The incremental cost effectiveness of in-patient versus out-patient rehabilitation after total hip arthroplasty - results of a pilot investigation.
Total hip arthroplasty (THA) is an established and cost effective procedure in the treatment of severe arthritis of the hip. However, bearing recent demographic changes in mind, the increasing demand for total hip arthroplasty during the next decades catalyzes health economic re-consideration of the overall health care process of initial surgery and subsequent rehabilitation. One point for discussion is due to postoperative rehabilitation, since direct costs of the latter crucially depend on whether in-patient (indoor) or out-patient (outdoor) rehabilitation is recommended. Whereas out-patient rehabilitation is obviously more cost efficient from a health insurer's perspective than its indoor alternative, it is open for discussion, whether the alternatives' clinical benefit profiles from a patient's perspective are of comparable order. Therefore this pilot investigation was implemented to assess the clinical benefit and cost effectiveness of in-patient versus out-patient rehabilitation after THA. A total of 28 patients (16 females) were enrolled in this retrospective matched pairs cohort study. All patients underwent THA in 2006 and were then assigned to either in-patient (n = 14) or out-patient (n = 14) postoperative rehabilitation at cooperating departments. The in-patient and out-patient samples were recruited from an epidemiological register trial on THA outcome, and matched 1:1 according to gender, age at surgery, working and family state. Preoperative assessment of (algo-) function as well as clinical outcome six months after surgery were based on the WOMAC questionnaire. Primary clinical endpoint of this investigation was the intraindividual increase in the WOMAC score (%), which was transformed into a utility scale ranging from 0 - 100% (optimum self-rating) and then into the number of gained quality adjusted life years (QALY). Primary economic endpoint were the total direct costs (Euro) for the overall treatment including surgery and rehabilitation from the health care insurer's perspective; costs for surgery and stationary care were calculated by means of German DRG rates, costs for postoperative rehabilitation by means of daily rates for indoor and outdoor care and the individual duration of rehabilitation. Based on these primary endpoints, the marginal cost effectiveness ratio (Euro/QALY) was estimated for the indoor and the outdoor based health care process, respectively. The matched pairs' median age difference was 2 years, their median difference in body mass index 0.8 kg/m superset2. Outdoor patients reported a median WOMAC score of 38% before and 87% after surgery, indoor patients of 41% and 88%. Matched pair evaluation revealed a median difference of 5% (interquartile range -18% - 26%) between the matched pair partners' respective WOMAC increases indicating gradual superiority of in-patient rehabilitation (sign test p = 0.719). This WOMAC difference corresponded to a median clinical benefit difference of 0.77 QALYs (interquartile range -2.13 - 3.18 QALYs) between indoor and outdoor patients. The total direct costs for surgery, postoperative care and rehabilitation were calculated 8706 Euro in median for out-patient and 9126 Euro in median for in-patient rehabilitation, their respective median matched pair difference was 420 Euro (198 - 475 Euro, p = 0.013). In summary, the marginal cost effectiveness ratios showed a matched pair difference of -841 Euro / QALY (sign test p = 0.791). The latter demonstrated - not significantly - smaller marginal costs of indoor rehabilitation. In this matched pilot investigation the overall health care process involving in-patient rehabilitation after total hip arthroplasty did not demonstrate a significantly superior cost effectiveness when compared to its out-patient alternative from a health care insurer's perspective. This observation is complemented by a rather small difference in clinical benefit. However, prospective investigations, which should randomize the rehabilitation alternatives onto appropriate patients, are necessary to confirm the above pilot results.


Dscam1 Forms a Complex with Robo1 and the N-Terminal Fragment of Slit to Promote the Growth of Longitudinal Axons.
The Slit protein is a major midline repellent for central nervous system (CNS) axons. In vivo, Slit is proteolytically cleaved into N- and C-terminal fragments, but the biological significance of this is unknown. Analysis in the Drosophila ventral nerve cord of a slit allele (slit-UC) that cannot be cleaved revealed that midline repulsion is still present but longitudinal axon guidance is disrupted, particularly across segment boundaries. Double mutants for the Slit receptors Dscam1 and robo1 strongly resemble the slit-UC phenotype, suggesting they cooperate in longitudinal axon guidance, and through biochemical approaches, we found that Dscam1 and Robo1 form a complex dependent on Slit-N. In contrast, Robo1 binding alone shows a preference for full-length Slit, whereas Dscam1 only binds Slit-N. Using a variety of transgenes, we demonstrated that Dscam1 appears to modify the output of Robo/Slit complexes so that signaling is no longer repulsive. Our data suggest that the complex is promoting longitudinal axon growth across the segment boundary. The ability of Dscam1 to modify the output of other receptors in a ligand-dependent fashion may be a general principle for Dscam proteins.


A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential.
The cytotoxic and immunogenic-activating properties of a cobalt(III)-cyclam complex bearing the non-steroidal anti-inflammatory drug, flufenamic acid is reported within the context of anti-cancer stem cell (CSC) drug discovery. The cobalt(III)-cyclam complex 1 displays sub-micromolar potency towards breast CSCs grown in monolayers, 24-fold and 31-fold greater than salinomycin (an established anti-breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)-cyclam complex 1 is 69-fold and 50-fold more potent than salinomycin and cisplatin towards three-dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that 1 induces DNA damage, inhibits cyclooxygenase-2 expression, and prompts caspase-dependent apoptosis. Breast CSCs treated with 1 exhibit damage-associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware, 1 is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic-activating effects on breast CSCs.


[Functional test with potassium chloride following long-term space mission].
To look into the potassiuretic function of kidneys in 11 cosmonauts on the second day post recovery after six-month MIR missions, functional testing with potassium chloride was performed. The following standard procedure was used before and after the missions: during morning hours fasting test-subjects consumed a 10% solution of potassium chloride in the amount of 0.55 ml/kg or 0.75 mmol of potassium per a kilogram of body mass with some additional liquid in the amount of 10 ml/kg of body mass. Later on, urine was collected for four hours. Administration of the potassium loading test after missions did not reveal any significant group-average changes in potassium excretion as compared with pre-flight levels; meanwhile, calcium excretion was increased. Reduced blood concentrations of potassium were determined in each of the cosmonauts immediately after landing. The main contributor to retaining of the renal potassiuretic function after prolonged missions appears to be the effective inflight physical countermeasures against the musculoskeletal deconditioning of the human body.


Exploring metabolic pathways in genome-scale networks via generating flux modes.
The reconstruction of metabolic networks at the genome scale has allowed the analysis of metabolic pathways at an unprecedented level of complexity. Elementary flux modes (EFMs) are an appropriate concept for such analysis. However, their number grows in a combinatorial fashion as the size of the metabolic network increases, which renders the application of EFMs approach to large metabolic networks difficult. Novel methods are expected to deal with such complexity. In this article, we present a novel optimization-based method for determining a minimal generating set of EFMs, i.e. a convex basis. We show that a subset of elements of this convex basis can be effectively computed even in large metabolic networks. Our method was applied to examine the structure of pathways producing lysine in Escherichia coli. We obtained a more varied and informative set of pathways in comparison with existing methods. In addition, an alternative pathway to produce lysine was identified using a detour via propionyl-CoA, which shows the predictive power of our novel approach. The source code in C++ is available upon request.


Improved pharmacokinetics of mercaptopurine afforded by a thermally robust hemihydrate.
Structural and thermal data were obtained for a novel hemihydrate of 6-mercaptopurine. The hemihydrate shows increased solubility and bioavailability when compared to the monohydrate form, better stability against conversion in aqueous media than the anhydrate form, and a dehydration temperature of 240 °C, the highest of any known hydrate crystal.


Initiation of meiosis and sporulation in Saccharomyces cerevisiae does not require a decrease in cyclic AMP.
Meiosis and sporulation of Saccharomyces cerevisiae are initiated in a guanine auxotroph by guanine deprivation (E. Bautz Freese, Z. Olempska-Beer, A. Hartig, and E. Freese, Dev. Biol. 102:438-451, 1984). We used this condition to examine a hypothesis (K. Matsumoto, I. Uno, and T. Ishikawa, Cell 32:417-423, 1983) that initiation of meiosis requires a low level of cAMP. We found that, after guanine deprivation, the intracellular concentration of cAMP transiently decreased not more than 20% and not at all if the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was added to the medium. Under these conditions, at least 76% of the cells sporulated in the absence of IBMX, and almost 100% sporulated in its presence. The sporulating cells continually excreted cAMP and utilized the gluconeogenic carbon source. The cells failed to sporulate efficiently and to form four-spored asci if simultaneously deprived of guanine and carbon. After guanine deprivation in glucose medium, sporulation remained suppressed and intracellular cAMP was unchanged. We conclude that, under conditions of guanine starvation, cAMP deficiency is not required for initiation of meiosis and sporulation, cAMP is produced in excess and excreted to the medium, the cells sporulate better if the cAMP concentration is increased by addition of IBMX, the cells require a gluconeogenic carbon source for complete and efficient sporulation, and suppression of sporulation by glucose is not mediated by cAMP.


Orthogonal translation enables heterologous ribosome engineering in E. coli.
The ribosome represents a promising avenue for synthetic biology, but its complexity and essentiality have hindered significant engineering efforts. Heterologous ribosomes, comprising rRNAs and r-proteins derived from different microorganisms, may offer opportunities for novel translational functions. Such heterologous ribosomes have previously been evaluated in E. coli via complementation of a genomic ribosome deficiency, but this method fails to guide the engineering of refractory ribosomes. Here, we implement orthogonal ribosome binding site (RBS):antiRBS pairs, in which engineered ribosomes are directed to researcher-defined transcripts, to inform requirements for heterologous ribosome functionality. We discover that optimized rRNA processing and supplementation with cognate r-proteins enhances heterologous ribosome function for rRNAs derived from organisms with ≥76.1% 16S rRNA identity to E. coli. Additionally, some heterologous ribosomes undergo reduced subunit exchange with E. coli-derived subunits. Cumulatively, this work provides a general framework for heterologous ribosome engineering in living cells.


