Alzheimer's Disease Biomarker Decision-Making among Patients with Mild Cognitive Impairment and Their Care Partners.

BACKGROUND: Alzheimer's disease (AD) biomarker tests can be ordered as part of the diagnostic workup of patients with mild cognitive impairment (MCI). Little is known about how patients with MCI and their care partners decide whether to pursue testing. OBJECTIVE: To examine factors that influence AD biomarker testing decisions among patients with MCI and their care partners. DESIGN: We performed structured research interviews with patients with MCI and their study partners to assess the importance of eight factors in the decision whether to undergo AD biomarker testing (6-point Likert scale; 1-extremely unimportant to 6-extremely important): cost, fear of testing procedures, learning if AD is the cause of cognitive problems, concern about health insurance, instructing future planning, informing treatment decisions, family members' opinions, and doctor recommendation. SETTING: Two researchers administered interviews with participants in-person (i.e., participant home, research center) or remotely (i.e., telephone, video-conference). PARTICIPANTS: We completed interviews with 65 patients with a diagnosis of MCI and 57 study partners, referred by dementia specialist clinicians from the University of California, Irvine health system. MEASUREMENTS: We used generalized estimating equations (GEE) to examine the mean importance of each factor among patients and study partners, and the mean difference in importance of each factor within dyads. RESULTS: One third of participants reported the patient had previously undergone AD biomarker testing. Fifty-five percent of patients and 65% of study partners who reported no previous testing indicated a desire for the patient to be tested. GEE analyses found that patients and study partners rated the following factors with highest importance: informing treatment decisions (mean score 5.29, 95% CI: 5.06, 5.52 for patients; mean score 5.56, 95% CI: 5.41, 5.72 for partners); doctor recommendation (4.94, 95% CI: 4.73, 5.15 for patients; 5.16, 95% CI: 4.97, 5.34 for partners); and instructing future planning (4.88, 95% CI: 4.59, 5.16 for patients; 5.11, 95% CI: 4.86, 5.35 for partners). High dyadic agreement was observed for all factors except fear of testing, which patients rated with lower importance than their study partners. CONCLUSIONS: Biomarker testing for AD in patients with MCI is a rapidly evolving practice and limited data exist on patient perspectives. In this study, most patients and their care partners were interested in testing to help inform treatment decisions and to plan for the future. Participants placed high importance on clinician recommendations for biomarker testing, highlighting the need for clear communication and education on the options, limitations, risks, and benefits of testing.

The use of rats to detect drug-resistant TB.

Although detection of drug-susceptible TB by Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling-trained African giant pouched rats has been known for more than a decade, the detection of drug-resistant TB (DR-TB) using rats has never been explored before. We present what we believe to be the first report on rifampicin-resistant TB (RR-TB) detected using Xpert® MTB/RIF Ultra, comparably identified by rats sniffing sputum samples from presumptive TB patients: 88% of RR-TB detected using Ultra were identified by the rats. Further evaluation of the usefulness of rats for large-scale DR-TB contact triage testing is needed, especially in low- and middle-income countries, where resources are limited.

Bien que la détection de la TB pharmacosensible par des rats géants de Gambie dressés par APOPO (Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling) soit connue depuis plus d'une décennie, la détection de la TB pharmacorésistante (DR-TB) à l'aide de rats n'a jamais été explorée auparavant. Nous présentons ce que nous pensons être le premier rapport sur la TB résistante à la rifampicine (RR-TB) détectée par test Xpert® MTB/RIF Ultra, identifiée de manière comparable par des rats reniflant des échantillons d'expectorations de patients avec une TB présumée : 88% des RR-TB détectées par test Ultra ont été identifiées par les rats. L'évaluation de l'utilité des rats dans le cadre de tests de triage des contacts de cas de DR-TB à grande échelle doit être poursuivie, en particulier dans les pays à revenu faible ou intermédiaire, où les ressources sont limitées.

US Adults' Likelihood to Participate in Dementia Prevention Drug Trials: Results from the National Poll on Healthy Aging.

