99), Semantic (n = 54) and Grammar (n = 27). Errors coded least frequently were Cultural errors (n = 7) and Printed errors (n = 5). CONCLUSIONS: To advance PROM validation practice, this study investigated a documented translation method that includes the careful specification of descriptions of item intents. Assumptions that translated PROMs have construct equivalence between linguistic contexts can be incorrect due to errors in translation. Of particular concern was the use of high level complex words by translators, which, if undetected, could cause flawed interpretation of data from people with low literacy. Item intent descriptions can support translations to maximise construct equivalence, and documented translation data can contribute evidence to justify score interpretation and use of translated PROMS in new linguistic contexts.

Applying the Electronic Health Literacy Lens: Systematic Review of Electronic Health Interventions Targeted at Socially Disadvantaged Groups.

BACKGROUND: Electronic health (eHealth) has the potential to improve health outcomes. However, eHealth systems need to match the eHealth literacy needs of users to be equitably adopted. Socially disadvantaged groups have lower access and skills to use technologies and are at risk of being digitally marginalized, leading to the potential widening of health disparities. OBJECTIVE: This systematic review aims to explore the role of eHealth literacy and user involvement in developing eHealth interventions targeted at socially disadvantaged groups. METHODS: A systematic search was conducted across 10 databases for eHealth interventions targeted at older adults, ethnic minority groups, low-income groups, low-literacy groups, and rural communities. The eHealth Literacy Framework was used to examine the eHealth literacy components of reviewed interventions. The results were analyzed using narrative synthesis. RESULTS: A total of 51 studies reporting on the results of 48 interventions were evaluated. Most studies were targeted at older adults and ethnic minorities, with only 2 studies focusing on low-literacy groups. eHealth literacy was not considered in the development of any of the studies, and no eHealth literacy assessment was conducted. User involvement in designing interventions was limited, and eHealth intervention developmental frameworks were rarely used. Strategies to assist users in engaging with technical systems were seldom included in the interventions, and accessibility features were limited. The results of the included studies also provided inconclusive evidence on the effectiveness of eHealth interventions. CONCLUSIONS: The findings highlight that eHealth literacy is generally overlooked in developing eHealth interventions targeted at socially disadvantaged groups, whereas evidence about the effectiveness of such interventions is limited. To ensure equal access and inclusiveness in the age of eHealth, eHealth literacy of disadvantaged groups needs to be addressed to help avoid a digital divide. This will assist the realization of recent technological advancements and, importantly, improve health equity.

The tbx2a/b transcription factors direct pronephros segmentation and corpuscle of Stannius formation in zebrafish.

The simplified and genetically conserved zebrafish pronephros is an excellent model to examine the cryptic processes of cell fate decisions during the development of nephron segments as well as the origins of associated endocrine cells that comprise the corpuscles of Stannius (CS). Using whole mount in situ hybridization, we found that transcripts of the zebrafish genes t-box 2a (tbx2a) and t-box 2b (tbx2b), which belong to the T-box family of transcription factors, were expressed in the caudal intermediate mesoderm progenitors that give rise to the distal pronephros and CS. Deficiency of tbx2a, tbx2b or both tbx2a/b reduced the size of the distal late (DL) segment, which was accompanied by a proximal convoluted segment (PCT) expansion. Further, tbx2a/b deficiency led to significantly larger CS clusters. These phenotypes were also observed in embryos with the from beyond (fby)c144 mutation, which encodes a premature stop codon in the tbx2b T-box sequence. Conversely, overexpression of tbx2a and tbx2b in wild-type embryos expanded the DL segment where cells were comingled with the adjacent DE, and also decreased CS cell number, but notably did not alter PCT development-providing independent evidence that tbx2a and tbx2b are each necessary and sufficient to promote DL fate and suppress CS genesis. Epistasis studies indicated that tbx2a acts upstream of tbx2b to regulate the DL and CS fates, and likely has other targets as well. Retinoic acid (RA) addition and inhibition studies revealed that tbx2a and tbx2b are negatively regulated by RA signaling. Interestingly, the CS cell expansion that typifies tbx2a/b deficiency also occurred when blocking Notch signaling with the chemical DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester). Ectopic activation of Notch in Tg(hsp70::Gal4; UAS::NICD)(NICD) embryos led to a reduced CS post heat-shock induction. To further examine the link between the tbx2a/b genes and Notch during CS formation, DAPT treatment was used to block Notch activity in tbx2a/b deficient embryos, and tbx2a/b knockdown was performed in NICD transgenic embryos. Both manipulations caused similar CS expansions, indicating that Notch functions upstream of the tbx2a/b genes to suppress CS ontogeny. Taken together, these data reveal for the first time that tbx2a/b mitigate pronephros segmentation downstream of RA, and that interplay between Notch signaling and tbx2a/b regulate CS formation, thus providing several novel insights into the genetic regulatory networks that influence these lineages.

