Multi-Disciplinary Expert Perspective on the Management of Type 2 Inflammation-Driven Severe CRSwNP: A Brief Overview of Pathophysiology and Recent Clinical Insights.

Severe chronic rhinosinusitis with nasal polyposis (CRSwNP) is a disabling airway disease that significantly impacts patients' lives through the severity of symptoms, the need for long-term medical treatment and the high risk of recurrence post-surgery. Biological agents targeting type 2 immune responses underlying the pathogenesis of CRSwNP have shown effectiveness in reducing polyp size and eosinophilic infiltrate, and in decreasing the need for additional sinus surgeries. However, despite recent progress in understanding and treating the disease, type 2 inflammation-driven severe CRSwNP continues to pose challenges to clinical management due to several factors such as persistent inflammation, polyp recurrence, heterogeneity of disease, and comorbidities. This article presents the findings of a scientific discussion involving a panel of ear, nose and throat (ENT) specialists and pulmonologists across Sweden and Finland. The discussion aimed to explore current management practices for type 2 inflammation-driven severe CRSwNP in the Nordic region. The main topics examined encompassed screening and referral, measurements of disease control, treatment goals, and future perspectives. The experts emphasized the importance of a collaborative approach in the management of this challenging patient population. The discussion also revealed a need to broaden treatment options for patients with type 2 inflammation-driven CRSwNP and comorbid conditions with shared type 2 pathophysiology. In light of the supporting evidence, a shift in the disease model from the presence of polyps to that of type 2 inflammation may be warranted. Overall, this discussion provides valuable insights for the scientific community and can potentially guide the future management of CRSwNP.

Advances in fixation strength of reorienting rectangular triple pelvic innominate osteotomies - A biomechanical investigation of two screw fixation techniques.

BACKGROUND: Reorientating pelvic osteotomies are performed to prevent femoral-acetabular impingement or degenerative arthritis. A Toennis-Kalchschmidt triple pelvis innominate osteotomy is used in symptomatic patients. This study aimed to investigate the biomechanical behaviour of two different acetabular screw configurations for triple pelvis innominate osteotomy osteosynthesis. METHODS: Two screw-orientation techniques in rectangular os ilium osteotomy were compared by osteotomising 12 artificial hemipelvises with triple pelvis innominate osteotomy protocol (fragment reorientation: 10.5° inclination and 10.0° anteversion) and randomising them in 2 groups (n = 6) for implantation with three 4.5 mm screws. Bidirectional group had a bidirectional screw orientation and Monoaxial group had a monoaxial direction of all three screws through iliac crest. All specimens were tested under progressively increasing cyclic loading until failure. Group-wise comparisons of acetabular cup medialisation, anteversion and inclination were evaluated via motion tracking at cycles 250, 500, 750, 1000, 1250, 1500, 1750, 2000, 2250, and 2500. Failure was defined as reaching 5° inclination or 5° anteversion. FINDINGS: Acetabular cup medialisation (p ≤ 0.026), anteversion (p ≤ 0.021) and inclination (p ≤ 0.039) all increased significantly during testing in both groups. There were no significant differences for the group-wise comparisons at the cycle points defined in the methods (p ≥ 0.182). No significant differences were detected between groups for cycles to failure and failure load (p = 0.873). INTERPRETATION: Bidirectional screw alignment does not lead to significant advantages compared to pure monoaxial if all three axial screws are evenly distributed over the osteotomy geometry. The triple pelvis innominate osteotomy is susceptible to changes in anteversion, inclination and medialisation under partial weight-bearing. Cautious rehabilitation protocols are recommended.

Integrated Analysis of the RASH Study with the Use of the "Burden of Therapy" (BOTh®TM) Methodology-A Novel Tool for Assessing Adverse Events in Metastatic Pancreatic Cancer.

This analysis of the RASH trial (NCT01729481) aimed at gaining a better understanding of the "Burden of Therapy" (BOTh®TM) in pancreatic ductal adenocarcinoma (PDAC). In the RASH study, 150 patients with newly diagnosed metastatic PDAC were treated with gemcitabine plus erlotinib (gem/erlotinib) for four weeks. Patients who developed a skin rash during this four-week run-in phase continued with the gem/erlotinib treatment, while rash-negative patients were switched to FOLFIRINOX. The study demonstrated a 1-year survival rate of rash-positive patients who received gem/erlotinib as first-line treatment that was comparable to previous reports of patients receiving FOLFIRINOX. To understand whether these comparable survival rates may be accompanied by better tolerability of the gem/erlotinib treatment compared to FOLFIRINOX, the BOTh®TM methodology was used to continuously quantify and depict the burden of therapy generated by treatment emergent events (TEAEs). Sensory neuropathy was significantly more common in the FOLFIRINOX arm, and prevalence as well as severity increased over time. In both arms, the BOTh®TM associated with diarrhea decreased over the course of treatment. The BOTh®TM caused by neutropenia was comparable in both arms but decreased in the FOLFIRINOX arm over time, possibly due to chemotherapy dose reductions. Overall, gem/erlotinib was associated with a slightly higher overall BOTh®TM, but the difference was not statistically significant (p = 0.6735). In summary, the BOTh®TM analysis facilitates the evaluation of TEAEs. In patients fit for intense chemotherapeutic regimens, FOLFIRINOX is associated with a lower BOTh®TM than gem/erlotinib.