BACKGROUND: Recruitment to dementia prevention clinical trials is challenging, and participants are not representative of US adults at risk. A better understanding of the general public's interest in dementia prevention research participation is needed to inform future recruitment strategies. OBJECTIVE: To examine US adults' characteristics associated with self-reported likelihood to participate in dementia prevention clinical trials. DESIGN: We conducted a cross-sectional survey using the October 2018 wave of the University of Michigan National Poll on Healthy Aging. SETTING: The National Poll on Healthy Aging is a nationally representative survey of adults using KnowledgePanel (Ipsos Public Affairs LLC), a probability-based panel of the civilian, noninstitutionalized US population. PARTICIPANTS: We analyzed data from 1,028 respondents, ages 50 to 64 years, who completed a web survey module on brain health. MEASUREMENTS: We used logistic regression models to examine associations between sociodemographic and dementia-related factors (e.g., family history) and self-reported likelihood to participate in a dementia prevention clinical trial of a new medicine ("very" or "somewhat likely" vs. "not likely" survey responses). Among respondents not likely to participate, we examined frequency of reasons endorsed for this decision, stratified by age, sex, and race and ethnicity. RESULTS: Of the 1,028 respondents, half were female, 68% Non-Hispanic White, 13% Hispanic, and 12% Non-Hispanic Black. Twelve percent of respondents reported being very likely to participate in a dementia prevention trial, 32% somewhat likely, and 56% not likely. Factors associated with higher likelihood to participate were higher perceived risk of dementia [OR, 2.17 (95% CI, 1.61, 2.93)], a positive family history of dementia [OR, 1.75 (95% CI, 1.27, 2.43)], and having discussed dementia prevention with a doctor [OR, 2.20 (95% CI, 1.10, 4.42)]. There were no differences in likelihood to participate by sociodemographic characteristics. Among 570 respondents not likely to participate, 39% said they did not want to be a guinea pig, 23% thought dementia would not affect them, 22% thought there would be too high a chance for harm, 15% indicated study participation would take too much time, and 5% reported fear of learning information about oneself. There were no differences across age, sex, and racial and ethnic groups. CONCLUSIONS: In this study, perceived risk of dementia, family history, and discussion of prevention with a doctor were associated with likelihood to participate in a dementia prevention clinical trial, whereas sociodemographic factors including race and ethnicity were not. Findings suggest that recruitment interventions focused on increasing knowledge of dementia risk and prevention trials and involving healthcare providers may be effective tools to improve enrollment rates, regardless of target community.

Infertility prevalence and the methods of estimation from 1990 to 2021: a systematic review and meta-analysis.

STUDY QUESTION: What is the contemporary prevalence of infertility in world populations and how do they differ by methodological and study characteristics? SUMMARY ANSWER: Pooled estimates of lifetime and period prevalence of 12-month infertility were 17.5% and 12.6%, respectively, but this varied by study population and methodological approach. WHAT IS KNOWN ALREADY: Infertility affects millions of individuals worldwide. Accurate measures of its magnitude are needed to effectively address and manage the condition. There are distinct challenges and variation in how infertility is defined and measured, limiting comparability of estimates across studies. Further research is needed to understand whether and how differences in methodological approaches and study characteristics account for heterogeneity in estimates. STUDY DESIGN SIZE DURATION: We conducted a systematic review and meta-analysis. Six electronic databases, websites of relevant organizations, and conference proceedings were systematically searched. Searches were limited to those published between 1 January 1990 and 11 March 2021, with no language restrictions. PARTICIPANTS/MATERIALS SETTING METHODS: Descriptive and random-effects meta-analysis models were used to examine range of estimates and generate estimates of pooled lifetime and period prevalence of 12-month infertility, respectively, among representative populations. Meta-regression using restricted maximum likelihood was applied to account for definitional and study characteristics and to obtain adjusted estimates. Risk of bias was assessed with a validated tool. MAIN RESULTS AND THE ROLE OF CHANCE: The search yielded 12 241 unique records of which 133 studies met the criteria for the systematic review. There were 65 and 69 studies that provided data for lifetime and period prevalence of 12-month infertility, respectively. Five methodological approaches were identified: prospective time-to-pregnancy (TTP) design, current duration design, retrospective TTP design, self-reported infertility measure and constructed infertility measure. Ranges for lifetime (3.3-39.7%) and period estimates (1.6-34.0%) were similar and wide even after accounting for methodological and study characteristics. Pooled estimates of lifetime and period prevalence were 17.5% (95% CI: 15.0, 20.3, n = 37 studies, I 2 = 99.5%) and 12.6% (95% CI: 10.7, 14.6, n = 43 studies, I 2 = 99.8%), respectively, with some variation in magnitude by region and methodological approach, but with most CIs overlapping. LIMITATIONS REASONS FOR CAUTION: Pooled estimates generated from meta-analysis were derived from 12-month infertility prevalence estimates that were heterogeneous across different domains, even after adjusting for definitional and study characteristics. The number of studies was small for certain strata from which pooled estimates were derived (e.g. there were only two studies for lifetime prevalence in Africa). WIDER IMPLICATIONS OF THE FINDINGS: While findings show a high prevalence of infertility globally and regionally, it also reveals variation in measures to ascertain and compare infertility prevalence. More systematic and comprehensive collection of data using a consistent definition is needed to improve infertility prevalence estimates at global, regional and country-levels. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the World Health Organization. The authors have no conflicts of interest. REGISTRATION NUMBER: PROSPERO CRD42020211704.

