Search

Hypokalemic periodic paralysis (HOKPP) is a rare neuromuscular disorder caused by altered transport of cellular potassium that leads to significant muscle weakness of the extremities. Paralytic attacks are induced by a drop in the serum potassium level and they have been associated with specific triggers. This case describes a 21-year-old male who has had recurrent presentations of acute paralytic attacks following vigorous physical activity. At presentation, this patient exhibited flaccid paralysis of all skeletal muscles below the neck, but was alert and oriented with stable vital signs. The patient was found to have a potassium level of 2.1 mmol/L and an EKG demonstrating U waves (characteristic of hypokalemia). The patient was treated with potassium supplementation with resolution of symptoms. The mainstay of prevention of long term permanent muscle weakness is avoidance of triggers that can lead to hypokalemia. Through education on disease process and lifestyle modifications, we were able to end the cycle of recurrent hospital readmissions and the subsequent financial burden this generated for the patient and his family.

Pertumbuhan permintaan teh di Indonesia terus meningkat, sedangkan produksi nasional tidak mencukupi. Oleh karena itu, impor terus meningkat sejak Asean Free Trade Agreement (AFTA) diberlakukan dengan 0% tarif impor. Murahnya teh impor menyebabkan produsen dalam negeri harus meningkatkan daya saing mereka, termasuk PT. XYZ sebagai salah satu produsen teh hijau terbesar di Indonesia. Penelitian ini bertujuan untuk: (1) mengevaluasi faktor lingkungan internal dan eksternal yang berpengaruh terhadap pengembangan rantai nilai PT XYZ; (2) merumuskan alternatif strategi yang dapat meningkatkan efisiensi produksi serta efektifitas rantai nilai PT XYZ; (3) menentukan prioritas strategi yang dapat diimplementasikan oleh PT XYZ untuk pengembangan rantai nilai teh. Metode penelitian yang digunakan adalah menggunakan observasi, wawancara dan kuesioner untuk menganalisis rantai nilai perusahaan, analisis industry internal dan eksternal, analisis SWOT, analisis AHP-SWOT untuk prioritas strategi dan implikasi manajerial. Hasil penelitian menunjukkan prioritas strategi adalah sebagai berikut: (1) peningkatan kapasitas produksi teh hijau; (2) pengembangan kerjasama perusahaan; (3) pengembangan produksi; (4) pengembangan produk dan pemasaran; (5) peningkatan standar operasional; (6) peningkatan publikasi usaha. The growth of tea demand in Indonesia increased, while the national production was not sufficient. Therefore, import is increasing since Asean Free Trade Agreement (AFTA) enforced with 0% tariff import. The cheapness of imported tea causing domestic producers must increase their competitiveness, including XYZ Company as the biggest green tea producers in Indonesia. The objectives of this study are to: (1) to evaluate the internal and external environmental condition that affect value chain development of XYZ Co.; (2) to formulate alternative strategy for improve production efficiency and value chain effectiveness of XYZ Co.; (3) to determine priority strategy which can be implemented by XYZ Co., for value chain of tea development. The method of the study used was by using observation, in depth interviews and questionnaires to analyze company’s value chain, internal and external industry analysis, SWOT analysis, AHP-SWOT for priority strategic and implication managerial. The result of the study showed that the priority strategy were as follow: (1) enhancement capacity production of green tea; (2) build strategically partnerships; (3) production development; (4) product and marketing development; (5) enhancement operational standard; (6) enhancement publication of business.