Counterpropagating beams in biased photorefractive crystals: anisotropic theory.
We formulate an anisotropic nonlocal theory of the space charge field induced by the coherent counterpropagating beams in biased photorefractive crystals. We establish that the competition between the drift and diffusion terms has to be taken into account when the crystal ĉ axis is tilted with respect to the propagation direction of the beams. We demonstrate that this configuration combines the features of both spatial soliton formation without energy exchange and two-wave mixing with energy exchange leading to pattern formation.


Uncultivated microbial eukaryotic diversity: a method to link ssu rRNA gene sequences with morphology.
Protists have traditionally been identified by cultivation and classified taxonomically based on their cellular morphologies and behavior. In the past decade, however, many novel protist taxa have been identified using cultivation independent ssu rRNA sequence surveys. New rRNA "phylotypes" from uncultivated eukaryotes have no connection to the wealth of prior morphological descriptions of protists. To link phylogenetically informative sequences with taxonomically informative morphological descriptions, we demonstrate several methods for combining whole cell rRNA-targeted fluorescent in situ hybridization (FISH) with cytoskeletal or organellar immunostaining. Either eukaryote or ciliate-specific ssu rRNA probes were combined with an anti-α-tubulin antibody or phalloidin, a common actin stain, to define cytoskeletal features of uncultivated protists in several environmental samples. The eukaryote ssu rRNA probe was also combined with Mitotracker® or a hydrogenosomal-specific anti-Hsp70 antibody to localize mitochondria and hydrogenosomes, respectively, in uncultivated protists from different environments. Using rRNA probes in combination with immunostaining, we linked ssu rRNA phylotypes with microtubule structure to describe flagellate and ciliate morphology in three diverse environments, and linked Naegleria spp. to their amoeboid morphology using actin staining in hay infusion samples. We also linked uncultivated ciliates to morphologically similar Colpoda-like ciliates using tubulin immunostaining with a ciliate-specific rRNA probe. Combining rRNA-targeted FISH with cytoskeletal immunostaining or stains targeting specific organelles provides a fast, efficient, high throughput method for linking genetic sequences with morphological features in uncultivated protists. When linked to phylotype, morphological descriptions of protists can both complement and vet the increasing number of sequences from uncultivated protists, including those of novel lineages, identified in diverse environments.


Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes.
Candida albicans and Candida glabrata account for the majority of candidiasis cases worldwide. Although both species are in the same genus, they differ in key virulence attributes. Within this work, live cell imaging was used to examine the dynamics of neutrophil activation after confrontation with either C. albicans or C. glabrata. Analyses revealed higher phagocytosis rates of C. albicans than C. glabrata that resulted in stronger PMN (polymorphonuclear cells) activation by C. albicans. Furthermore, we observed differences in the secretion of chemokines, indicating chemotactic differences in PMN signalling towards recruitment of further immune cells upon confrontation with Candida spp. Supernatants from co-incubations of neutrophils with C. glabrata primarily attracted monocytes and increased the phagocytosis of C. glabrata by monocytes. In contrast, PMN activation by C. albicans resulted in recruitment of more neutrophils. Two complex infection models confirmed distinct targeting of immune cell populations by the two Candida spp.: In a human whole blood infection model, C. glabrata was more effectively taken up by monocytes than C. albicans and histopathological analyses of murine model infections confirmed primarily monocytic infiltrates in C. glabrata kidney infection in contrast to PMN-dominated infiltrates in C. albicans infection. Taken together, our data demonstrate that the human opportunistic fungi C. albicans and C. glabrata are differentially recognized by neutrophils and one outcome of this differential recognition is the preferential uptake of C. glabrata by monocytes.


Significant relationships between a simple marker of redox balance and lifestyle behaviours; Relevance to the Framingham risk score.
Oxidative stress has been closely linked to the progressive cell damage associated with emerging non-communicable disease (NCDs). Early detection of these biochemical abnormalities before irreversible cell damage occurs may therefore be useful in identifying disease risk at an individual level. In order to test this hypothesis, this study assessed the relationship between a simple measure of redox status and lifestyle risk factors for NCDs, and the population-based risk score of Framingham. In a cross-sectional study design, 100 apparently healthy middle-aged males (n = 48) and females (n = 52) were asked to complete a comprehensive lifestyle assessment questionnaire, followed by body fat percentage and blood pressure measurements, and blood collection. The ratio of plasma total antioxidant capacity to hydroperoxide (TAC/HPX) was used as an index of redox balance. One-way ANOVA and multiple linear regression analysis were performed to analyse the association between TAC/HPX, lifestyle components and other plasma biomarkers. The TAC/HPX ratio was higher in males compared to females (t96 = 2.34, P = 0.021). TAC/HPX was also lower in participants with poor sleep quality (t93 = 2.39, P = 0.019), with high sleep apnoea risk (t62.2 = 3.32, P = 0.002), with high caffeine (F(2, 93) = 3.97, P = 0.022) and red meat intake (F(2, 93) = 5.55, P = 0.005). These associations were independent of gender. Furthermore, the TAC/HPX ratio decreased with increasing body fat percentage (F(2, 95) = 4.74, P = 0.011) and depression score (t94 = 2.38, P = 0.019), though these associations were dependent on gender. Importantly, a negative association was observed between TAC/HPX levels and the Framingham risk score in both males (r(45) = -0.39, P = 0.008) and females (r(50) = -0.33, P = 0.019) that was independent of other Framingham risk score components. Findings from this study suggests that a relatively simple measure of redox balance such as the TAC/HPX ratio may be a sensitive indicator of redox stress, and may therefore serve as a useful biomarker for assessing an individual's specific NCD risk linked to unhealthy lifestyle practices.


Time Course of Septic Shock in Immunocompromised and Nonimmunocompromised Patients.
To address the impact of underlying immune conditions on the course of septic shock with respect to both mortality and the development of acute infectious and noninfectious complications. An 8-year (2008-2015) monocenter retrospective study. A medical ICU in a tertiary care center. Patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients were classified in four subgroups with respect to their immune status: nonimmunocompromised and immunocompromised distributed into hematologic or solid malignancies and nonmalignant immunosuppression. Outcomes were in-hospital death and the development of ischemic and hemorrhagic complications and ICU-acquired infections. The determinants of death and complications were addressed by multivariate competing risk analysis. None. Eight hundred one patients were included. Among them, 305 (38%) were immunocompromised, distributed into solid tumors (122), hematologic malignancies (106), and nonmalignant immunosuppression (77). The overall 3-day, in-ICU, and in-hospital mortality rates were 14.1%, 37.3%, and 41.3%, respectively. Patients with solid tumors displayed increased in-hospital mortality (cause-specific hazard, 2.20 [95% CI, 1.64-2.96]; p < 0.001). ICU-acquired infections occurred in 211 of the 3-day survivors (33%). In addition, 95 (11.8%) and 70 (8.7%) patients exhibited severe ischemic or hemorrhagic complications during the ICU stay. There was no association between the immune status and the occurrence of ICU-acquired infections. Nonmalignant immunosuppression and hematologic malignancies were independently associated with increased risks of severe ischemic events (cause-specific hazard, 2.12 [1.14-3.96]; p = 0.02) and hemorrhage (cause-specific hazard, 3.17 [1.41-7.13]; p = 0.005), respectively. The underlying immune status impacts on the course of septic shock and on the susceptibility to ICU-acquired complications. This emphasizes the complexity of sepsis syndromes in relation with comorbid conditions and raises the question of the relevant endpoints in clinical studies.


Functional Connectivity Between the Temporoparietal Cortex and Cerebellum in Autism Spectrum Disorder.
The neural basis of autism spectrum disorder (ASD) is not yet understood. ASD is marked by social deficits and is strongly associated with cerebellar abnormalities. We studied the organization and cerebellar connectivity of the temporoparietal junction (TPJ), an area that plays a crucial role in social cognition. We applied localized independent component analysis to resting-state fMRI data from autistic and neurotypical adolescents to yield an unbiased parcellation of the bilateral TPJ into 11 independent components (ICs). A comparison between neurotypical and autistic adolescents showed that the organization of the TPJ was not significantly altered in ASD. Second, we used the time courses of the TPJ ICs as spatially unbiased "seeds" for a functional connectivity analysis applied to voxels within the cerebellum. We found that the cerebellum contained a fine-grained, lateralized map of the TPJ. The connectivity of the TPJ subdivisions with cerebellar zones showed one striking difference in ASD. The right dorsal TPJ showed markedly less connectivity with the left Crus II. Disturbed cerebellar input to this key region for cognition and multimodal integration may contribute to social deficits in ASD. The findings might also suggest that the right TPJ and/or left Crus II are potential targets for noninvasive brain stimulation therapies.


Screening of odor-receptor pairs in Caenorhabditis elegans reveals different receptors for high and low odor concentrations.
Olfactory systems sense and respond to various odorants. Olfactory receptors, which in most organisms are G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, directly bind volatile or soluble odorants. Compared to the genomes of mammals, the genome of the nematode Caenorhabditis elegans contains more putative olfactory receptor genes, suggesting that in nematodes there may be combinatorial complexity to the receptor-odor relationship. We used RNA interference (RNAi) screening to identify nematode olfactory receptors necessary for the response to specific odorants. This screening identified 194 candidate olfactory receptor genes linked to 11 odorants. Additionally, we identified SRI-14 as being involved in sensing high concentrations of diacetyl. Rescue and neuron-specific RNAi experiments demonstrated that SRI-14 functioned in ASH neurons, specific chemosensory neurons, resulting in avoidance responses. Calcium imaging revealed that ASH neurons responded to high diacetyl concentrations only, whereas another class of chemosensory neurons, AWA neurons, reacted to both low and high concentrations. Loss of SRI-14 function hampered ASH responses to high diacetyl concentrations, whereas loss of ODR-10 function reduced AWA responses to low odorant concentrations. Chemosensory neurons ectopically expressing SRI-14 responded to a high concentration of diacetyl. Thus, nematodes have concentration-dependent odor-sensing mechanisms that are segregated at the olfactory receptor and sensory neuron levels.