An investigation of child health in relation to housing renovations for a disadvantaged immigrant population in Malmö, Sweden.

AIMS: The aim of the study was to describe child health in relation to housing renovations in more than 800 rental units, consisting of repairs of dilapidated kitchens and bathrooms, in the disadvantaged neighbourhood of Herrgården in Rosengård, Malmö, Sweden. METHODS: Data on housing conditions and self-reported health were collected during home visits to families living in Herrgården (building renovations area) and a comparison area (neighbouring Törnrosen, with generally better housing conditions). At baseline, 130 families with 359 children participated, while 51 families with 127 children participated at follow-up. All data were collected between 2010 and 2012. Additionally, regional register data on health-care usage/in- and outpatient contacts within the public health-care system between 2008 and 2013 were also collected for all 8715 children registered as living in the two areas. RESULTS: Self-reported health seemed to somewhat improve in both areas, with 74% versus 86% and 78% versus 88% reporting good or very good health in Herrgården and in the comparison area at baseline and follow-up, respectively. In Herrgården, crowdedness increased, while it decreased in the comparison area. The number of health-care contacts remained stable over time in Herrgården, while it decreased in the comparison area. CONCLUSIONS: Partial housing renovations did not seem to result in clear health improvements as measured with the indicators used in the present study. This could possibly be due to persisting health effects due to increased crowdedness or persisting poor housing conditions, as only kitchens and bathrooms were renovated.

Examination of a Structural Preference in Quaternary Alkali-Metal (A) Rare-Earth (R) Copper Tellurides by Combining Experimental and Quantum-chemical Means.

In the quest for materials addressing the grand challenges of the future, there is a critical need for a broad understanding of their electronic structures because the knowledge of the electronic structure of a given solid allows us to recognize its structural preferences and to rationalize its properties. As previous research on quaternary chalcogenides containing active metals (a group-I- or -II-element), early transition-metals, and late transition-metals indicated that such materials could pose as alluring systems in the developments of thermoelectrics, our impetus was stimulated to probe the suitability of tellurides belonging to the prolific A3R4Cu5Te10-family. In doing so, we first used quantum-chemical techniques to explore the electronic and vibrational properties of representatives crystallizing with different A3R4Cu5Te10 structure types. The outcome of these explorations indicated that the aspects that control the formation of a given type of A3R4Cu5Te10 structure are rather subtle so that transitions between different types of A3R4Cu5Te10 structures could be induced by manipulating the ambient conditions. To probe this prediction, we explored the thermal behavior for the example of one quaternary telluride, that is, Rb3Er4Cu5Te10, and thereby identified a new type of A3R4Cu5Te10 structure. Because understanding the structural features of the A3R4Cu5Te10 family plays an important role in the analyses of the aforementioned explorations, we also present an overview about the structural features and the members of this class of quaternary tellurides. In this connection, we also provide a structural report of four tellurides, that is, K3Tb4Cu5Te10 and Rb3R4Cu5Te10 (R = Tb, Dy, Ho), which have been obtained from high-temperature solid-state reactions for the very first time.

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy-Analysis of the Phase 3 XELAVIRI Trial.

INTRODUCTION: Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. METHODS: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. RESULTS: In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965). CONCLUSIONS: Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

Gender-dependent survival benefit from first-line irinotecan in metastatic colorectal cancer. Subgroup analysis of a phase III trial (XELAVIRI-study, AIO-KRK-0110).