In comparison with the mandatory noise reduction rating (NRR) testing of every hearing protector sold in the United States, real-world tests of hearing protector attenuation are scarce. This study evaluated data from three potential field-test methods as compared with the subject-fit data from Method B of ANSI S12.6-1997 for the E.A.R(R) Express trade mark Pod Plug trade mark. The new field-test methods were the FitCheck headphone (FCH) method, FitCheck in sound field (FCSF) method, and bone-conduction loudness balance (BCLB) method, all of which can be administered in small single-person audiometric booths such as are commonly found in industry. Twenty normal-hearing and audiometrically competent subjects naive to hearing protector use were tested with the laboratory and the three field-test methods in a repeated-measures design. Repeated-measures models with structured covariance matrices were used to analyze the data. Significant effects were found for method, frequency, and first-order frequency-by-gender and frequency-by-method interactions. These effects and interactions were expected given the different psychophysical tasks. The FCSF and BCLB methods provided attenuations that were not significantly different from those found with Method B. Although the attenuations measured for the FCH method were statistically different (greater) than the attenuations from the other methods, the differences were within the magnitude of acceptable test-retest audiometric variability. The results suggest that the FCH and FCSF methods were both feasible and reliable methods for field testing. The FCH method is limited to testing earplugs, and the FCSF requires additional equipment to outfit the test booth, but could be used for testing all types of protectors. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Regular insulin given with the evening meal could contribute to the risk of nocturnal hypoglycemia in adolescents with type 1 diabetes using a multiple injection regimen. To test this hypothesis, we compared glucodynamics and free insulin levels on two separate study nights. RESEARCH DESIGN AND METHODS--A total of 14 adolescents were recruited. On both nights, identical doses of regular insulin or insulin lispro were administered 30 min or 10 min, respectively, before the evening meal, using a double-blind randomized crossover study design. Doses of NPH insulin and carbohydrate content of the evening meal and snack were kept identical. Blood samples were taken every 15 min for blood glucose and every 60 min for free insulin and ketones. RESULTS--After insulin lispro administration, glucose levels were significantly lower between the evening meal and the bedtime snack (analysis of variance [ANOVA] P = 0.02), and four hypoglycemic episodes were recorded. This corresponded to a higher (458 +/- 48 vs. 305 +/- 33 pmol/l, P = 0.02), earlier (64 +/- 4.6 vs. 103 +/- 12 min, P = 0.01), and shorter-lasting (245 +/- 21 vs. 365 +=/- 39 min, P = 0.01) insulin peak in contrast to regular insulin. After the bedtime snack, glucose levels increased dramatically during the lispro night and stayed higher, up to 0300 in the morning (ANOVA P = 0.01), corresponding to lower mean insulin levels (146 +/- 20 vs. 184 +/- 27 pmol/l, P = 0.04). No differences were seen in glucose and insulin levels between 0300 and 0800. Four episodes of nocturnal hypoglycemia were documented after the bedtime snack during the regular insulin night, in contrast to one episode after insulin lispro. No differences in ketone levels were observed. CONCLUSIONS--The replacement of regular insulin with insulin lispro may reduce the risk of late hypoglycemia, but redistribution of the evening carbohydrate may be needed to ensure good metabolic control and prevent early postprandial hypoglycemia. [ABSTRACT FROM AUTHOR]