Circularly polarized x rays: another probe of ultrafast molecular decay dynamics.
Dissociative nuclear motion in core-excited molecular states leads to a splitting of the fragment Auger lines: the Auger-Doppler effect. We present here for the first time experimental evidence for an Auger-Doppler effect following F1s → a(1g)* inner-shell excitation by circularly polarized x rays in SF(6). In spite of a uniform distribution of the dissociating S-F bonds near the polarization plane of the light, the intersection between the subpopulation of molecules selected by the core excitation with the cone of dissociation induces a strong anisotropy in the distribution of the S-F bonds that contributes to the scattering profile measured in the polarization plane.


The Complexities of "Struggling to Live Life".
Purpose The purpose of the study was to explore and describe perceptions and experiences of young adults with type 1 diabetes mellitus (T1DM) living in Appalachia, Tennessee. Methods Qualitative descriptive analysis of in-depth interviews of 9 young adults (male = 3, female = 6) 18 to 30 years of age living in Appalachian counties in Tennessee provided the basis of identifying the salient concerns from the perspective of this diverse group related to living daily with T1DM. Data analysis was facilitated by using NVivo 11 Pro and consisted of iterative review of the accounts in 3 phases: immersion, reduction, and interpretation. Results Findings revealed that young Appalachian adults had some common, consistent experiences living with T1DM. Major themes included the struggle toward adulthood, the daily struggle of living with diabetes, the strong desire to live life, the supportive environment, the development of one's identity by diabetes, the disruptiveness of diabetes' demands, and the pros and cons of technological development in diabetes management. Conclusion Health vulnerabilities are multiplied for young adults living with T1DM in Appalachian Tennessee. Participants pointed to living in communities with social stigma, lack of T1DM knowledge, and lack of access to health care that compares with the quality of care they experienced when in pediatric care. They also expressed fear about pregnancy, diabetes complications, and the dangers of hypoglycemia. Individual and community-based empowerment programs focusing on T1DM accompanied by insurance reimbursement and T1DM policy reinforcement are necessary to reduce health disparities and improve quality of life in this underserved population of young adults in Appalachia.


Cardiogenic shock complicates successful treatment of refractory thrombotic thrombocytopenia purpura with rituximab.
Treatment of thrombotic thrombo-cytopenia purpura (TTP) with daily therapeutic plasma exchange (TPE) may be accompanied by a variety of adjunctive interventions including most recently rituximab. Rituximab, a murine and human monoclonal antibody directed against CD20 antigen on B lymphocytes, is primarily used for treatment of non-Hodgkin's lymphomas. Because of severe and fatal infusion reactions including heart failure, rituximab carries a boxed warning. A 20-year-old female presented with TTP. She underwent 17 daily (1 day skipped) TPE. Her platelet (PLT) count reached 150 x 10(9) per L and then gradually declined to 36 x 10(9) per L despite continuing TPE. Because of the refractory behavior of her disease, rituximab was administered. After the rituximab infusion, she developed a nonproductive cough which progressed to a productive cough, acute respiratory failure, chest pain, and hypotension and was moved to intensive care for management of biventricular cardiogenic shock (ejection fraction was 5%-10%). Once stable in the intensive care unit, TPE was resumed. Her PLT count reached 241 x 10(9) per L, and her lactate dehydrogenase decreased to normal after four TPEs. Her heart failure completely resolved and she was discharged. Rituximab was added to her medical record as a drug allergy. Refractory TTP has been reported to respond favorably to rituximab when used as an adjunct. Interventions, however, can also carry significant risk as illustrated by the cardiogenic shock in our patient. Use of rituximab for refractory TTP should follow a careful assessment of benefits.


Back pain in seniors: the Back pain Outcomes using Longitudinal Data (BOLD) cohort baseline data.
Back pain represents a substantial burden globally, ranking first in a recent assessment among causes of years lived with disability. Though back pain is widely studied among working age adults, there are gaps with respect to basic descriptive epidemiology among seniors, especially in the United States. Our goal was to describe how pain, function and health-related quality of life vary by demographic and geographic factors among seniors presenting to primary care providers with new episodes of care for back pain. We examined baseline data from the Back pain Outcomes using Longitudinal Data (BOLD) registry, the largest inception cohort to date of seniors presenting to a primary care provider for back pain. The sample included 5,239 patients ≥ 65 years old with a new primary care visit for back pain at three integrated health systems (Northern California Kaiser-Permanente, Henry Ford Health System [Detroit], and Harvard Vanguard Medical Associates [Boston]). We examined differences in patient characteristics across healthcare sites and associations of patient sociodemographic and clinical characteristics with baseline patient-reported measures of pain, function, and health-related quality of life. Patients differed across sites in demographic and other characteristics. The Detroit site had more African-American patients (50%) compared with the other sites (7-8%). The Boston site had more college graduates (68%) compared with Detroit (20%). Female sex, lower educational status, African-American race, and older age were associated with worse functional disability as measured by the Roland-Morris Disability Questionnaire. Except for age, these factors were also associated with worse pain. Baseline pain and functional impairment varied substantially with a number of factors in the BOLD cohort. Healthcare site was an important factor. After controlling for healthcare site, lower education, female sex, African-American race, and older age were associated with worse physical disability and all of these factors except age were associated with worse pain. Clinical Trials.gov NCT01776242; Registration date: June 13, 2012.


Lack of Transmission among Close Contacts of Patient with Case of Middle East Respiratory Syndrome Imported into the United States, 2014.
In May 2014, a traveler from the Kingdom of Saudi Arabia was the first person identified with Middle East respiratory syndrome coronavirus (MERS-CoV) infection in the United States. To evaluate transmission risk, we determined the type, duration, and frequency of patient contact among health care personnel (HCP), household, and community contacts by using standard questionnaires and, for HCP, global positioning system (GPS) tracer tag logs. Respiratory and serum samples from all contacts were tested for MERS-CoV. Of 61 identified contacts, 56 were interviewed. HCP exposures occurred most frequently in the emergency department (69%) and among nurses (47%); some HCP had contact with respiratory secretions. Household and community contacts had brief contact (e.g., hugging). All laboratory test results were negative for MERS-CoV. This contact investigation found no secondary cases, despite case-patient contact by 61 persons, and provides useful information about MERS-CoV transmission risk. Compared with GPS tracer tag recordings, self-reported contact may not be as accurate.


The role of lysosomes as intermediates in betacoronavirus PHEV egress from nerve cells.
Betacoronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. However, whether all betacoronaviruses members use the same pathway to exit cells remains unknown. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV) egress occurs by Arl8b-dependent lysosomal exocytosis, a cellular egress mechanism shared by SARS-CoV-2 and MHV. Notably, PHEV acidifies lysosomes and activates lysosomal degradative enzymes, while SARS-CoV-2 and MHV deacidify lysosomes and limit the activation of lysosomal degradative enzymes. In addition, PHEV release depends on V-ATPase-mediated lysosomal pH. Furthermore, this is the first study to evaluate βCoV using lysosome for spreading through the body, and we have found that lysosome played a critical role in PHEV neural transmission and brain damage caused by virus infection in the central nervous system. Taken together, different betacoronaviruses could disrupt lysosomal function differently to exit cells.


The 'preliminary neuropsychological battery'. An instrument to grade the cognitive level of minimally responsive patients.
An early, formalized cognitive evaluation of'minimally responsive' patients could be important in the planning of their care and rehabilitation as well as in providing a realistic prognosis and studying the modality of the cognitive recovery. A short, bedside, neuropsychologically-oriented test-battery, the Preliminary Neuropsychological Battery, a psychometric tool which enables the cognitive evaluation of these patients and of patients unable to give verbal or complex motor answers, has been devised. The BNP was administered to a sample of 40 head-injured patients and to a sample of 34 healthy subjects. The aim was (i) to evaluate its usefulness, and (ii) to study its correlation with cortical functions as assessed by a more extensive battery. The findings suggest that the BNP is useful for assessing the general cognitive level of head-injured post-comatose patients. It was able to detect patients deserving a wider, analytic, neuropsychological assessment. Attentional defects emerged as an important variable determining the BNP score.


[Self-responsibility in health care using the example of medication management from the chronically ill patient's perspective].
With rising costs in health care, especially in the area of pharmaceuticals, patients are expected to be more involved in managing their care. Concepts such as shared decision-making or self-management support in chronic illness have been suggested as a way to facilitate this process and to empower patients. It is unclear however, whether the self-responsible patient role outlined in these concepts aligns with the patient's needs. The aim of this paper is to examine this proposed self-responsible role with regard to the patient's medication management needs and to discuss whether self-responsibility and autonomy are suitable concepts when illness-related challenges become difficult or complex. Selected findings from a qualitative longitudinal study on medication management from the perspective of people with chronic conditions are presented. Results from interviews with 27 patients indicate that both the patient's view and the challenges people with chronic conditions face in everyday life remain a 'blind spot' in health care. Providing information to improve health literacy may not be enough; there is a need to systematically support patients in developing skills to adequately (self-)manage a chronic condition.


Haematocrit levels and anaemia in Ethiopian children.
The paucity of data on the haematological profile of Ethiopian children prompted this survey. In October and November, 1987, a survey of haematocrit levels utilizing capillary blood and morphological studies on blood films by means of the Wright stain was conducted in the peri-urban community of Koladiba in Northwestern Ethiopia. All but 21 children (0.5-6 years) in the community participated. The mean and median haematocrit levels in children 0.5-6 years was 38% each with a range of 26-52%. Lowest haematocrit was found between 1-2 years of age. The 3rd and 97th percentile values were 31-45% and identical with the mean +/- 2 S.D. values. On a third of the children (251), blood film studies were done and 20% had microcytic hypochromic red blood cells. When an altitude corrected cut-off point of 38% was employed to define anaemia, the prevalence rate was 47.2%, the highest rate (60%) in children 1-2 years. However, use of a cut-off point based on the third percentile or +/- 2 SD (31%), resulted in an underestimation of anaemia rates by 40%. The findings of this study are consistent with previous reports on anaemia rates and haematocrit levels in Ethiopian children residing in a similar environment. Although the iron content of the Ethiopian diet is one of the highest in the world, nutritional anaemia is a public health problem. Intervention measures using iron supplementation and nutrition education through existing primary health care network are recommended.