No-slip billiards with particles of variable mass distribution.

Astute variations in the geometry of mathematical billiard tables have been and continue to be a source of understanding their wide range of dynamical behaviors, from regular to chaotic. Viewing standard specular billiards in the broader setting of no-slip (or rough) collisions, we show that an equally rich spectrum of dynamics can be called forth by varying the mass distribution of the colliding particle. We look at three two-parameter families of billiards varying both the geometry of the table and the particle, including as special cases examples of standard billiards demonstrating dynamics from integrable to chaotic, and show that markedly divergent dynamics may arise by changing only the mass distribution. Furthermore, for certain parameters, billiards emerge, which display unusual dynamics, including examples of full measure periodic billiards, conjectured to be nonexistent for the standard billiards in Euclidean domains.

Communicating diagnostic uncertainty in the acute and emergency medical setting: A systematic review and ethical analysis of the empirical literature.

BACKGROUND: diagnostic uncertainty is ubiquitous. Its communication to patients requires further investigation. AIMS: To determine: 1) What is known about how and why diagnostic uncertainty is communicated in acute care; 2) evidence of the effects of (not) communicating diagnostic uncertainty in the acute setting; 3) associated ethical issues. METHODS: systematic review of Medline, Web of Science and SCOPUS for (acute or emergency care) AND (diagnostic uncertainty) AND (ethics OR behaviours). Critical interpretive synthesis and ethical analysis were conducted. RESULTS AND CONCLUSION: Nine studies (primarily surveys and interviews) were identified. Doctors are not trained in communicating diagnostic uncertainty and perceive it to have negative effects on patients; however not communicating diagnostic uncertainty can disempower patients, resulting in delayed/missed diagnoses or inappropriate use of resource.

Metagenomic insights into the taxonomy, function, and dysbiosis of prokaryotic communities in octocorals.

BACKGROUND: In octocorals (Cnidaria Octocorallia), the functional relationship between host health and its symbiotic consortium has yet to be determined. Here, we employed comparative metagenomics to uncover the distinct functional and phylogenetic features of the microbiomes of healthy Eunicella gazella, Eunicella verrucosa, and Leptogorgia sarmentosa tissues, in contrast with the microbiomes found in seawater and sediments. We further explored how the octocoral microbiome shifts to a pathobiome state in E. gazella. RESULTS: Multivariate analyses based on 16S rRNA genes, Clusters of Orthologous Groups of proteins (COGs), Protein families (Pfams), and secondary metabolite-biosynthetic gene clusters annotated from 20 Illumina-sequenced metagenomes each revealed separate clustering of the prokaryotic communities of healthy tissue samples of the three octocoral species from those of necrotic E. gazella tissue and surrounding environments. While the healthy octocoral microbiome was distinguished by so-far uncultivated Endozoicomonadaceae, Oceanospirillales, and Alteromonadales phylotypes in all host species, a pronounced increase of Flavobacteriaceae and Alphaproteobacteria, originating from seawater, was observed in necrotic E. gazella tissue. Increased abundances of eukaryotic-like proteins, exonucleases, restriction endonucleases, CRISPR/Cas proteins, and genes encoding for heat-shock proteins, inorganic ion transport, and iron storage distinguished the prokaryotic communities of healthy octocoral tissue regardless of the host species. An increase of arginase and nitric oxide reductase genes, observed in necrotic E. gazella tissues, suggests the existence of a mechanism for suppression of nitrite oxide production by which octocoral pathogens may overcome the host's immune system. CONCLUSIONS: This is the first study to employ primer-less, shotgun metagenome sequencing to unveil the taxonomic, functional, and secondary metabolism features of prokaryotic communities in octocorals. Our analyses reveal that the octocoral microbiome is distinct from those of the environmental surroundings, is host genus (but not species) specific, and undergoes large, complex structural changes in the transition to the dysbiotic state. Host-symbiont recognition, abiotic-stress response, micronutrient acquisition, and an antiviral defense arsenal comprising multiple restriction endonucleases, CRISPR/Cas systems, and phage lysogenization regulators are signatures of prokaryotic communities in octocorals. We argue that these features collectively contribute to the stabilization of symbiosis in the octocoral holobiont and constitute beneficial traits that can guide future studies on coral reef conservation and microbiome therapy. Video Abstract.