BACKGROUND: XELAVIRI compared sequential (Arm A) versus initial (Arm B) irinotecan in combination with fluoropyrimidine plus bevacizumab in patients with metastatic colorectal cancer, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown. The present analysis was performed to evaluate the effect of gender on treatment outcome and tolerability. METHODS: The study end-points overall response rate (ORR), progression-free survival (PFS), TFS and overall survival (OS) were evaluated in female versus male patients and in molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. RESULTS: In total, 281 male and 140 female patients (n = 421) were evaluated. Among the male patients, the ORR was 33.6% without and 58.3% with initial irinotecan (P < 0.001). PFS (hazard ratio [HR] 0.54; 95% confidence interval [CI] 0.42-0.69; P < 0.001) and OS (HR 0.63; 95% CI 0.47-0.85; P = 0.002) were also significantly better with initial irinotecan. Among the female patients, the ORR was 42.7% in Arm A and 43.1% in Arm B, PFS was similar (HR 1.09; 95% CI 0.76-1.55; P = 0.649) without and with initial irinotecan. A strong trend for inferior outcome with regard to OS with initial irinotecan was observed (HR 1.46; 95% CI 0.95-2.24; P = 0.081) and the trend reached significance in the multivariate analysis (HR 1.78; 95% CI 1.08-2.95; P = 0.02). Formal interaction of treatment and gender was observed for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Treatment-related adverse events were not significantly different between male and female patients. CONCLUSIONS: The present analysis suggests that gender interacts with efficacy of initial irinotecan when used in combination with fluoropyrimidines and bevacizumab. Although male patients derived a significant and clinically meaningful benefit from initial combination chemotherapy, this was not observed in female patients.

Impact of age on efficacy and early mortality of initial sequential treatment versus upfront combination chemotherapy in patients with metastatic colorectal cancer: a subgroup analysis of a phase III trial (AIO KRK0110, XELAVIRI study).

INTRODUCTION: The XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial. METHODS: Patients were stratified for age in three cohorts (<65 years, 65-74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing. RESULTS: The efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65-74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63). CONCLUSION: Combination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.

Should Antibiotic-Impregnated Cement Be Used During Primary Total Ankle Arthroplasty (TAA)?

RECOMMENDATION: Unknown. There is insufficient evidence for the routine use of antibiotic-impregnated cement during primary total ankle arthroplasty (TAA). LEVEL OF EVIDENCE: Consensus. DELEGATE VOTE: Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).

Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110).

PURPOSE: The XELAVIRI trial investigated the optimal treatment strategy for patients with untreated metastatic colorectal cancer. We tested the noninferiority of initial treatment with a fluoropyrimidine plus bevacizumab, followed by the addition of irinotecan at first progression (arm A) versus upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B) in a 1:1 randomized, controlled phase III trial. METHODS: The primary efficacy end point was time to failure of the strategy (TFS). Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8. In the case of demonstrated noninferiority of TFS, an analysis of symptomatic toxicities during TFS would define the superior strategy. Secondary end points included the effect of molecular subgroups on efficacy parameters. RESULTS: A total of 421 randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set. Median age was 71 and 69 years, respectively. Noninferiority of TFS was not shown (hazard ratio [HR], 0.86; 90% CI, 0.73 to 1.02). In detail, patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P = .005), whereas patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P = .58) did not (Cox model for interaction of study arm and RAS status: P = .03). Comparable results were obtained for overall survival. CONCLUSION: Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.

High-Q inverted silica microtoroid resonators monolithically integrated into a silicon photonics platform.

We report on the monolithic integration of a new class of reflown silica microtoroid resonators with silicon nanowaveguides fabricated on top of the silica film. Connectivity with other silicon photonics devices is enabled by inversion of the toroid geometry, defined by etching a circular opening rather than a disk in an undercut silica membrane. Intrinsic quality factors of up to 2 million are achieved and several avenues of process improvement are identified that can help attain the higher quality factors (> 108) that are possible in reflown microtoroids. Moreover, due to the microtoroid being formed by standard microfabrication and post-processing by local laser induced heating, these devices are in principle compatible with monolithic co-fabrication with other electro-optic components.

Air-clad suspended nanocrystalline diamond ridge waveguides.

A hybrid group IV ridge waveguide platform is demonstrated, with potential application across the optical spectrum from ultraviolet to the far infrared wavelengths. The waveguides are fabricated by partial etching of sub-micron ridges in a nanocrystalline diamond thin film grown on top of a silicon wafer. To create vertical confinement, the diamond film is locally undercut by exposing the chip to an isotropic fluorine plasma etch via etch holes surrounding the waveguides, resulting in a mechanically stable suspended air-clad waveguide platform. Optical characterization of the waveguides at 1550 nm yields an average optical loss of 4.67 ± 0.47 dB/mm. Further improvement to the fabrication process is expected to significantly reduce this waveguide loss.

High burden of atopy in immigrant families in substandard apartments in Sweden - on the contribution of bad housing to poor health in vulnerable populations.