New developments in osteoarthritis. Sex differences in magnetic resonance imaging-based biomarkers and in those of joint metabolism.
Sex differences in the prevalence, incidence, and severity of osteoarthritis (OA) have long been known. Some differences in the evaluation of this issue across studies may be related to differences in study design, sampling, study size, study populations, targeted joint sites, and definitions of OA. This report highlights recent studies of sex differences in individual joint components imaged by magnetic resonance imaging and in systemic biomarkers of joint metabolism. Particularly important are those studies that examine this issue in young unaffected adults and children before the development of disease. Despite some variation across studies, women appear for the most part to have a thinner and more reduced volume of cartilage in the knee than men, and this may occur from early childhood. It is not clear whether women have a more accelerated rate of cartilage volume loss than men. Few data exist on sex differences in systemic biomarkers of joint metabolism. In these studies, it is critically important to characterize the total body burden of OA and the presence of comorbid conditions likely to influence a given biomarker. Lastly, future research should dovetail studies of sex differences in imaging and biochemical biomarkers with genetics to maximize insight into the mechanisms behind observed sex differences.


Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function.
Underlying mechanisms contributing to the imbalance in bone turnover during osteoporosis remain only partially explained. Reduced sensory nerve function may contribute to this imbalance, as sensory neuropeptides affect the activity of osteoblasts and osteoclasts in vivo, especially during bone adaptation. In this study, we investigated bone adaptation in mice following two weeks of tibial compression (peak magnitude 3 N or 7 N). To induce decreased sensory nerve function, mice were treated with capsaicin as neonates. We hypothesized that decreased sensory nerve function would diminish the adaptation of bone to mechanical loading, assessed with μCT and dynamic histomorphometry. We found that tibial compression induced significant changes in cortical microarchitecture that depended on compression magnitude and location along the length of the tibia; in contrast, there was no effect of loading on trabecular bone of the tibial metaphysis. Tibial compression significantly increased periosteal, and decreased endosteal, bone formation. Contrary to our initial hypothesis, capsaicin-treated mice generally displayed a similar, if not larger, adaptive response to mechanical loading, including greater increases in bone mineral content and mineral apposition rate. To integrate mechanical loading of bone with sensory nerve activation, we examined whether concentration of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) in bone were affected following 1 or 5 days of 5 N tibial compression or hindlimb unloading. We found that 1 day of tibial compression significantly increased CGRP concentrations in bone, and hindlimb unloading also exhibited a trend toward increased CGRP in bone. These results may suggest a role of sensory nerves in the bone adaptation response to the mechanical environment, though this remains unclear.


Acetyl Group Migration in Xylan and Glucan Model Compounds as Studied by Experimental and Computational Methods.
It was recently demonstrated by us that acetyl groups in oligosaccharides can migrate not only within one saccharide unit but also between two different saccharide units. Kinetics of this phenomenon were previously investigated in both mannan model compounds and a naturally occurring polysaccharide. In addition to mannans, there are also several other naturally acetylated polysaccharides, such as xyloglucans and xylans. Both xyloglucans and xylans are some of the most common acetylated polysaccharides in nature, displaying important roles in the plant cells. Considering the various biological roles of natural polysaccharides, it could be hypothesized that the intramolecular migration of acetyl groups might also be associated with regulation of the biological activity of polysaccharides in nature. Consequently, a better understanding of the overall migration phenomenon across the glycosidic bonds could help to understand the potential role of such migrations in the context of the biological activity of polysaccharides. Here, we present a detailed investigation on acetyl group migration in the synthesized xylan and glucan trisaccharide model compounds by a combination of experimental and computational methods, showing that the migration between the saccharide units proceeds from a secondary hydroxyl group of one saccharide unit toward a primary hydroxyl group of the other unit.


The Differential Impact of Retirement on Informal Caregiving, Volunteering, and Grandparenting: Results of a 3-Year Panel Study.
Research on retirees' engagement in informal caregiving, formal volunteering, and grandparenting often views retirement as a permanent exit from the workforce. Retirement processes are, however, increasingly diverse: some retire fully while others remain in paid work after retirement from a career job. A relevant but understudied question is how these different retirement processes relate to changes in engagement in unpaid productive activities. Building on role theory, we hypothesize that full and working retirees face different consequences of retirement and, therefore, differ in engagement in unpaid productive activities. We analyze data that were collected in 2015 and 2018 among 4,882 Dutch individuals aged 60-65 and employed at baseline. Around half had fully retired at follow-up and 10% worked after their retirement. At follow-up, more respondents are regularly volunteering (from 17% to 27%) and grandparenting (from 39% to 53%) than at baseline, while caregiving remains rather stable (from 33% to 30%). Conditional change models show that full retirement is associated with an increased likelihood of volunteering and grandparenting, but not caregiving. Engagement in postretirement work is related to an increased likelihood of looking after the grandchildren, but not to volunteering or providing informal care. Our findings suggest that volunteering is important for replacing weak ties after full retirement, while grandparenting might be a new, central role in retirement-irrespective of work engagement. Retirees seem to engage in unpaid productive activities for different reasons.


Faecal glucocorticoid metabolites as a measure of adrenocortical activity in polar bears (Ursus maritimus).
Analysis of faecal glucocorticoid metabolites (FGMs) is frequently applied to assess adrenocortical activity in animal conservation and welfare studies. Faecal sample collection is non-invasive and feasible under field conditions. FGM levels are also less prone to circadian rhythms, episodic fluctuations and short acute stressors than glucocorticoid (GC) levels obtained from other matrices, for example blood or saliva. To investigate the suitability of FGM measurement in polar bears (Ursus maritimus), a species listed as Vulnerable by the IUCN (International Union for Conservation of Nature), a cortisol enzyme immunoassay (EIA) was biologically validated by demonstrating a significant increase in FGMs after five zoo-to-zoo transports. In addition to validating the method, the study also documented an average delay of 7 h until the first occurrence of food colorants in the monitored polar bears, which provides essential information for future studies. After validation, the assay was applied to measure FGM concentrations of five polar bears over a 1-year period. Several pre-defined potentially stressful events were recorded in an event log to measure their effect on FGM concentrations. A mixed model analysis revealed significant increases in FGM concentrations after social tension and environmental changes, whereas season and sex had no significant effect. The study demonstrates that the applied cortisol EIA is suitable for measuring FGM levels in polar bears and that using a carefully validated assay for FGM analysis in combination with a detailed sampling protocol can serve as a valuable tool for evaluating mid- to long-term stress in polar bears. FGM levels can be used to monitor stress in captive polar bears in order to optimize housing conditions but also to elucidate stress responses in wild populations for targeted conservation measures.


Can acquired immunodeficiency syndrome and Creutzfeldt-Jakob disease be transmitted via otologic homografts?
Materials commonly employed in the preparation of otologic homografts such as ethanol and formaldehyde are effective in vitro in inactivating human immunodeficiency virus (HIV). However, to our knowledge, the complete permeation of homograft materials with preservative has not been demonstrated. Ethanol and formaldehyde have not been shown to be effective in inactivating the Creutzfeldt-Jakob agent. The literature on sterilization procedures for these agents is reviewed. Standard procedures for preparation of otologic homografts are examined. It is recommended that donor HIV serologic status be determined when otologic homografts must be used. Further research is required to determine the efficacy of otologic homograft sterilization techniques against HIV and Creutzfeldt-Jakob disease.


A novel mechanism for the transcriptional regulation of Wnt signaling in development.
Axial patterning of the embryonic brain requires a precise balance between canonical Wnt signaling, which dorsalizes the nervous system, and Sonic hedgehog (Shh), which ventralizes it. The ventral anterior homeobox (Vax) transcription factors are induced by Shh and ventralize the forebrain through a mechanism that is poorly understood. We therefore sought to delineate direct Vax target genes. Among these, we identify an extraordinarily conserved intronic region within the gene encoding Tcf7l2, a key mediator of canonical Wnt signaling. This region functions as a Vax2-activated internal promoter that drives the expression of dnTcf7l2, a truncated Tcf7l2 isoform that cannot bind β-catenin and that therefore acts as a potent dominant-negative Wnt antagonist. Vax2 concomitantly activates the expression of additional Wnt antagonists that cooperate with dnTcf7l2. Specific elimination of dnTcf7l2 in Xenopus results in headless embryos, a phenotype consistent with a fundamental role for this regulator in forebrain development.


Study of the time-varying cortical connectivity changes during the attempt of foot movements by spinal cord injured and healthy subjects.
In this study we estimated time-varying cortical connectivity patterns from a group of Spinal Cord Injured (SCI) patients during the attempt to move a paralyzed limb. These data were compared with the time-varying connectivity patterns estimated in a control group during the real execution of the movement by using time-varying Partial Directed Coherence. Connectivity was estimated from high resolution EEG recordings with the use of realistic head modelling and the linear inverse estimation of the cortical activity in a series of Regions of Interest of the cortex (ROIs). The experimental evidences obtained support the conclusion that the SCI population involved a larger cortical network than those generated by the healthy subjects during the task performance. Such network differs for the involvement of the parietal cortices, which increases in strength near to the movement imagination onset for the SCI when compared to the normal population. Such details about the temporal evolution of the connectivity patterns cannot be obtained with the application of the standard estimators of connectivity.