Pathological and Microbiological Study of Mortality in a Captive Breeding Colony of the Endangered Lord Howe Island Stick Insect ( Dryococelus australis).

The authors describe pathological and microbiological features of mortalities in a captive breeding colony of Lord Howe Island stick insects ( Dryococelus australis) over a period of 18 months. There were 2 peaks of mortality in this period. In the first, insects presented dead with minimal premonitory signs of illness. In the second, affected insects were ataxic with contracted limbs and inability to climb or right themselves. Gross lesions were uncommon but included pigmented plaques on the gut and cloacal prolapse. Histological lesions in both outbreaks indicated a cellular innate immune response including nodulation characterized by Gram-negative bacterial bacilli entrapped within nodules of pigmented hemocytes, and melanization characterized by melanin within hemocyte nodules and around bacteria. Hemolymph culture findings varied and often yielded a mixed growth. Pure growth of Serratia marcescens was cultured in 44% of animals in Outbreak 1, while pure growth of Pseudomonas aeruginosa was cultured in 30% of animals in Outbreak 2. Cases with S. marcescens-positive culture often showed inflammation at the foregut-midgut junction. The frequency of mixed bacterial culture results did not allow firm conclusions about causality to be made, and may indicate primary bacterial infection or increased susceptibility to hemolymph colonization with an opportunistic pathogen. These findings highlight the utility of histopathology combined with ancillary testing when investigating mortality in captive insect colonies.

Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux.

Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett's metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT-immortalized NES cell line NES-B10T was exposed 5 min/day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells.NEW & NOTEWORTHY This study provides evidence of the origins of Barrett's metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett's metaplasia and esophageal adenocarcinoma.

How well are health information websites displayed on mobile phones? Implications for the readability of health information.

Issue addressed More than 87% of Australians own a mobile phone with Internet access and 82% of phone owners use their smartphones to search for health information, indicating that mobile phones may be a powerful tool for building health literacy. Yet, online health information has been found to be above the reading ability of the general population. As reading on a smaller screen may further complicate the readability of information, this study aimed to examine how health information is displayed on mobile phones and its implications for readability. Methods Using a cross-sectional design with convenience sampling, a sample of 270 mobile webpages with information on 12 common health conditions was generated for analysis, they were categorised based on design and position of information display. Results The results showed that 71.48% of webpages were mobile-friendly but only 15.93% were mobile-friendly webpages designed in a way to optimise readability, with a paging format and queried information displayed for immediate viewing. Conclusion With inadequate evidence and lack of consensus on how webpage design can best promote reading and comprehension, it is difficult to draw a conclusion on the effect of current mobile health information presentation on readability. So what? Building mobile-responsive websites should be a priority for health information providers and policy-makers. Research efforts are urgently required to identify how best to enhance readability of mobile health information and fully capture the capabilities of mobile phones as a useful device to increase health literacy.

Nephron proximal tubule patterning and corpuscles of Stannius formation are regulated by the sim1a transcription factor and retinoic acid in zebrafish.