Background Family carers play a central role in supporting people at the end of life, but often suffer detrimental impacts on their own mental health as a result. This project conducted evidence synthesis of research into factors that may affect carers’ mental health to help identify ways of maintaining their mental health. It worked closely with a carer Review Advisory Panel to help ensure the findings made sense and were communicated meaningfully from the carers’ perspective. Aim To present: (1) principles and components that facilitated successful patient and public involvement in an evidence synthesis project to help inform patient and public involvement in similar projects; (2) recommendations for carer support that were instigated and produced by the Review Advisory Panel. Process and principles Nine Review Advisory Panel meetings including four to five carers, a lay Chair and three researchers were held. Solid ‘groundwork’ was invested in recruitment and relationship-building prior to meetings, and it was ensured that there was agreement of how to work together and clarification of expectations at the first meeting. Key meeting principles were: having a majority of carers, and a Chair with both carer and patient and public involvement experience, to ensure carer voices remained at the fore substantial researcher representation, including the project lead, to highlight the value placed on Review Advisory Panel meetings flexibility to follow carers’ agendas, enabling ‘space to talk’ and ‘space to change’ appropriate and prompt carer payment, again emphasising patient and public involvement value to the project. Added general principles were: ongoing training, ample funded time for Review Advisory Panel preparation and ongoing communication outside meetings. COVID moved all meetings online after the first meeting, but the principles were maintained. Outputs The project saw an evolution from patient and public involvement consultation to co-production. The main patient and public involvement output was recommendations for supporting carers based on project findings, instigated and produced by the Review Advisory Panel. Reflection on successful components and challenges Five carers (including the Chair) and six researchers responded to questions by e-mail. Analysis by one researcher, aided by two other researchers, was then reviewed by all participants and revised. Both carers and researchers felt the components that made the patient and public involvement work were: (1) a shared sense of purpose of and gains from the Review Advisory Panel; (2) personal gains; (3) mutual commitment and respect; and (4) bridging between academic and lay perspectives, through investment in training, ensuring carers were able to meaningfully comment, and continuous negotiation and compromise. Challenges were that the COVID-induced move from face-to-face to online meetings reduced informality, flexibility, personal connection and non-verbal communication. However, earlier groundwork facilitated group resilience to these challenges. Patient and public involvement representation on the wider Research Management Group proved less successful, flagging the importance of negotiating and defining patient and public involvement roles at all project levels. Conclusion The patient and public involvement principles employed, including meeting composition and chairing, and flexibility to follow carers’ agendas, appeared to facilitate the evolution from consultation to co-production of carer recommendations, but require further testing. Preconditions for successful remote working should be further investigated, as the different advantages of face-to-face and virtual meetings may be combined through hybrid working. The iterative and responsive working required for genuine co-production may require more flexible patient and public involvement funding models. Study registration This study is registered as PROSPERO registration 2019 CRD42019130279 at https://www.crd.york.ac.uk/prospero/. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (grant 18/01/01) and will be published in full in Health and Social Care Delivery Research. See the NIHR Journals Library website for further project information. Plain language summary Background Family carers are crucial in supporting people nearing the end of life, but their own mental health may often suffer as a consequence. This project summarised what is known about what makes carers’ mental health better or worse. Researchers worked with a carer Review Advisory Panel to ensure that project findings were understandable and useful to carers. Aims To report key findings on what made the teamwork between researchers and carers successful; to help improve teamwork in other projects; and to present carers’ own recommendations on how to improve their mental health. Process and principles Nine Review Advisory Panel meetings were held which included four to five carers, a lay Chair and three researchers. Important early preparation included getting to know each other and agreeing how to work together. Key meeting principles were: (1) bringing carer voices to the fore by having a majority of carers and an experienced carer as Chair; (2) highlighting the value placed on meetings by having several researchers attend, including the project lead; (3) flexibility to include carers’ own agenda and project changes; and (4) appropriate and prompt carer payment. Meetings had to adapt to online working due to COVID-19. Outputs Carers moved from being advisors to taking more initiative and producing their own carer recommendations, which became a main project output. Reflection Written reflections by carers and researchers indicated that successful teamwork arose from a shared sense of purpose and gains, mutual commitment and respect, and bridging between researcher and carer perspectives through training, communication, negotiation and compromise. Early preparation helped the group adapt to the challenges of online working. Carer representation on other project committees could have been improved. Conclusion Project principles enabled good researcher–carer teamwork and produced valuable carer recommendations, but need proper investment in time and resources. Online working can be successful, but needs good face-to-face preparation.

Abstract Background Iron homeostasis is a key metabolism for most organisms. In many bacterial species, coordinate regulation of iron homeostasis depends on the protein product of a Fur gene. Fur also plays roles in virulence, acid tolerance, redox-stress responses, flagella chemotaxis and metabolic pathways. Results We conducted physiological and transcriptomic studies to characterize Fur in Shewanella oneidensis, with regard to its roles in iron and acid tolerance response. A S. oneidensisfur deletion mutant was defective in growth under iron-abundant or acidic environment. However, it coped with iron depletion better than the wild-type strain MR-1. Further gene expression studies by microarray of the fur mutant confirmed previous findings that iron uptake genes were highly de-repressed in the mutant. Intriguingly, a large number of genes involved in energy metabolism were iron-responsive but Fur-independent, suggesting an intimate relationship of energy metabolism to iron response, but not to Fur. Further characterization of these genes in energy metabolism suggested that they might be controlled by transcriptional factor Crp, as shown by an enriched motif searching algorithm in the corresponding cluster of a gene co-expression network. Conclusion This work demonstrates that S. oneidensis Fur is involved in iron acquisition and acid tolerance response. In addition, analyzing genome-wide transcriptional profiles provides useful information for the characterization of Fur and iron response in S. oneidensis.