Protection against ozone-induced pulmonary inflammation and cell death by endotoxin pretreatment in mice: role of HO-1.
Ozone is a ubiquitous air pollutant that can cause acute pulmonary inflammation and cell injury and may contribute to the exacerbation of chronic pulmonary diseases. The molecular mechanisms of ozone-induced cell injury, as well as protective mechanisms against ozone-injury, are not well understood. Since ozone is a reactive oxidant, and heme oxygenase-1 (HO-1) is an antioxidant enzyme induced by many oxidative stimuli, we hypothesized that HO-1 is one of the protective mechanisms against ozone-induced cell injury, as well as pulmonary inflammation. In the current study, C57Bl/6 mice were pretreated with a low level of endotoxin (lipopolysaccharide, LPS) (0.5 mg/kg) to induce HO-1, and 16 h later were exposed to 1 ppm ozone for 3 h. Endotoxin pretreatment caused a significant protection against ozone-induced pulmonary inflammation and cell injury in bronchoalveolar lavage (BAL) cells. The protection by endotoxin pretreatment against ozone-induced inflammation and necrosis in BAL cells was abolished by the cotreatment with a heme oxygenase inhibitor, tin protoporphyrin IX dichloride (SnPP), suggesting that HO-1 is responsible for the protection against ozone-induced pulmonary inflammation and BAL cell necrosis. Therefore, since HO-1 is induced following ozone exposure, HO-1 may contribute to the development of cellular adaptation to chronic ozone exposure.


Variation in incidences of tuberculosis in subgroups of South African gold miners.
To determine risk factors and to identify groups at high risk of tuberculosis (TB) among South African gold miners. A retrospective cohort analysis was carried out with hospital and personnel databases on a random sample of the workforce of Freegold Mines, served by Ernest Oppenheimer Hospital, Welkom, South Africa. The outcome measure of interest was a reported first episode of TB while employed at Freegold. A person-years analysis was carried out to estimate incidence ratios between different categories of age group, period, cumulative service, mining occupation, and silicosis status. A separate analysis was carried out on a subgroup of men (non-random) whose HIV status was known. The main finding of the study was that TB was more strongly associated with age than expected with a rate ratio of reported incidence of 21 for the oldest age group compared with the youngest, after adjustment for period, cumulative service, occupation, and silicosis status. There was also a significant association between TB and occupations such as drilling with a rate ratio of 2.3 compared with low dust surface and maintenance workers, after adjustment for age, period, cumulative service, and silicosis. Analysis of the HIV tested subgroup showed that these results are unlikely to be the result of confounding due to HIV infection. Prevalence of HIV in this group has been rising sharply since 1991, but the increase was slowing towards the end of the study period. A profile of mineworkers who are at high risk of TB can be defined by age, mining occupation, silicosis status, and HIV infection with predicted rates of 100/1000 person-years. TB screening programmes should take special cognisance of high risk groups of gold miners.


Transport-limited Growth of Coccolith Crystals.
Biogenic crystals present a variety of complex morphologies that form with exquisite fidelity. In the case of the intricate morphologies of coccoliths, calcite crystals produced by marine algae, only a single set of crystallographic facets is utilized. It is unclear which growth process can merge this simple crystallographic habit with the species-specific architectures. Here, we use a suite of state-of-the-art electron microscopies to follow both the growth trajectories of the crystals ex situ, and the cellular environment in situ, in the species Emiliania huxleyi. We show that crystal growth alternates between a space filling and a skeletonized growth mode, where the crystals elongate via their stable crystallographic facets, but the final morphology is a manifestation of growth arrest. This process is reminiscent of the balance between reaction-limited and transport-limited growth regimes underlying snowflake formation. We suggest that localized ion transport regulates the kinetic instabilities that are required for transport-limited growth, leading to reproducible morphologies. This article is protected by copyright. All rights reserved.


Endoprosthetic Reconstruction in Ewing's Sarcoma Patients: A Systematic Review of Postoperative Complications and Functional Outcomes.
Ewing's sarcoma (ES) is a rare primary bone cancer managed by radiotherapy, chemotherapy and surgical resection. The existing literature on limb salvage surgery with endoprostheses combines data for ES patients with osteosarcoma. This review aimed to evaluate surgical and functional outcomes of endoprosthetic reconstruction in exclusively Ewing's patients. We believe that this is the first comprehensive review to evaluate the outcomes of limb salvage surgery with endoprostheses exclusively in Ewing's sarcoma patients. Clinical data and outcomes were collected from PubMed, Embase, Medline and Scopus. The inclusion criteria were studies on limb salvage surgery in ES patients, where individual patient data was available. Seventeen studies with a total of 57 Ewing's patients were included in this review. Fifty-three of the ES patients preserved the limb after limb salvage with endoprostheses. The average five-year implant survivorship was 85.9% based on four studies in this review. Postoperative complications were categorised by Henderson's failure modes. Soft tissue failure was the most common, occurring in 35.1% of patients, followed by deep infection in 15.7% of patients. There was a suggestion of 'good' functional outcomes with limb salvage surgery. The salient limitation of this review is the variability and rarity of the patient population. Homogenous data in a larger population is necessary to provide more insight into outcomes of limb reconstruction in ES.


I-kappa-kinase-2 (IKK-2) inhibition potentiates vincristine cytotoxicity in non-Hodgkin's lymphoma.
IKK-2 is an important regulator of the nuclear factor-κB (NF-κB) which has been implicated in survival, proliferation and apoptosis resistance of lymphoma cells. In this study, we investigated whether inhibition of IKK-2 impacts cell growth or cytotoxicity of selected conventional chemotherapeutic agents in non-Hodgkin's lymphoma.Two established model systems were used; Follicular (WSU-FSCCL) and Diffuse Large Cell (WSU-DLCL2) Lymphoma, both of which constitutively express p-IκB. A novel, selective small molecule inhibitor of IKK-2, ML120B (N-[6-chloro-7-methoxy-9H-β-carbolin-8-yl]-2-methylnicotinamide) was used to perturb NF-κB in lymphoma cells. The growth inhibitory effect of ML120B (M) alone and in combination with cyclophosphamide monohydrate (C), doxorubicin (H) or vincristine (V) was evaluated in vitro using short-term culture assay. We also determined efficacy of the combination in vivo using the SCID mouse xenografts. ML120B down-regulated p-IκBα protein expression in a concentration dependent manner, caused growth inhibition, increased G0/G1 cells, but did not induce apoptosis. There was no significant enhancement of cell kill in the M/C or M/H combination. However, there was strong synergy in the M/V combination where the vincristine concentration can be lowered by a hundred fold in the combination for comparable G2/M arrest and apoptosis. ML120B prevented vincristine-induced nuclear translocation of p65 subunit of NF-κB. In vivo, ML120B was effective by itself and enhanced CHOP anti-tumor activity significantly (P = 0.001) in the WSU-DLCL2-SCID model but did not prevent CNS lymphoma in the WSU-FSCCL-SCID model. For the first time, this study demonstrates that perturbation of IKK-2 by ML120B leads to synergistic enhancement of vincristine cytotoxicity in lymphoma. These results suggest that disruption of the NF-κB pathway is a useful adjunct to cytotoxic chemotherapy in lymphoma.


Robust and thermoplastic hydrogels with surface micro-patterns for highly oriented growth of osteoblasts.
Biocompatible hydrogels with high strength, high precision patterns, and arbitrary 3D shapes are extremely desired soft platforms in the biomedicine fields. On the basis of the thermal-reversible sol-gel transition of agarose and the formation of nanofibers below 35 °C, a robust and thermoplastic hydrogel (TPG) was fabricated by in situ polymerization of acrylamide in the agarose matrix. The tensile fracture stress/strain values of the TPG were unexpectedly higher than those of both agarose and polyacrylamide hydrogels as a result of the double networks reinforced with nanofibers. The TPG could reversibly soften and harden by heating and cooling treatment, respectively, leading to an excellent mechanical recoverability and reprocessing ability. Thus, arbitrary 3D-shaped hydrogels and micro-patterns embossed on the TPG surface with a high resolution of 1 μm were constructed. The rigid TPG exhibited a remarkable affinity for the adhesion and proliferation of cells. In particular, the TPGs with microgrooves could highly guide the oriented growth of osteoblasts, showing potential applications in the field of tissue engineering.


Health-related quality of life in patients with extremity bone sarcoma after surgical treatment: a systematic review.
We conducted a systematic review of studies reporting on measurement of health-related quality of life (HRQoL), with a special focus on the use of the preference-weighted instruments, in patients with extremity bone sarcoma treated with limb-salvage surgery or amputation. We searched MedLine, Embase, Cochrane Library and Web of Science for English-language studies reporting on HRQoL of patients with bone sarcoma from inception to 28 August 2023. All records found were independently reviewed by two reviewers. We used the Newcastle-Ottawa Scale (NOS) and the CONSORT 2010 checklist to assess the quality of the cohort and randomised studies, respectively. The search identified 1225 records, of which 16 studies were included for data extraction. Only one study used a preference-weighted instrument for measuring HRQoL in a small sample of patients (n = 28). Ten studies used the generic SF-36 questionnaire, but no preference-weighted HRQoL based on SF-6D was derived from the SF-36 scores. Most studies comparing HRQoL between amputation and limb-salvage surgery reported no significant differences. Twelve cohort studies scored six or more out of nine points based on the NOS. The only randomised study scored 54% on the CONSORT 2010 checklist. The approaches used to measure HRQoL were inconsistent and outcome scores varied substantially. Only one study used preference-weighted instruments for HRQoL measurement. Future research into the surgical treatment of extremity bone sarcoma should consider the use of preference-weighted instruments to measure HRQoL, which will therefore enable economic evaluation for the growing orthopaedic armamentarium of novel surgical interventions. This systematic review was registered with the PROSPERO International prospective register of systematic reviews (CRD42021282380).


Demonstration of tunable optical delay lines based on apodized grating waveguides.
High-speed and tunable integrated optical delay lines are demonstrated based on silicon grating waveguides apodized by the super-Gaussian function. The submicron channel waveguides with inward-apodized gratings are fabricated by deep-ultraviolet optical lithography. Characterization of the compact delay lines shows that they offer true-time delays as long as 132 ps, tuning range of ~86 ps, and a minimum bit rate of ~13 Gb/s. For lower bit rates, delays as high as 220 ps and tuning range of 174 ps are feasible.