BACKGROUND: Atopic disorders are a global concern. Studies in migrant populations can illuminate the interplay of genetic and environmental factors. Exposures related to bad housing (indoor dampness, mould growth, crowding etc.) are likely to play a role in how socioeconomic inequalities can turn into health disparities for disadvantaged populations. The sizable immigrant population living in very poor-quality housing in Malmö, Sweden, became the focus of a cross-sectional study. OBJECTIVE: To describe atopic disorders and sensitizations in a population living in substandard housing in Malmö, Sweden, with an emphasis on their relation to harmful exposures from the built environment. METHODS: Families were recruited via identification of any children with symptomatic airway afflictions from health care records, and also asymptomatic children from school lists. Interviewer-led health questionnaire data and data from self-reports about living conditions were obtained together with data from home inspections carried out by health communicators. Families underwent skin prick tests (SPT) against common aeroallergens. RESULTS: As could be expected from background demographic information, it turned out that we effectively studied an immigrant population inhabiting very precarious housing outside the center of Malmö. A total of 359 children from 130 families (total 650 participants) were included. Overall the prevalence of potentially harmful environmental exposures was high (signs of moisture or mould in more than 50% of apartments, indoor smoking in 37% of households). Atopic disorders were common among both adults and children. SPTs showed a spectrum of sensitizations consistent with unselected populations in Sweden. Paternal sensitization in the SPT was associated with higher risk of sensitization for offspring than maternal sensitization. Few statistically significant associations of atopic sensitization with studied environmental exposures were detected (for example objective signs of dampness /mould in bathrooms). There were marked discrepancies between asthma diagnoses obtained from the health records and parental reports of such diagnoses and treatment for their children. CONCLUSIONS: The atopic burden in this selected immigrant population was high, and results point to unmet medical needs. Health care systems caring for such populations need to be aware of their specific health needs; comprehensive asthma and allergy care should include consideration of harmful environmental exposures, adhering to the precautionary principle.

Poor housing conditions in association with child health in a disadvantaged immigrant population: a cross-sectional study in Rosengård, Malmö, Sweden.

OBJECTIVES: To describe the home environment in terms of housing conditions and their association with child health in a disadvantaged immigrant population. DESIGN: A cross-sectional observational study. SETTING: Enrolment took place during 2010-2011 in Rosengård, Malmö, Sweden. PARTICIPANTS: Children aged 0-13 years in 2 study neighbourhoods were recruited from local health records and from schools. 359 children participated, with a participation rate of 40%. Data on health, lifestyle and apartment characteristics from questionnaire-led interviews with the mothers of the children were obtained together with data from home inspections carried out by trained health communicators. OUTCOME MEASURES: Logistic regression analysis was used to estimate ORs for various health outcomes, adjusted for demographic information and lifestyle factors. RESULTS: The housing conditions were very poor, especially in one of the study neighbourhoods where 67% of the apartments had been sanitised of cockroaches, 27% were infested with cockroaches and 40% had a visible mould. The association between housing conditions and health was mostly inconclusive, but there were statistically significant associations between current asthma and dampness (OR=4.1, 95% CI 1.7 to 9.9), between asthma medication and dampness (OR=2.8, 95% CI 1.2 to 6.4), and between mould and headache (OR=4.2, 95% CI 1.2 to 14.8). The presence of cockroaches was associated with emergency care visits, with colds, with headache and with difficulty falling asleep, and worse general health was associated with mould and presence of cockroaches. CONCLUSIONS: The associations between dampness and asthma, and the association between mould and headache, are in line with current knowledge. The presence of cockroaches seemed to be associated with various outcomes, including those related to mental well-being, which is less described in the literature. The results of the present study are hypothesis generating and provide strong incentives for future studies in this study population.

Evaluation of a revised version of computer-assisted diagnosis system, BONENAVI version 2.1.7, for bone scintigraphy in cancer patients.