Madagascar is one of the world’s top twelve “megadiversity” hot spots hosting unique and threatened flora and fauna. Parasites are a major component of biodiversity but remain largely uncharacterized in wildlife. In this study we combine microscopic and molecular assessment of hemoparasites in endemic reptile species from Madagascar. We detected three distinct parasites: the apicomplexans Hepatozoon and Sarcocystis, and filarial nematodes. The prevalence and intensity of these apicomplexans were low overall, while microfilarial infections in chameleons were relatively high. We detected mixed infections of two Hepatozoon haplotypes in Madagascarophis colubrinus, and of Hepatozoon and microfilariae in a Furcifer sp. Phylogenetic analyses of Hepatozoon showed evidence of prey-predator transmission, with identical sequences found in the snakes M. colubrinus and Ithycyphus oursi, and their prey Furcifer sp. Based on previous studies regarding the life cycle of Hepatozoon domerguei Landau, Chabaud, Michel, and Brygoo, 1970 in these hosts and due to their morphological similarity, we propose that this Hepatozoon haplotype is Hepatozoon domerguei. Future studies, including the examination of invertebrate hosts, are needed to verify this preliminary taxonomic identification. A distinct hemogregarine haplotype was found in Oplurus sp., which displayed morphologically different gametocytes, some of which were apparently inside leukocytes. The Sarcocystis identified from Tracheloptychus petersi was identical to that reported in a North African snake, indicating that the same lineage is found in geographically distinct regions. By combining morphological and genetic information, Foleyella furcata (Linstow, 1899) filarial nematodes were identified in several Furcifer chameleons. This study provides insights into the distribution, diversity and host-parasite interactions of hemoparasites in wild reptile populations from Madagascar.

Abstract Background Macrophages have heterogeneous phenotypes and complex functions within both innate and adaptive immune responses. To date, most experimental studies have been performed on macrophages derived from bone marrow, spleen and peritoneum. However, differences among macrophages from these particular sources remain unclear. In this study, the features of murine macrophages from bone marrow, spleen and peritoneum were compared. Results We found that peritoneal macrophages (PMs) appear to be more mature than bone marrow derived macrophages (BMs) and splenic macrophages (SPMs) based on their morphology and surface molecular characteristics. BMs showed the strongest capacity for both proliferation and phagocytosis among the three populations of macrophage. Under resting conditions, SPMs maintained high levels of pro-inflammatory cytokines expression (IL-6, IL-12 and TNF-α), whereas BMs produced high levels of suppressive cytokines (IL-10 and TGF-β). However, SPMs activated with LPS not only maintained higher levels of (IL-6, IL-12 and TNF-α) than BMs or PMs, but also maintained higher levels of IL-10 and TGF-β. Conclusions Our results show that BMs, SPMs and PMs are distinct populations with different biological functions, providing clues to guide their further experimental or therapeutic use.

Abstract Background Peptide nucleic acid fluorescent in situ hybridization (PNA-FISH) is a rapid and established method for identification of Candida sp., Gram positive, and Gram negative bacteria from positive blood cultures. This study reports clinical experience in the evaluation of 103 positive blood cultures and 17 positive peritoneal fluid cultures from 120 patients using PNA-FISH. Our study provides evidence as to potential pharmaceutical cost savings based on rapid pathogen identification, in addition to the novel application of PNA-FISH to peritoneal fluid specimens. Methods Identification accuracy and elapsed time to identification of Gram positives, Gram negatives, and Candida sp., isolated from blood and peritoneal fluid cultures were assessed using PNA-FISH (AdvanDx), as compared to standard culture methods. Patient charts were reviewed to extrapolate potential pharmaceutical cost savings due to adjustment of antimicrobial or antifungal therapy, based on identification by PNA-FISH. Results In blood cultures, time to identification by standard culture methods for bacteria and Candida sp., averaged 83.6 hours (95% CI 56.7 to 110.5). Identification by PNA-FISH averaged 11.2 hours (95% CI 4.8 to 17.6). Overall PNA-FISH identification accuracy was 98.8% (83/84, 95% CI 93.5% to 99.9%) as compared to culture. In peritoneal fluid, identification of bacteria by culture averaged 87.4 hours (95% CI −92.4 to 267.1). Identification by PNA-FISH averaged 16.4 hours (95% CI −57.3 to 90.0). Overall PNA-FISH identification accuracy was 100% (13/13, 95% CI 75.3% to 100%). For Candida sp., pharmaceutical cost savings based on PNA-FISH identification could be $377.74/day. For coagulase-negative staphylococcus (CoNS), discontinuation of vancomycin could result in savings of $20.00/day. Conclusions In this retrospective study, excellent accuracy of PNA-FISH in blood and peritoneal fluids with reduced time to identification was observed, as compared to conventional culture-based techniques. Species-level identification based on PNA-FISH could contribute to notable cost savings due to adjustments in empiric antimicrobial or antifungal therapy as appropriate to the pathogen identified.