Knowledge, attitude and practice of oral and dental healthcare in pregnant women.
Pregnant women are more susceptible to periodontal disease like gingivitis. Periodontal disease may be associated with adverse pregnancy outcomes. There is no published literature on dental health in pregnant women in Brunei, Darussalam. The objective of this study was to assess women's knowledge and attitude towards oral and dental health during pregnancy and to examine their self-care practices in relation to oral and dental health. This study was carried out at the maternal child health clinic, Jubli Perak Sengkurong Health Centre, Brunei, Darussalam. This was a cross-sectional descriptive and analytical study conducted at the maternal child health center in Brunei, Darussalam. The study group was comprised of 95 pregnant women attending the MCH clinic, Jubli Perak Sengkurong Health Centre, September 2010, using convenience sampling method. A self-administered questionnaire was used, after it was pre-tested and validated. Statistical analysis was done using SPSS version16. Of the total study group, 97.9% responded to the questionnaire and participated in the study. All the women brushed at least twice daily. However, only 40.9% flossed daily, 31.2% brushed after meals and 26.9% had a dental check-up at least twice a year. The knowledge related to dental care was also poor among the pregnant women. Though the majority of them (96.8%) agreed that women should have a dental check-up during pregnancy, only 55.9% actually practiced this. This raises serious concern since pregnant women may need extra oral and dental care due to susceptibility to gum diseases during pregnancy, which may contribute to low birth weight babies and premature births. This study highlights important gaps in dental knowledge and practices related to oral and dental healthcare among pregnant women in Brunei, Darussalam. More intense dental health education, including oral health promotion in maternal child health centers can lead to improved oral and dental health, and ultimately pregnancy outcomes.


Lymphoma in inflammatory bowel disease.
Nine patients with lymphoma occurring in association with inflammatory bowel disease were admitted to The Mount Sinai Hospital between 1960 and 1983. Five (two men and three women) occurred among 1156 patients (0.43%) with ulcerative colitis (UC) and four (men), among 1480 patients (0.27%) with Crohn's disease (CD), a strong male preponderance in the latter group. In all four of the patients with CD and in four of the five patients with UC, the lymphomas were extraintestinal. The mean age of onset of UC in these patients was late (46 years, 19 years older than in our overall series), with lymphomas occurring a mean of only 12 years later. By contrast, patients with CD had bowel disease much younger (mean age, 26 years), and their lymphomas appeared after a longer disease duration (mean, 24 years). The risk factors for the one patient with colonic lymphoma were similar to those with colitis-associated colorectal carcinoma: extensive and long-standing colitis and relatively young age when malignant disease developed. Four of the patients with lymphoma had associated colonic carcinoma; in three of them, the carcinoma appeared within the first decade of colitis, an unusual occurrence. A second malignant lesion also occurred in three patients with UC.


Atrial Fibrillation Detection via Accelerometer and Gyroscope of a Smartphone.
We present a smartphone-only solution for the detection of atrial fibrillation (AFib), which utilizes the built-in accelerometer and gyroscope sensors [inertial measurement unit, (IMU)] in the detection. Depending on the patient's situation, it is possible to use the developed smartphone application either regularly or occasionally for making a measurement of the subject. The smartphone is placed on the chest of the patient who is adviced to lay down and perform a noninvasive recording, while no external sensors are needed. After that, the application determines whether the patient suffers from AFib or not. The presented method has high potential to detect paroxysmal ("silent") AFib from large masses. In this paper, we present the preprocessing, feature extraction, feature analysis, and classification results of the envisioned AFib detection system based on clinical data acquired with a standard mobile phone equipped with Google Android OS. Test data was gathered from 16 AFib patients (validated against ECG), as well as a control group of 23 healthy individuals with no diagnosed heart diseases. We obtained an accuracy of 97.4% in AFib versus healthy classification (a sensitivity of 93.8% and a specificity of 100%). Due to the wide availability of smart devices/sensors with embedded IMU, the proposed methods could potentially also scale to other domains such as embedded body-sensor networks.


Congenital disorders of the function of polymorphonuclear neutrophils.
This review has concentrated on clinical syndromes for which a congenital basis of polymorphonuclear neutrophil dysfunction has been identified. The first clinical syndrome found to be associated with dysfunctional polymorphs was chronic granulomatous disease of childhood. Identification of a cellular defect in oxidative metabolism and microbicidal activity of polymorphonuclear neutrophils from patients with CGD stimulated intense investigation of the function of phagocytes in several clinical entities characterized by increased susceptibility to infection. Other diseases with a probable congenital basis for polymorph dysfunction include Chediak-Higashi syndrome, myeloperoxidase deficiency, severe glucose-6-phosphate dehydrogenase deficiency, and Down's syndrome. Functional defects have also been identified in neutrophils with morphologic abnormalities, such as the Pelger-Huet anomaly and the May-Hegglin anomaly, and in neutrophils without alkaline phosphatase or with a disorder of the glutathione system. The evidence for a relation between these cellular disorders and susceptibility to infection is tentative. Patients with congenital disorders of polymorphonuclear neutrophil microbicidal function frequently suffer prolonged infections in spite of appropriate antimicrobial therapy, and severe lesions recur with discouraging frequency. These lesions are usually soft tissue or bone abscesses, and the etiologic agents are typically staphylococci, gram-negative enteric species, or fungi. The infectious disease problems of patients with phagocytic cell disorders are usually quite distinct from the problems of patients without immunoglobulins or with complement deficiency. Patients with agammaglobulinemia, for example, suffer recurrent septicemia or meningitis due to Streptococcus pneumonia or H. influenzae. Septicemia, especially with the pyogenic bacterial species, is unusual in patients with polymorphoinuclear dysfunction. A major contribution of the currently intense investigation of cells from patients with congenital disorders of phagocyte function has been the greatly increased understanding of the molecular events necessary for the normal function of these cells. The role of the oxidative metabolic burst during phagocytosis has been clearly identified as essential to the microbicidal function of polymorphs and monocytes, and the glutathione system has been identified as essential to the regulation of these oxidative reactions. It is anticipated that these studies may lead to practical methods for "stimulating the phagocytes" in patients with increased susceptibility to infection.


Compact Point-of-Care Device for Self-Administered HIV Viral Load Tests from Whole Blood.
Human immunodeficiency virus (HIV) is a significant problem to consider as it can lead to acquired immune deficiency syndrome (AIDS). Fortunately, AIDS is manageable through antiretroviral therapy (ART). However, frequent viral load monitoring is needed to monitor the effectiveness of the therapy. The current reverse transcription-polymerase chain reaction (RT-PCR) viral load monitoring is highly effective, but is challenged by being resource-intensive and inaccessible, and its turnaround time does not meet demand. An unmet need exists for an affordable, rapid, and user-friendly point-of-care device that could revolutionize and ensure therapeutic effectiveness, particularly in resource-limited settings. In this work, we explored a point-of-care HIV viral load device to address this need. This device can perform streamlined plasma separation, viral RNA extraction, and real-time reverse transcription loop-mediated isothermal amplification (RT-LAMP) semiquantitative testing in an ultracompact device. We developed an absorption-based membrane plasma separation method suitable for finger-prick blood samples, achieving an efficiency of 80%. We also designed a syringe-based RNA extraction method for on-site plasma processing with a viral recovery efficiency of 86%. We created a portable device with a smartphone interface for real-time semiquantitative RT-LAMP, which is useful for monitoring viral load. The device uses lyophilized reagents, processed with our lyophilization method, which remain stable for 16 weeks. The device can accurately categorize viral load into low, medium, and high categories with 95% accuracy. We believe this point-of-care HIV self-test device, offering convenience and long-term storage, could aid patients in home-based ART treatment monitoring.


Love the way you're teaching us': A purpose-developed clinical communication workshop for first year midwifery students.
Preparing students for communication in clinical healthcare settings can be challenging, particularly given it may be the first time they have considered how and why they communicate. The challenge is to find an effective process for the development of clinical communication skills in a highly content-driven curriculum. The objective of this study was to empower first-year midwifery students to reflect on their experiences of communication to inform and expand their clinical communication by drawing on two distinct disciplines - midwifery and linguistics. This paper reports on the findings of a study that examined the implementation of innovative, preparatory workshops for first-year midwifery students. Data from quantitative and qualitative surveys were collected pre- and post-workshop, and post-clinical placement, and analysed using linguistic mapping and thematic analysis. Perceptible shifts in self-evaluation of competence were noted post the workshop and clinical placement. Students developed and used metalanguage appropriately to describe and evaluate communication while demonstrating increased awareness of the complexity of professional communication. They were able to find a balance between the vital technical information, and the interpersonal aspects of communication. This impacted positively on their perception of women as partners.


Application of model-free analysis in the MR assessment of pulmonary perfusion dynamics.
Dynamic contrast-enhanced (DCE) MRI has been used to quantitatively evaluate pulmonary perfusion based on the assumption of a gamma-variate function and an arterial input function (AIF) for deconvolution. However, these assumptions may be too simplistic and may not be valid in pathological conditions, especially in patients with complex inflow patterns (such as in congenital heart disease). Exploratory data analysis methods make minimal assumptions on the data and could overcome these pitfalls. In this work, two temporal clustering methods--Kohonen clustering network (KCN) and Fuzzy C-Means (FCM)--were concatenated to identify pixel time-course patterns. The results from seven normal volunteers show that this technique is superior for discriminating vessels and compartments in the pulmonary circulation. Patient studies with five cases of acquired or congenital pulmonary perfusion disorders demonstrate that pathologies can be highlighted in a concise map that combines information of the mean transit time (MTT) and pulmonary blood volume (PBV). The method was found to provide greater insight into the perfusion dynamics that might be overlooked by current model-based analyses, and may serve as a basis for optimal hemodynamic quantitative modeling of the interrogated perfusion compartments.