Is Reluctance to Share Alzheimer's Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?

BACKGROUND: Preclinical Alzheimer's disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed. OBJECTIVE: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment. DESIGN: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure. SETTING: We conducted interviews on campus at the University of California, Irvine. PARTICIPANTS: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study. MEASUREMENTS: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment. RESULTS: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results. CONCLUSIONS: This is one of the first studies to explore how potential preclinical Alzheimer's disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.

Measurement of the heat flux normalized spin Seebeck coefficient of thin films as a function of temperature.

The spin Seebeck effect (SSE) has generated interest in the thermoelectric and magnetic communities for potential high efficiency energy harvesting applications and spintronic communities as a source of pure spin current. Understanding the underlying mechanisms requires characterization of potential materials across a range of temperatures; however, for thin films, the default measurement of an applied temperature gradient (across the sample) has been shown to be compromised by the presence of thermal resistances. Here, we demonstrate a method to perform low temperature SSE measurements where, instead of monitoring the temperature gradient, the heat flux passing through the sample is measured using two calibrated heat flux sensors. This has the advantage of measuring the heat loss through the sample as well as providing a reliable method to normalize the SSE response of thin film samples. We demonstrate this method with an SiO2/Fe3O4/Pt sample where a semiconducting-insulating transition occurs at the Verwey transition, TV, of Fe3O4 and quantify the thermomagnetic response above and below TV.

Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.

[Iatrogenic femoral head fracture during a closed reduction of posterior dislocation of hip. Case report]. / Fractura iatrogénica de la cabeza femoral durante una reducción cerrada de luxación posterior de cadera. Reporte de un caso.

The fracture dislocation of the hip is a rare lesion described up to 4 to 17% of the cases and usually secondary to automobile accidents. Generally of poor prognosis and with already well documented complications such as avascular necrosis of the femoral head, osteoarthritis and heterotopic ossification. The iatrogenic fracture of the neck or head of the proximal femur is a complication even more rare and is not documented its incidence in the world literature. Having as probable causes the irreducibility of a dislocation of hip, more than one attempt of closed reduction, inadequate technique and some problems with the anesthesia and relaxation of the patient. We present the case of a young patient attended in the first eight hours after his accident with an iatrogenic fracture of the femoral head with follow up to 18 months and emphasizing the importance of making an anatomic open reduction and stable fixation in order to get favorable results.

La fractura luxación de la articulación coxofemoral es una lesión rara descrita de 4 a 17% de los casos por lo regular secundaria a accidentes automovilísticos. Generalmente de mal pronóstico y con complicaciones ya bien documentadas como la necrosis avascular de la cabeza femoral, la osteoartritis y la osificación heterotópica. La fractura iatrogénica del cuello o de la cabeza femoral es una complicación aún más rara cuya incidencia no está documentada en la literatura mundial. Como probables causas se tienen la irreductibilidad de una luxación de cadera al hacer más de un intento de manipulaciones cerradas, la ausencia de una adecuada anestesia y la falta de relajación del paciente. Se presenta el caso de una paciente joven atendida en las primeras ocho horas posteriores al accidente con fractura iatrogénica de la cabeza femoral con seguimiento a 18 meses, haciendo énfasis en la importancia de realizar una reducción anatómica y fijación estable para obtener resultados favorables.

Anti-C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model.

Essentials Inhibitor formation remains a challenging complication of hemophilia A care. The Bethesda assay is the primary method used for determining bleeding risk and management. Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance. Antibodies that increase clearance contribute to antibody pathogenicity. SUMMARY: Background The development of neutralizing anti-factor VIII (FVIII) antibodies remains a challenging complication of modern hemophilia A care. In vitro assays are the primary method used for quantifying inhibitor titers, predicting bleeding risk, and determining bleeding management. However, other mechanisms of inhibition are not accounted for in these assays, which may result in discrepancies between the inhibitor titer and clinical bleeding symptoms. Objectives To evaluate FVIII clearance in vivo as a potential mechanism for antibody pathogenicity and to determine whether increased FVIII dosing regimens correct the associated bleeding phenotype. Methods FVIII-/- or FVIII-/- /von Willebrand factor (VWF)-/- mice were infused with anti-FVIII mAbs directed against the FVIII C1, C2 or A2 domains, followed by infusion of FVIII. Blood loss via the tail snip bleeding model, FVIII activity and FVIII antigen levels were subsequently measured. Results Pathogenic anti-C1 mAbs that compete with VWF for FVIII binding increased the clearance of FVIII-mAb complexes in FVIII-/- mice but not in FVIII-/- /VWF-/- mice. Additionally, pathogenic anti-C2 mAbs that inhibit FVIII binding to VWF increased FVIII clearance in FVIII-/- mice. Anti-C1, anti-C2 and anti-A2 mAbs that do not inhibit VWF binding did not accelerate FVIII clearance. Infusion of increased doses of FVIII in the presence of anti-C1 mAbs partially corrected blood loss in FVIII-/- mice. Conclusions A subset of antibodies that inhibit VWF binding to FVIII increase the clearance of FVIII-mAb complexes, which contributes to antibody pathogenicity. This may explain differences in the bleeding phenotype observed despite factor replacement in some patients with hemophilia A and low-titer inhibitors.