Abstract Background The pronounced morphological conservatism within Tarentola geckos contrasted with a high genetic variation in North Africa, has led to the hypothesis that this group could represent a cryptic species complex, a challenging system to study especially when trying to define distinct evolutionary entities and address biogeographic hypotheses. In the present work we have re-examined the phylogenetic and phylogeographic relationships between and within all Mediterranean species of Tarentola, placing the genealogies obtained into a temporal framework. In order to do this, we have investigated the sequence variation of two mitochondrial (12S rRNA and 16S rRNA), and four nuclear markers (ACM4, PDC, MC1R, and RAG2) for 384 individuals of all known Mediterranean Tarentola species, so that their evolutionary history could be assessed. Results Of all three generated genealogies (combined mtDNA, combined nDNA, and mtDNA+nDNA) we prefer the phylogenetic relationships obtained when all genetic markers are combined. A total of 133 individuals, and 2,901 bp of sequence length, were used in this analysis. The phylogeny obtained for Tarentola presents deep branches, with T. annularis, T. ephippiata and T. chazaliae occupying a basal position and splitting from the remaining species around 15.38 Mya. Tarentola boehmei is sister to all other Mediterranean species, from which it split around 11.38 Mya. There are also two other major groups: 1) the T. mauritanica complex present in North Africa and Europe; and 2) the clade formed by the T. fascicularis/deserti complex, T. neglecta and T. mindiae, occurring only in North Africa. The cladogenesis between these two groups occurred around 8.69 Mya, coincident with the late Miocene. Contrary to what was initially proposed, T. neglecta and T. mindiae are sister taxa to both T. fascicularis and T. deserti. Conclusions At least in the Iberian Peninsula and Northwest Africa, the lineages obtained have some geographic coherency, whilst the evolutionary history of the forms from Northeast Africa remains unclear, with a paraphyletic T. fascicularis with respect to T. deserti. The separation between the T. mauritanica complex and the clade formed by the T. fascicularis/deserti complex, T. neglecta and T. mindiae is coincident with the uplift of the Atlas Mountain chain, and the establishment of two distinct bioclimatic regions on each side of the barrier.

Abstract Background The Gram-negative bacterium Photorhabdus asymbiotica (Pa) has been recovered from human infections in both North America and Australia. Recently, Pa has been shown to have a nematode vector that can also infect insects, like its sister species the insect pathogen P. luminescens (Pl). To understand the relationship between pathogenicity to insects and humans in Photorhabdus we have sequenced the complete genome of Pa strain ATCC43949 from North America. This strain (formerly referred to as Xenorhabdus luminescens strain 2) was isolated in 1977 from the blood of an 80 year old female patient with endocarditis, in Maryland, USA. Here we compare the complete genome of Pa ATCC43949 with that of the previously sequenced insect pathogen P. luminescens strain TT01 which was isolated from its entomopathogenic nematode vector collected from soil in Trinidad and Tobago. Results We found that the human pathogen Pa had a smaller genome (5,064,808 bp) than that of the insect pathogen Pl (5,688,987 bp) but that each pathogen carries approximately one megabase of DNA that is unique to each strain. The reduced size of the Pa genome is associated with a smaller diversity in insecticidal genes such as those encoding the Toxin complexes (Tc's), Makes caterpillars floppy (Mcf) toxins and the Photorhabdus Virulence Cassettes (PVCs). The Pa genome, however, also shows the addition of a plasmid related to pMT1 from Yersinia pestis and several novel pathogenicity islands including a novel Type Three Secretion System (TTSS) encoding island. Together these data suggest that Pa may show virulence against man via the acquisition of the pMT1-like plasmid and specific effectors, such as SopB, that promote its persistence inside human macrophages. Interestingly the loss of insecticidal genes in Pa is not reflected by a loss of pathogenicity towards insects. Conclusion Our results suggest that North American isolates of Pa have acquired virulence against man via the acquisition of a plasmid and specific virulence factors with similarity to those shown to play roles in pathogenicity against humans in other bacteria.