Significant Liver Atrophy Due to Vascular Compromise Associated With Adult Congenital Diaphragmatic Hernia.
Diaphragmatic hernia in adults is mostly post-traumatic in origin, and rarely congenital. In both situations, the right side is less commonly involved due to the protection offered by the liver and earlier closure of the right pleuroperitoneal canal. A congenital diaphragmatic hernia may present in adulthood with multi-visceral contents, of which the liver is an extremely rare content, mentioned only in a few previous reports. A herniated liver may mimic a pulmonary tumor and may be completely atrophic due to sustained compression of the venous outflow. Careful operative planning is essential to identify and reduce the liver, along with other contents. We are reporting two adults with a congenital diaphragmatic hernia, with multi-visceral contents and an atrophied liver. The first patient was a 28-year-old man with a remote history of trauma found to have a large right diaphragmatic hernia on imaging. The right liver was completely atrophied due to right hepatic venous compression, while the left liver underwent massive hypertrophy and rotation of the left portal axis. Exploratory laparotomy and reduction of contents, along with mesh repair, were accomplished with satisfactory results. The second patient was a 26-year-old man with Down's syndrome detected to have multiple bowel loops in the right thorax on imaging. At laparoscopy, a Larrey's type of Morgagni hernia with a right paramedian defect was found. The left liver was atrophied into a leaf-like appendage due to possible portal obliteration and was dissected away from the diaphragm edge. Appropriate mesh repair was completed by a minimally invasive technique.


Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes.
Growing evidence suggests that interleukin-6 (IL-6) may play a pathogenetic role in postmenopausal bone loss and in other age-related pathological conditions. In this study, we have examined the age-related changes in the serum levels of IL-6 and the soluble receptors that modulate its biological activity--soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130)--in 220 women (from 25 to 104yr old), including 22 centenarians. Serum IL-6 rose exponentially with age (r=0.74, p<0.0001). The median level of IL-6 increased almost ten-fold with age, from 1.16pg/ml in premenopausal women to 10.27pg/ml in centenarians. Serum sIL-6R and sgp130 showed an increase until the seventh decade and a progressive decrease in older ages (r=0.39, p<0.0001 and r=0.26, p=0.008, respectively). IL-6, sIL-6R and sgp130 were significantly higher in women within 10yr of menopause as compared to premenopausal subjects (1.51 vs. 1.16pg/ml, p=0.012; 41.9 vs. 35.7ng/ml, p=0.002; and 253.4 vs. 230.7ng/ml, p=0.008, respectively). In postmenopausal women, a negative correlation was found between sIL-6R and the lumbar bone mineral density (BMD) (r=-0.28, p=0.002) even after adjusting for age and weight. Furthermore, sIL-6R levels were higher in osteoporotic compared to normal women (47.9 vs. 39.5ng/ml, p=0.001). In conclusion, our results show that the serum levels of IL-6, sIL-6R and sgp130 exhibit different patterns of age- and menopause-related changes, and that the biological activity of IL-6 may be increased with age with potential implications in the age-related diseases such as osteoporosis.


Surface characteristics of resin composite materials after finishing and polishing.
This in vitro study determined the surface roughness (Ra) and absolute gloss (AG) values for 2 resin composites: a microhybrid and a microfill. Eight groups (n = 4) of each resin composite were prepared, along with 4 controls (Mylar strip) for the 2 resin composites. After finishing with a medium polishing disc, the specimens from each resin composite material were subjected to 7 polishing procedures, and Ra measurements and AG values were determined. Two-way ANOVA and Fisher's LSD multiple comparisons revealed significant differences (P ≤ 0.05). For both materials, the control group produced the lowest Ra values and highest AG values, and the medium polishing disc produced the highest Ra values and lowest AG values. Of the 2 resin composites, the microhybrid had lower mean Ra and higher mean AG than the microfill for the majority of the polishing procedures. Pearson's r correlation coefficient (P ≤ 0.001) indicated an inverse linear relationship between Ra and AG.


[Problems in the assortedness of marriages in mental retardation].
The study of the educational and intellectual status of the parents of 402 oligophrenic patients revealed a high degree of marital homogeneity in the parents with regard to their intellectual development as compared to the control group of healthy subjects (419 families). The tendency to intellectual homogeneity was especially high in the parents of patients with undifferentiated forms of oligophrenia. It was also elicited that the educational and intellectual status in the oligophrenic siblings was significantly lower than in the control siblings which may be explained by genetic, cultural and familial factors.


High juvenile mortality is associated with sex-specific adult survival and lifespan in wild roe deer.
Male mammals typically have shorter lifespans than females [1]. Sex differences in survival may result, in part, from sex-specific optima in investment in reproduction, with higher male mortality rates from sexual competition selecting for a "live-fast die-young" strategy in this sex [2]. In the wild, lifespan is also influenced by environmental conditions experienced early in life. Poor conditions elevate juvenile mortality, which may selectively remove individuals with a particular phenotype or genotype from a cohort [3], and can alter the subsequent phenotypic condition and fate of those that survive to adulthood [4]. Males and females can respond differently to the same early-life environmental experiences [5, 6], but whether such environmental pressures generate sex differences in lifespan has rarely been considered. We show that sex differences in adult survival and lifespan in cohorts of roe deer (Capreolus capreolus) range from virtually absent in some years to females living 30% longer than males in others. The extent of this sex difference in adult longevity is strongly linked to the level of mortality each cohort experiences as juveniles, with high juvenile mortality generating a strong sex difference in both adult survival and lifespan. In females, high juvenile mortality leads to increased adult survival for those remaining individuals, whereas in males survival is actually reduced. Early environmental conditions and the selective pressures they impose may help to explain variability in sex-specific aging across animal taxa.


A review of public health regulations on lead.
A review of public health regulations pertaining to lead exposure is the subject of this paper. Although lead had been used for centuries in the fabrication of a host of products, it was not until the mid-nineteenth century that the clinical pattern of lead poisoning was described in the medical literature. With this recognition gradually came government health regulations designed to limit human exposure to lead from occupational and environmental sources. The British, in particular, developed during the period 1890 to 1920 comprehensive rules and regulations pertaining to occupational lead exposures. The development and imposition of U.S. health regulations occurred later in the twentieth century; federal regulations not generally appearing until the 1970's. At present, several U.S. government agencies have promulgated regulations intended to prevent lead poisoning from paint; limit lead in ambient air, drinking water, workplace environments and consumer products; and reduce lead in fuels and fuel additives used in motor vehicles. These regulations are reviewed in terms of their extent of coverage. There is evidence, in some instances indirect in nature, that human exposure to lead in U.S. populations has been reduced, though comprehensive data are lacking. The Centers for Disease Control has reported that the mean blood lead level in the U.S. has decreased 36%, paralleling a reduction in the lead content of gasoline. For occupational lead exposure, comprehensive morbidity data do not exist, but an evaluation of NIOSH health hazard evaluations (HHE's) specific to lead show a gradual reduction since 1977 in the percentage of HHE's for which airborne lead exceeded 0.20 mg/m3, which at one time had been the federal standard for occupational lead exposure, prior to reduction of the U.S. standard to 0.05 mg/m3.


Brief report: adaptive behavior and cognitive skills for toddlers on the autism spectrum.
This study examined adaptive behavior and cognitive skills for 125 toddlers on the autism spectrum using the recently updated Vineland-II and Bayley-III. Delays in adaptive skills were apparent at 2 years of age. As a group, toddlers on the autism spectrum had a profile of Vineland-II standard scores in which Motor Skills > Daily Living Skills > Socialization > Communication. Vineland-II scores were significantly correlated with Bayley-III Cognitive scores. Performance on the ADOS was significantly negatively correlated with Bayley-III Cognitive standard scores and standard scores in the Daily Living Skills and Communication domains of the Vineland-II. However, calibrated ADOS scores did not contribute significant variance to Vineland-II scores beyond that predicted by age and Bayley-III scores.


Apoptosis (programmed cell death) and the evaluation of chemosensitivity in chronic lymphocytic leukemia and lymphoma.
Chronic lymphocytic leukemia and lymphoma cells were treated with antitumor drugs in vitro and analyzed by flow cytometry to measure the number of apoptotic (AP) cells and DNA damage in the cells that escaped apoptotic death. AP cells were identified by a high sensitivity of DNA to thermal denaturation, which induced binding of antibody to single-stranded DNA, and by decreased stainability of cells with the intercalating DNA dye propidium iodide. The appearance of AP cells was prevented by Zn++ and inhibited by phorbol ester. AP cells were induced by alkylating agents, antimetabolites, and anthracyclines. A linear relationship between L-phenylalanine mustard dose and the number of AP cells was observed. A synergistic interaction between drugs was detected by an increased number of AP cells and by the intensity of DNA damage in non-apoptotic cells. A most interesting example of synergism was the combination of alkylating agents with fludarabine. Linearity of dose-response curves, and the capability to detect drug synergism and to evaluate variable response of cells from different patients to single agents and combinations suggest that flow cytometry of apoptosis will provide a basis for chemosensitivity tests in leukemia and lymphoma.


Evaluation of Long-Term Nutrition Outcomes After Duodenal Switch: A Systematic Review and Meta-Analysis.
Biliopancreatic diversion with duodenal switch (BPD-DS) is the most effective and durable metabolic and bariatric surgery to achieve a target weight loss. However, many surgeons are hesitant to adopt BPD-DS due to a lack of training, technical complexity, and long-term nutrition deficiencies. This meta-analysis aimed to investigate long-term nutrition outcomes after primary BPD-DS in the management of obesity. Cochrane, Embase, PubMed, Scopus, and Web of Science were searched for articles from their inception to February 2023 by 2 independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) system. The review was registered prospectively with PROSPERO (CRD42023391316). From 834 studies screened, 8 studies met the eligibility criteria, with a total of 3443 patients with obesity undergoing primary BPD-DS. At long-term follow-up (≥5 years), 25.4% of patients had vitamin A deficiency (95% CI: -.012, .520, I2 = 94%), and 57.3% had vitamin D deficiency (95% CI: .059, 1.086, I2 = 86%). Calcium deficiency was observed in 125 patients (22.2%, 95% CI: .061, .383, I2 = 97%), and 69.7% had an abnormal parathyroid hormone level (95% CI: .548, .847, I2 = 78%). Ferritin level was abnormal in 30 patients (29.0%, 95% CI: .099, .481, I2 = 79%). Despite displaying comparable nutrition-related outcomes to mid-term follow-up, our study demonstrated that BPD-DS could result in a high level of long-term nutrition deficiency after BPD-DS for selected patients. However, further randomized controlled studies with standardized supplementation regimens and improvement in compliance are necessary to evaluate and prevent long-term nutritional deficiencies after BPD-DS.