The mechanisms that establish nephron segments are poorly understood. The zebrafish embryonic kidney, or pronephros, is a simplified yet conserved genetic model to study this renal development process because its nephrons contain segments akin to other vertebrates, including the proximal convoluted and straight tubules (PCT, PST). The zebrafish pronephros is also associated with the corpuscles of Stannius (CS), endocrine glands that regulate calcium and phosphate homeostasis, but whose ontogeny from renal progenitors is largely mysterious. Initial patterning of zebrafish renal progenitors in the intermediate mesoderm (IM) involves the formation of rostral and caudal domains, the former being reliant on retinoic acid (RA) signaling, and the latter being repressed by elevated RA levels. Here, using expression profiling to gain new insights into nephrogenesis, we discovered that the gene single minded family bHLH transcription factor 1a (sim1a) is dynamically expressed in the renal progenitors-first marking the caudal domain, then becoming restricted to the proximal segments, and finally exhibiting specific CS expression. In loss of function studies, sim1a knockdown expanded the PCT and abrogated both the PST and CS populations. Conversely, overexpression of sim1a modestly expanded the PST and CS, while it reduced the PCT. These results show that sim1a activity is necessary and partially sufficient to induce PST and CS fates, and suggest that sim1a may inhibit PCT fate and/or negotiate the PCT/PST boundary. Interestingly, the sim1a expression domain in renal progenitors is responsive to altered levels of RA, suggesting that RA regulates sim1a, directly or indirectly, during nephrogenesis. sim1a deficient embryos treated with exogenous RA formed nephrons that were predominantly composed of PCT segments, but lacked the enlarged PST observed in RA treated wild-types, indicating that RA is not sufficient to rescue the PST in the absence of sim1a expression. Alternately, when sim1a knockdowns were exposed to the RA inhibitor diethylaminobenzaldehyde (DEAB), the CS was abrogated rather than expanded as seen in DEAB treated wild-types, revealing that CS formation in the absence of sim1a cannot be rescued by RA biosynthesis abrogation. Taken together, these data reveal previously unappreciated roles for sim1a in zebrafish pronephric proximal tubule and CS patterning, and are consistent with the model that sim1a acts downstream of RA to mitigate the formation of these lineages. These findings provide new insights into the genetic pathways that direct nephron development, and may have implications for understanding renal birth defects and kidney reprogramming.

Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling.

The zebrafish pronephros provides a conserved model to study kidney development, in particular to delineate the poorly understood processes of how nephron segment pattern and cell type choice are established. Zebrafish nephrons are divided into distinct epithelial regions that include a series of proximal and distal tubule segments, which are comprised of intercalated transporting epithelial cells and multiciliated cells (MCC). Previous studies have shown that retinoic acid (RA) regionalizes the renal progenitor field into proximal and distal domains and that Notch signaling later represses MCC differentiation, but further understanding of these pathways has remained unknown. The transcription factor mecom (mds1/evi1 complex) is broadly expressed in renal progenitors, and then subsequently marks the distal tubule. Here, we show that mecom is necessary to form the distal tubule and to restrict both proximal tubule formation and MCC fate choice. We found that mecom and RA have opposing roles in patterning discrete proximal and distal segments. Further, we discovered that RA is required for MCC formation, and that one mechanism by which RA promotes MCC fate choice is to inhibit mecom. Next, we determined the epistatic relationship between mecom and Notch signaling, which limits MCC fate choice by lateral inhibition. Abrogation of Notch signaling with the γ-secretase inhibitor DAPT revealed that Notch and mecom did not have additive effects in blocking MCC formation, suggesting that they function in the same pathway. Ectopic expression of the Notch signaling effector, Notch intracellular domain (NICD), rescued the expansion of MCCs in mecom morphants, indicating that mecom acts upstream to induce Notch signaling. These findings suggest a model in which mecom and RA arbitrate proximodistal segment domains, while MCC fate is modulated by a complex interplay in which RA inhibition of mecom, and mecom promotion of Notch, titrates MCC number. Taken together, our studies have revealed several essential and novel mechanisms that control pronephros development in the zebrafish.

Factors Predisposing Patients to Nonhome Discharge After Surgery for Degenerative Cervical Myelopathy: A Retrospective Analysis.