Abstract Background Iron homeostasis of Shewanella oneidensis, a γ-proteobacterium possessing high iron content, is regulated by a global transcription factor Fur. However, knowledge is incomplete about other biological pathways that respond to changes in iron concentration, as well as details of the responses. In this work, we integrate physiological, transcriptomics and genetic approaches to delineate the iron response of S. oneidensis. Results We show that the iron response in S. oneidensis is a rapid process. Temporal gene expression profiles were examined for iron depletion and repletion, and a gene co-expression network was reconstructed. Modules of iron acquisition systems, anaerobic energy metabolism and protein degradation were the most noteworthy in the gene network. Bioinformatics analyses suggested that genes in each of the modules might be regulated by DNA-binding proteins Fur, CRP and RpoH, respectively. Closer inspection of these modules revealed a transcriptional regulator (SO2426) involved in iron acquisition and ten transcriptional factors involved in anaerobic energy metabolism. Selected genes in the network were analyzed by genetic studies. Disruption of genes encoding a putative alcaligin biosynthesis protein (SO3032) and a gene previously implicated in protein degradation (SO2017) led to severe growth deficiency under iron depletion conditions. Disruption of a novel transcriptional factor (SO1415) caused deficiency in both anaerobic iron reduction and growth with thiosulfate or TMAO as an electronic acceptor, suggesting that SO1415 is required for specific branches of anaerobic energy metabolism pathways. Conclusion Using a reconstructed gene network, we identified major biological pathways that were differentially expressed during iron depletion and repletion. Genetic studies not only demonstrated the importance of iron acquisition and protein degradation for iron depletion, but also characterized a novel transcriptional factor (SO1415) with a role in anaerobic energy metabolism.

Abstract Background The fish pathogen Aliivibrio salmonicida is the causative agent of cold-water vibriosis in marine aquaculture. The Gram-negative bacterium causes tissue degradation, hemolysis and sepsis in vivo. Results In total, 4 286 protein coding sequences were identified, and the 4.6 Mb genome of A. salmonicida has a six partite architecture with two chromosomes and four plasmids. Sequence analysis revealed a highly fragmented genome structure caused by the insertion of an extensive number of insertion sequence (IS) elements. The IS elements can be related to important evolutionary events such as gene acquisition, gene loss and chromosomal rearrangements. New A. salmonicida functional capabilities that may have been aquired through horizontal DNA transfer include genes involved in iron-acquisition, and protein secretion and play potential roles in pathogenicity. On the other hand, the degeneration of 370 genes and consequent loss of specific functions suggest that A. salmonicida has a reduced metabolic and physiological capacity in comparison to related Vibrionaceae species. Conclusion Most prominent is the loss of several genes involved in the utilisation of the polysaccharide chitin. In particular, the disruption of three extracellular chitinases responsible for enzymatic breakdown of chitin makes A. salmonicida unable to grow on the polymer form of chitin. These, and other losses could restrict the variety of carrier organisms A. salmonicida can attach to, and associate with. Gene acquisition and gene loss may be related to the emergence of A. salmonicida as a fish pathogen.

Abstract Background The physiological function of the cellular prion protein (PrPC) remains unknown. However, PrPC has been reported to possess a cytoprotective activity that prevents death of neurons and other cells after a toxic stimulus. To explore this effect further, we attempted to reproduce several of the assays in which a protective activity of PrP had been previously demonstrated in mammalian cells. Results In the first set of experiments, we found that PrP over-expression had a minimal effect on the death of MCF-7 breast carcinoma cells treated with TNF-α and Prn-p0/0 immortalized hippocampal neurons (HpL3-4 cells) subjected to serum deprivation. In the second set of assays, we observed only a small difference in viability between cerebellar granule neurons cultured from PrP-null and control mice in response to activation of endogenous or exogenous Bax. Conclusion Taken together, our results suggest either that cytoprotection is not a physiologically relevant activity of PrPC, or that PrPC-dependent protective pathways operative in vivo are not adequately modeled by these cell culture systems. We suggest that cell systems capable of mimicking the neurotoxic effects produced in transgenic mice by N-terminally deleted forms of PrP or Doppel may represent more useful tools for analyzing the cytoprotective function of PrPC.