Treating a novel plasticity defect rescues episodic memory in Fragile X model mice.

Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild-type mice. Two factors contributed to this defect: (i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and (ii) impaired retrograde synaptic signaling by the endocannabinoid 2-arachidonoylglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB1, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment.

Accuracy of giant African pouched rats for diagnosing tuberculosis: comparison with culture and Xpert® MTB/RIF.

SETTING: Enhanced tuberculosis (TB) case finding using detection rats in Tanzania. OBJECTIVES: To assess the diagnostic accuracy of detection rats compared with culture and Xpert® MTB/RIF, and to compare enhanced case-finding algorithms using rats in smear-negative presumptive TB patients. DESIGN: A fully paired diagnostic accuracy study in which sputum of new adult presumptive TB patients in Tanzania was tested using smear microscopy, 11 detection rats, culture and Xpert. RESULTS: Of 771 eligible participants, 345 (45%) were culture-positive for Mycobacterium tuberculosis, and 264 (34%) were human immunodeficiency virus (HIV) positive. The sensitivity of the detection rats was up to 75.1% (95%CI 70.1-79.5) when compared with culture, and up to 81.8% (95%CI 76.0-86.5) when compared with Xpert, which was statistically significantly higher than the sensitivity of smear microscopy. Corresponding specificity was 40.6% (95%CI 35.9-45.5) compared with culture. The accuracy of rat detection was independent of HIV status. Using rats for triage, followed by Xpert, would result in a statistically higher yield than rats followed by light-emitting diode fluorescence microscopy, whereas the number of false-positives would be significantly lower than when using Xpert alone. CONCLUSION: Although detection rats did not meet the accuracy criteria as standalone diagnostic or triage testing for presumptive TB, they have additive value as a triage test for enhanced case finding among smear-negative TB patients if more advanced diagnostics are not available.

Tissue Engineering to Repair Diaphragmatic Defect in a Rat Model.

Tissue engineering is an emerging strategy for repairing damaged tissues or organs. The current study explored using decellularized rat diaphragm scaffolds combined with human amniotic fluid-derived multipotent stromal cells (hAFMSC) to provide a scaffold, stem cell construct that would allow structural barrier function during tissue ingrowth/regeneration. We created an innovative cell infusion system that allowed hAFMSC to embed into scaffolds and then implanted the composite tissues into rats with surgically created left-sided diaphragmatic defects. Control rats received decellularized diaphragm scaffolds alone. We found that the composite tissues that combined hAFMSCs demonstrated improved physiological function as well as the muscular-tendon structure, compared with the native contralateral hemidiaphragm of the same rat. Our results indicate that the decellularized diaphragm scaffolds are a potential support material for diaphragmatic hernia repair and the composite grafts with hAFMSC are able to accelerate the functional recovery of diaphragmatic hernia.

Origin of the Force: The Force-From-Lipids Principle Applied to Piezo Channels.

Piezo channels are a ubiquitously expressed, principal type of molecular force sensor in eukaryotes. They enable cells to decode a myriad of physical stimuli and are essential components of numerous mechanosensory processes. Central to their physiological role is the ability to change conformation in response to mechanical force. Here we discuss the evolutionary origin of Piezo in relation to other MS channels in addition to the force that gates Piezo channels. In particular, we discuss whether Piezo channels are inherently mechanosensitive in accordance with the force-from-lipid paradigm which has been firmly established for bacterial MS channels and two-pore domain K+ (K2P) channels. We also discuss the evidence supporting a reliance on or direct interaction with structural scaffold proteins of the cytoskeleton and extracellular matrix according to the force-from-filament principle. In doing so, we explain the false dichotomy that these distinctions represent. We also discuss the possible unifying models that shed light on channel mechanosensitivity at the molecular level.