OBJECTIVE: The objective of this study is to evaluate factors associated with discharge to subacute care after surgery for degenerative cervical myelopathy. DESIGN: This is a retrospective chart review of adults who underwent cervical spine surgery for degenerative cervical myelopathy between 2014 and 2020 ( N = 135). RESULTS: Patients discharged to a subacute setting were older (68.1 ± 8.6 vs. 64.1 yrs ± 8.8, P = 0.01), more likely to be unmarried (55.8% vs. 33.7% married, P = 0.01), and more likely to have Medicare or Medicaid (83.7% vs. 65.9% private insurance, P = 0.03) than patients discharged home. A posterior surgical approach was associated with discharge to a subacute setting (62.8% vs. 43.5% anterior approach, P = 0.04). A total of 87.8% of patients discharged to a subacute setting required moderate or maximum assistance for bed mobility versus 26.6% of patients discharged home ( P < 0.0001). Compared with patients discharged home, patients discharged to a subacute setting ambulated a shorter distance in their first physical therapy evaluation after surgery (8.9 ± 35.8 vs. 53.7 ± 61.78 m in the home discharge group, P < 0.0001). CONCLUSIONS: Analysis of these factors may guide discussions about patient expectations for postoperative discharge placement.

Long-term survivability of surgical and nonsurgical management of spinal epidural abscess.

BACKGROUND CONTEXT: Spinal epidural abscess (SEA) is a rare and life-threatening infection within the epidural space with significant functional impairment and morbidity. Active debate remains over whether to operate for SEAs, with limited existing data comparing the long-term survivability after surgical versus nonsurgical management. PURPOSE: This study aims to determine the long-term survival of patients who underwent surgical and nonsurgical management for SEA. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: A total of 250 consecutive SEA patients. OUTCOME MEASURES: Survival and mortality rates, complications. METHODS: All patients treated at a tertiary medical center for a primary SEA from January 2000 to June 2020 are identified. Data collection is by retrospective chart review. Cox proportional hazards regression models are used for all survival analyses while controlling for potential confounding variables and with multiple testing corrections. RESULTS: A total of 35 out of 250 patients died with an overall all-cause mortality of 14%. More than half of all deaths occurred within 90 days after treatment. The 90-day, 3-year, and 5-year survival rates are 92.8%, 89.2%, and 86.4%, respectively. Among surgery patients, the all-cause mortality was 13.07%, compared to 16.22% for medically-managed patients. Surgical treatment (decompression, fusion, debridement) significantly reduced the risk of death by 62.4% compared to medical therapy (p=.03), but surgery patients experienced a significantly longer mean length of stay (p=.01). Risk factors of short-term mortality included hypoalbuminemia (<3.5 g/dL), American Society of Anesthesiologists (ASA) 4+, and cardiac arrest. Risk factors of long-term mortality were immunocompromised state, elevated WBC count >12,000, sepsis, septic shock, ASA 4+, and cardiac arrest (p<.05). In terms of complications, surgically-managed patients experienced a higher proportion of deep vein thrombosis (p<.05). CONCLUSIONS: The overall long-term survivability of SEA treatment is relatively high at (86% at 5-year) in this study. The following SEA mortality risk factors were identified: hypoalbuminemia (short-term), immunocompromised state (long-term), leukocytosis (long-term), sepsis and septic shock (long-term), ASA 4+ and cardiac arrest (overall). For primary SEA patients, surgical management may reduce mortality risk compared to nonsurgical management.

Effects of High Frequency Chest Wall Oscillation (HFCWO) on Clinical Symptoms in COPD.

Background: Mucociliary clearance plays a critical role in pulmonary host defense. Abnormal mucociliary clearance contributes to the pathogenesis of pulmonary disorders, including COPD. In bronchiectasis, treatments targeting mucus obstruction in the airways include the use of high frequency chest wall oscillation (HFCWO) therapy. This prospective outcome based study was designed to investigate the changes in symptoms and quality of life (QOL) to measure the effect of adjunctive HFCWO therapy to standard of care therapy for patients with COPD. Research Question: When HFCWO is indicated and used as intended, will the quality of life for those patients with COPD improve and sustain improvement. Study Design and Methods: We conducted a prospective, openl-label, observational study in COPD patients without concomitant bronchiectasis. Participants had assessments of QOL at baseline (day 0) and then at 30 and 90 days after initiation of HFCWO therapy. The St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) was employed and longitudinally followed at each timepoint. Paired t-tests were used to compare means between each time points adjusted for multiple comparisons. A linear mixed model for the analysis of longitudinal data was then constructed to determine the simultaneous contribution of race, gender, ethnicity, time, and selected interactions in the primary outcome of change in SGRQ-C across 0, 30, and 90 days. Results: The cohort of patients (n=102) demonstrated a significant reduction in the SGRQ-C at 30 and sustained at 90 days compared to baseline. In addition, two component scores of the SGRQ-C questionnaire ("Symptoms" and Impacts") were significantly reduced at 30 and 90 days. Interpretation: This prospective, observational study demonstrates statistically significant and clinically favorable responses to HFCWO as an adjunctive therapy for patients with a primary diagnosis of COPD without concomitant bronchiectasis. Results of this study inform the design of additional additional studies of HFCWO to prove efficacy inCOPD patients.