Increased basic fibroblast growth factor levels in serum and blister fluid from patients with vitiligo.
Basic fibroblast growth factor (bFGF) is a pleiotropic growth factor which has a high capacity for stimulating normal melanocyte proliferation and suppressing melanogenesis. The close and complicated relationship between bFGF, melanocyte proliferation and melanogenesis raises the theoretical possibility that bFGF may also be involved in the pathomechanism leading to vitiligo. The aim of this study was to compare the serum and suction blister fluid bFGF levels of vitiligo patients (9 females, 11 males) with those of healthy controls (3 females, 8 males). Vitiliginous skin-blister fluid bFGF levels and serum levels were significantly higher in vitiligo patients compared with healthy normal controls. Our data indicate that bFGF might be involved in the pathogenetic chain of events leading to vitiligo. Further studies are needed to define the exact role of bFGF and various other melanocytic mitogens in this disease.


[Cardiac resynchronization therapy with defibrillation capability: considerations on a not yet proven therapeutic superiority].
Cardiac resynchronization therapy (CRT) has proven a very useful tool to treat heart failure (HF). In HF patients with severely depressed left ventricular dysfunction and ventricular dyssynchrony who remain symptomatic despite optimal medical therapy, the "reverse remodeling" induced by CRT leads to a significant improvement of survival and quality of life. The addition of the cardioversion-defibrillation function to CRT (CRT-D) is considered a further beneficial effect to reduce overall mortality secondary to a decrease in sudden death rate. Unfortunately, the amount of this additional benefit is still uncertain; in particular, how much the cardioversion-defibrillation function contributes to prolong patient survival remains to be elucidated. Such uncertainty leads to a different therapeutic approach to HF patients, i.e., an extended or restricted use of CRT-D devices. Even the most recent guidelines do not provide a clear answer to this question. The present review summarizes the current evidence regarding efficacy, effectiveness, safety, and cost-effectiveness of CRT and CRT-D, and suggests some practical solutions to the appropriate use of CRT-D on the basis of clinical, ethical and socio-economic considerations.


Flavonoids in the poisonous plant Oxytropis falcata.
Three new flavonoids, oxytropisoflavans A (1) and B (2) and (6aR,11aR)-3,8-dihydroxy-9,10-dimethoxypterocarpan (3), together with 30 known flavonoids (4-33), were isolated from the aerial parts and roots of Oxytropis falcata. The absolute configurations of 3 and C-3 in 1 and 2 were deduced by circular dichroism. The structure of flavonoid 2 was confirmed by single-crystal X-ray diffraction analysis and that of flavonoid 3 by total synthesis of its racemate. Oxytropisoflavan A (1) is an unprecedented chalcan-isoflavan biflavonoid, whereas oxytropisoflavan B (2) possesses a rare modified A-ring. Pterocarpan 3 has good radical-scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay.


Asthma, type 1 and type 2 diabetes mellitus, and inflammatory bowel disease amongst South Asian immigrants to Canada and their children: a population-based cohort study.
There is a high and rising rate of immune-mediated diseases in the Western world. Immigrants from South Asia have been reported to be at higher risk upon arrival to the West. We determined the risk of immune-mediated diseases in South Asian and other immigrants to Ontario, Canada, and their Ontario-born children. Population-based cohorts of patients with asthma, type 1 diabetes (T1DM), type 2 diabetes (T2DM), and inflammatory bowel disease (IBD) were derived from health administrative data. We determined the standardized incidence, and the adjusted risk of these diseases in immigrants from South Asia, immigrants from other regions, compared with non-immigrant residents of Ontario. The risk of these diseases in the Ontario-born children of immigrants were compared to the children of non-immigrants. Compared to non-immigrants, adults from South Asia had higher risk of asthma (IRR 1.56, 95%CI 1.51-1.61) and T2DM (IRR 2.59, 95%CI 2.53-2.65). Adults from South Asia had lower incidence of IBD than non-immigrants (IRR 0.32, 95%CI 0.22-0.49), as did immigrants from other regions (IRR 0.29, 95%CI 0.20-0.42). Compared to non-immigrant children, the incidence of asthma (IRR 0.66, 95%CI 0.62-0.71) and IBD (IRR 0.47, 95%CI 0.33-0.67) was low amongst immigrant children from South Asia. However, the risk in Ontario-born children of South Asian immigrants relative to the children of non-immigrants was higher for asthma (IRR 1.75, 95%CI 1.69-1.81) and less attenuated for IBD (IRR 0.90, 95%CI 0.65-1.22). Early-life environmental exposures may trigger a genetic predisposition to the development of asthma and IBD in South Asian immigrants and their Canada-born children.


Linking family cohesion and flexibility with expressed emotion, family burden and psychological distress in caregivers of patients with psychosis: A path analytic model.
The present study aimed to evaluate a path analytic model accounting for caregivers' psychological distress that takes into account perceived family cohesion and flexibility, expressed emotion and caregiver's burden associated with the presence of mental illness in the family. 50 first-episode and 50 chronic patients diagnosed with schizophrenia or bipolar disorder (most recent episode manic severe with psychotic features) recruited from the Inpatient Psychiatric Unit of the University Hospital of Heraklion, Crete, Greece, and their family caregivers participated in the study. Family functioning was assessed in terms of cohesion and flexibility (FACES-IV), expressed emotion (FQ), family burden (FBS) and caregivers' psychological distress (GHQ-28). Structural equation modelling was used to evaluate the direct and indirect effects of family dynamics on caregivers' psychological distress. The results showed that neither family cohesion nor family flexibility exerted significant direct effects on caregivers' psychological distress. Instead, the effect of flexibility was mediated by caregivers' criticism and family burden indicating an indirect effect on caregivers' psychological distress. These results apply equally to caregivers of first episode and chronic patients. Family interventions aiming to improve dysfunctional family interactions by promoting awareness of family dynamics could reduce the burden and improve the emotional well-being of family caregivers.


Type 1 diabetes.
Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.


Selection on Polemonium brandegeei (Polemoniaceae) flowers under hummingbird pollination: in opposition, parallel, or independent of selection by hawkmoths?
Particular floral phenotypes are often associated with specific groups of pollinators. However, flowering plants are often visited, and may be effectively pollinated by more than one type of animal. Therefore, a major outstanding question in floral biology asks: what is the nature of selection on floral traits when pollinators are diverse? This study examined how hummingbirds selected on the floral traits of Polemonium brandegeei, a species pollinated by both hummingbirds and hawkmoths. In array populations of P. brandegeei, we measured pollen movement, and female (seeds set) and male (seeds sired) fitness under hummingbird pollination. We then compared the patterns of selection by hummingbirds with our previous study examining selection by hawkmoths. We documented contrasting selection on sex organ positioning through female function, with hummingbirds selecting for stigmas exserted beyond the anthers and hawkmoths selecting for stigmas recessed below the anthers. Furthermore, hummingbirds selected for longer and wider corolla tubes, and hawkmoths selected for narrower corolla tubes. Therefore, contrasting selection by hawkmoths and hummingbirds may account for variation in sex organ arrangements and corolla dimensions in P. brandegeei. We documented how floral traits under selection by multiple pollinators can result in either an intermediate "compromise" between selective pressures (sex organs) or apparent specialization (corolla tube length) to one pollinator.


[Calcified cerebral embolism as a cause of ischemic stroke].
A 60-year-old woman with a history of hypertension presented with acute onset of left-sided weakness and drowsiness. Non-contrast CT at baseline and follow-up showed a focal high density lesion in the right middle cerebral artery, consistent with a calcified embolus. CT angiography confirmed its location.


ClonEvol: clonal ordering and visualization in cancer sequencing.
Reconstruction of clonal evolution is critical for understanding tumor progression and implementing personalized therapies. This is often done by clustering somatic variants based on their cellular prevalence estimated via bulk tumor sequencing of multiple samples. The clusters, consisting of the clonal marker variants, are then ordered based on their estimated cellular prevalence to reconstruct clonal evolution trees, a process referred to as 'clonal ordering'. However, cellular prevalence estimate is confounded by statistical variability and errors in sequencing/data analysis, and therefore inhibits accurate reconstruction of the clonal evolution. This problem is further complicated by intra- and inter-tumor heterogeneity. Furthermore, the field lacks a comprehensive visualization tool to facilitate the interpretation of complex clonal relationships. To address these challenges we developed ClonEvol, a unified software tool for clonal ordering, visualization, and interpretation. ClonEvol uses a bootstrap resampling technique to estimate the cellular fraction of the clones and probabilistically models the clonal ordering constraints to account for statistical variability. The bootstrapping allows identification of the sample founding- and sub-clones, thus enabling interpretation of clonal seeding. ClonEvol automates the generation of multiple widely used visualizations for reconstructing and interpreting clonal evolution. ClonEvol outperformed three of the state of the art tools (LICHeE, Canopy and PhyloWGS) for clonal evolution inference, showing more robust error tolerance and producing more accurate trees in a simulation. Building upon multiple recent publications that utilized ClonEvol to study metastasis and drug resistance in solid cancers, here we show that ClonEvol rediscovered relapsed subclones in two published acute myeloid leukemia patients. Furthermore, we demonstrated that through noninvasive monitoring ClonEvol recapitulated the emerging subclones throughout metastatic progression observed in the tumors of a published breast cancer patient. ClonEvol has broad applicability for longitudinal monitoring of clonal populations in tumor biopsies, or noninvasively, to guide precision medicine. ClonEvol is written in R and is available at https://github.com/ChrisMaherLab/ClonEvol.