Abstract Background Quality of life (QoL) is now established as an important outcome for evaluating the impact of disease, and for assessing the efficacy of treatments. However, individuals change with time and the basis on which they make a QoL judgement may also change, a phenomenon increasingly referred to as response shift. Here, the individual may change his or her internal standards, values, and/or conceptualization on the target construct as a result of external factors such as a treatment or a change in health status. This has important implications for assessing the effects of treatments as a change in QoL may reflect a response shift, a treatment effect, or a complex combination of both. In this study, we used an individualised quality of life (IQoL) measure, the SEIQoL, together with a then-test to determine whether response shift would influence the measurement of treatment efficacy in edentulous patients. Methods Data are reported here for the first phase of a randomised controlled clinical trial designed to assess the impact, on IQoL, of implant supported dentures compared with high quality conventional dentures. IQoL was measured using the SEIQoL-DW in 117 patients (mean age 64.8; 32% male) at baseline (T1) and 3 months (T2) after receiving high quality conventional dentures. The work was carried out in dental teaching hospitals in Dublin and Belfast. Results Unadjusted SEIQoL index scores revealed no significant impact of treatment at three months (baseline: 75.0; 3 months: 73.2, p = .33, n.s.). However, the then-test at 3 months revealed that patients retrospectively rated their baseline IQoL as significantly lower (P < .001) than they had rated it at the time (then-test baseline: 69.2). Comparison of the 3 month scores with this readjusted baseline indicated a significant treatment effect (then-test baseline: 69.2; 3 months: 73.2, p = 0.016). 81% of patients nominated at least one different IQoL domain at 3 months. Conclusion The positive impact of denture treatment for edentulous patients on IQoL was seen only when response shifts were taken into consideration. The nature of the response shifts was highly complex but the data indicated a degree of re-conceptualisation and reprioritisation. Assessment of the impact of treatments using patient-generated reports must take account of the adaptive nature of patients.

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrP C ). Why these mutations are pathogenic, and how they alter the properties of PrP C are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrP Sc , the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrP C may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Several social determinants of health and other structural factors drive racial and ethnic disparities in COVID-19 risk, morbidity, and mortality. Public-private collaborations with community pharmacies have been successful in expanding access to COVID-19 testing and reaching historically underserved communities. The objectives of this study were to describe individuals who sought testing for COVID-19 at a national community pharmacy chain and to understand potential racial and ethnic inequities in testing access, positivity, and infection with emerging variants of concern., Methods: We conducted a cross-sectional study of individuals aged ≥18 who were tested for COVID-19 (SARS-CoV-2) at a Walgreens pharmacy or Walgreen-affiliated mass testing site between May 1, 2021 and February 28, 2022. Positivity was defined as the proportion of positive tests among all administered tests. A geographically balanced random subset of positive tests underwent whole genome sequencing to identify specific viral variants (alpha, delta, and omicron). Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) to compare the likelihood of testing positive and testing positive with an emerging variant of concern across race and ethnicity groups., Results: A total of 18,576,360 tests were analyzed (16.0% tests were positive for COVID-19; 59.5% of tests were from White individuals and 13.1% were from Black individuals). American Indian or Alaska Native (OR = 1.12; 95%CI = 1.10-1.13), Hispanic or Latino (1.20; 95%CI = 1.120, 1.21), and Black (1.12; 95%CI = 1.12, 1.13) individuals were more likely to test positive for COVID-19 compared to White individuals. Non-White individuals were also more likely to test positive for emerging variants of concern (e.g., Black individuals were 3.34 (95%CI = 3.14-3.56) times more likely to test positive for omicron compared to White individuals during the transition period from delta to omicron)., Discussion: Using a national database of testing data, we found racial and ethnic differences in the likelihood of testing positive for COVID-19 and testing positive for emerging viral strains. These results demonstrate the feasibility of public-private collaborations with local pharmacies and pharmacy chains to support pandemic response and reach harder to reach populations with important health services., Competing Interests: TS, AS, RLS-R, and EO were employed by the company Walgreen Co. DAH has received consulting fees from the company Sanofi for consulting and research unrelated to the present study. KNH has received grant funding paid directly to Brown University for collaborative research from Insight Therapeutics, Sanofi, and Genentech for research on complex insulin regimens, influenza outbreak control, and influenza vaccination in nursing homes. KNH has also served as a consultant for the Canadian Agency for Drugs and Technologies in Health. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Singh, Smith-Ray, Ogunkoya, Shah, Harris, Hayes and Mor.)