Tuning polymer-backbone coplanarity and conformational order to achieve high-performance printed all-polymer solar cells.

All-polymer solar cells (all-PSCs) offer improved morphological and mechanical stability compared with those containing small-molecule-acceptors (SMAs). They can be processed with a broader range of conditions, making them desirable for printing techniques. In this study, we report a high-performance polymer acceptor design based on bithiazole linker (PY-BTz) that are on par with SMAs. We demonstrate that bithiazole induces a more coplanar and ordered conformation compared to bithiophene due to the synergistic effect of non-covalent backbone planarization and reduced steric encumbrances. As a result, PY-BTz shows a significantly higher efficiency of 16.4% in comparison to the polymer acceptors based on commonly used thiophene-based linkers (i.e., PY-2T, 9.8%). Detailed analyses reveal that this improvement is associated with enhanced conjugation along the backbone and closer interchain π-stacking, resulting in higher charge mobilities, suppressed charge recombination, and reduced energetic disorder. Remarkably, an efficiency of 14.7% is realized for all-PSCs that are solution-sheared in ambient conditions, which is among the highest for devices prepared under conditions relevant to scalable printing techniques. This work uncovers a strategy for promoting backbone conjugation and planarization in emerging polymer acceptors that can lead to superior all-PSCs.

Factors Associated With the Rate of Recovery After Cervical Decompression Surgery for Degenerative Cervical Myelopathy: A Retrospective Analysis.

Introduction Degenerative cervical myelopathy (DCM) is a debilitating spinal condition with a wide variety of symptoms that can differ greatly among individuals. Common symptoms include numbness, extremity weakness, loss of balance, and gait instability. Decompression surgeries are commonly indicated for the treatment of DCM with varying outcomes reported in the literature. However, there is little evidence on the rate of recovery defined as the time until improvement in symptoms such as numbness, balance, and strength after surgery for DCM. The purpose of this study was to determine the rate of neurological recovery after surgery for DCM and its subsequent association with various risk factors to guide clinicians while providing care and improve patient education. Methods This study was a retrospective case series (n=180 patients) examining patients who underwent cervical decompression surgery for DCM. All patients had a clinical presentation of DCM, were diagnosed with DCM, had radiographic degenerative changes and cervical stenosis, and received surgical management from 2010 to 2020 in a tertiary hospital system. Data recorded included age, smoking status, duration of pre-operative symptoms, preoperative and postoperative pain, and postoperative rate of recovery (days until improvement) in numbness, upper extremity strength, and balance. Results Patients (n=180) had an average age of 65.7 years (SD ±9.2 years, range 43-93 years). The mean ± standard deviation for the rate of recovery (days until improvement) in numbness, upper extremity strength, and balance was 84.5 ± 94.4 days, 50.6 ± 42.8 days, and 60.4 ± 69.9 days, respectively. There was only a marginally significant association between the rate of recovery for numbness after surgery and patient age (p=0.053). The average rate of recovery in numbness for patients older than 60 years was significantly longer than those younger than 60 years (99.3 versus 60.2 days). Preoperative smoking status was significantly associated with persistent moderate to severe pain (p=0.032) within the six-month postoperative period. No significant correlations were seen between the rate of recovery for balance or strength and patient age or preoperative duration of symptoms. Conclusion There was great variability in the rate of recovery for postoperative symptoms after surgery for DCM. A longer time for improvement in postoperative numbness was only marginally correlated with the increased patient age after surgery for DCM. There was no correlation found between strength or balance recovery times and patient age. Smoking status was associated with moderate to severe postoperative pain after surgery for DCM. Furthermore, the duration of preoperative symptoms was not associated with improvement in postoperative symptoms after surgery for DCM. More research is needed to determine factors impacting the rate of recovery after surgery for DCM.