Objectives: An unintended consequence of efforts to reduce antipsychotic medications in nursing homes is the increase in use of other psychotropic medications; however, evidence of substitution remains limited. Our objective was to measure individual-level prescribing patterns consistent with substitution of trazodone for antipsychotics., Design: Retrospective cohort study., Setting and Participants: Residents of Ontario nursing homes aged 66-105 years with an admission assessment between April 1, 2010, and March 31, 2019, who were receiving an antipsychotic and had no antidepressant medication use at admission to the nursing home., Methods: We used linked health administrative data to examine changes in medication use over three quarterly assessments following admission. Antipsychotic and trazodone use were measured at each assessment. The rate of trazodone initiation was compared between residents no longer dispensed an antipsychotic (discontinued) and those with an ongoing antipsychotic (continued) using discrete time survival analysis, controlling for baseline resident characteristics., Results: We identified 13,306 residents dispensed an antipsychotic with no antidepressant use at admission (mean age 84 years, 61.5% women, 82.8% with dementia). As of the first quarterly assessment, nearly 20% of residents no longer received an antipsychotic and 9% received a new trazodone medication. Over time, residents who discontinued antipsychotics had a rate of trazodone initiation that was 82% higher compared to residents who continued (adjusted hazard ratio 1.82, 95% CI 1.66-2.00)., Conclusions and Implications: Residents admitted to a nursing home with antipsychotic use had a higher rate of trazodone initiation if they discontinued (vs continued) an antipsychotic. These findings suggest antipsychotic substitution with trazodone after entering a nursing home., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery., Competing Interests: Declaration of interests S.N.C., D.A.H., E.G.S., and A.S.D. are co-inventors on patents related to this work. A.S.D. is an ad hoc consultant for Axial Therapeutics. S.N.C. is an ad hoc consultant for Metis Therapeutics. E.G.S. is an ad hoc consultant for Vicarious Surgical, Inc. and has educational support/speaker fees from Cine-Med and Intuitive Surgical, Inc. A.T. is a cofounder and consultant for AltrixBio., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Social anxiety is characterised by fear of negative evaluation and negative perceptual biases; however, the cognitive mechanisms underlying these negative biases are not well understood. We investigated a possible mechanism which could maintain negative biases: altered adaptation to emotional faces. Heightened sensitivity to negative emotions could result from weakened adaptation to negative emotions, strengthened adaptation to positive emotions, or both mechanisms. We measured adaptation from repeated exposure to either positive or negative emotional faces, in individuals high versus low in social anxiety. We quantified adaptation strength by calculating the point of subjective equality (PSE) before and after adaptation for each participant. We hypothesised: (1) weaker adaptation to angry vs happy faces in individuals high in social anxiety, (2) no difference in adaptation to angry vs happy faces in individuals low in social anxiety, and (3) no difference in adaptation to sad vs happy faces in individuals high in social anxiety. Our results revealed a weaker adaptation to angry compared to happy faces in individuals high in social anxiety (Experiment 1), with no such difference in individuals low in social anxiety (Experiment 1), and no difference in adaptation strength to sad vs happy faces in individuals high in social anxiety (Experiment 2).

Post-Conviction Traumatic Stress (PCTS) describes the cognitive, psychological, and physiological symptoms of trauma that result from a range of experiences with the criminal justice system. This pilot study aimed to empirically validate the construct of PCTS utilizing the Post-Traumatic Checklist (PCL-5), an existing measure of Post-Traumatic Stress Disorder (PTSD) according to DSM-5 diagnostic criteria. Using mixed methods, the survey asked about the traumagenic impact of arrests, court proceedings, incarceration, probation/parole supervision, and sex offender registration requirements in a sample of people required to register as sexual offenders (RSOs; n = 290) and their family members ( n = 126). The PCL-5 was used to estimate the prevalence of PTSD and to explore the unique presentation of symptoms. Findings indicated that 69% of registrants and 62% of family members reported clinically significant indicators of PTSD. Examples of specific symptom presentations are illustrated through qualitative responses. Implications for clinical treatment, policy, and future research related to PCTS are discussed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.