OBJECTIVE: BONENAVI is a computer-assisted diagnosis system that analyzes bone scintigraphy automatically. We experienced more than a few segmentation errors with the previous BONENAVI version (2.0.5). We have since obtained a revised version (2.1.7) and evaluate it. METHODS: Bone scans of patients were analyzed by BONENAVI version 2.0.5 and a revised version 2.1.7 with regard to segmentation errors, sensitivity, and specificity. Patients with skeletal metastases from prostate cancer, lung cancer, breast cancer, and other cancers were included in the study as true-positive cases. Patients with no skeletal metastasis (regardless of hot spots), and patients with abnormal bone scans but no skeletal metastasis were included as negative cases. Bone-scan patients were subjected to artificial neural network (ANN) evaluation. Values equal to or above 0.5 were regarded as positive, and those below 0.5 as negative. The patients whose clinical status did not correspond to their ANN scores were assessed for any similarities. RESULTS: The frequency of segmentation errors was statistically significantly reduced when using BONENAVI version 2.1.7. The differences in sensitivity and specificity for the results of version 2.0.5 versus version 2.1.7 were not different, giving a high Cohen's kappa coefficient. In the patients who showed an increased ANN value with version 2.1.7, a few false-positive thoracic lesions were identified. Patients whose ANN value was significantly high with version 2.0.5 showed no tendencies. CONCLUSION: Revised BONENAVI version 2.1.7 for bone scintigraphy was superior with regard to segmentation errors. However, its sensitivity and specificity were similar to those of version 2.0.5. The false-positive identification of thoracic lesions in revised version 2.1.7 might be subject to remedy.

Age-dependent regulation of tendon crimp structure, cell length and gap width with strain.

The black-and-white patterning of tendon fascicles when visualized by light microscopy, also known as crimp, is a well-known feature of fiber-forming collagens. However, not much is known about its development, function and response to strain. The objective of this study is to investigate the interaction of tenocyte and crimp morphology as well as their changes with increasing age and acute strain. In contrast to previous studies, which used indirect measures, such as polarized light, to investigate the crimp structure, this study visualizes internal crimp structure in three dimensions without freezing, sectioning, staining or fixing the tissue, via two-photon imaging of green fluorescent protein expressing cells within mouse tail tendon fascicles. This technique further allows straining of the live tissue while visualizing changes in crimp morphology and cell shape with increasing specimen length. Combining this novel microscopy technique with computational image and data analysis revealed a complex relationship between tenocytes and the extracellular matrix that evolves with increasing age. While the reduction of crimping with strain was observed as expected, most of the crimps were gone at 0-1% strain already. Even relatively low strains of 3% led to pronounced changes in the crimp structure after relaxation, particularly in the young animals, which could not be seen with bright-field imaging. Cell length and gap width increased with strain. However, while the cells were able to return to their original length even after high strains of 6%, the gaps between the cells widened, which may imply modified cell-cell communication after overstretching.

Exposure to harmful housing conditions is common in children admitted to Wellington Hospital.

AIM: To measure the prevalence of exposure to potentially modifiable risk factors in the homes of children hospitalised in Wellington. METHODS: Parents/caregivers of all children admitted to Wellington Public Hospital during a two-week period in July 2012 completed a standardised questionnaire in a face-to-face interview. The questionnaire collected sociodemographic, health and housing condition data. RESULTS: We interviewed parents/caregivers of 106 children, of whom 72% were aged 0-4 years. Respiratory conditions were the most common cause of admission. One third of parents noticed dampness and mould in their house, 50% stated that their house was colder than they preferred during the past month, 20% lived in uninsulated houses, 20% lived in overcrowded houses, and 38% were exposed to second hand smoke (SHS). Compared to New Zealand European (NZE) children, the odds ratios (OR) for Pacific children living in cold and overcrowded houses and being exposed to SHS were 14.0 (95%CI 3.0-66.0), 10.8 (95%CI 2.6-44.1) and 16.0 (95%CI 4.8-55.5) respectively. OR for Maori children living in cold and overcrowded houses and being exposed to SHS were 3.0 (95%CI 1.0-9.0), 6.8 (95%CI 1.6-30.1) and 8.0 (95%CI 2.5-28.6) respectively, compared to NZE children. The OR for children from deprived neighbourhoods (NZDep2006 areas 7-10) living in cold and overcrowded houses and being exposed to SHS were 4.1 (95%CI 1.8-9.6), 5.7 (95%CI 1.9-17.0) and 4.1 (95%CI 1.6-9.6) respectively. CONCLUSIONS: Among children admitted to Wellington Hospital there is a high prevalence of exposure to cold, damp and overcrowded houses and many children are exposed to SHS. Maori and Pacific children and children living in socioeconomically deprived areas are more likely than others to be exposed to these potential risk factors for childhood hospitalisation. This audit of child admissions could be repeated to provide surveillance of modifiable risk factors. A shortened version of the questionnaire could be used to screen children to identify those with harmful exposures in their home environment, provided suitable intervention programmes can be established.

Effect of Calstabin1 depletion on calcium transients and energy utilization in muscle fibers and treatment opportunities with RyR1 stabilizers.

Depletion of calstabin1 (FKBP12) from the RyR1 channel and consequential calcium leakage from the sarcoplasmic reticulum (SR) is found in certain disease conditions such as dystrophy, aging or muscle overuse. Here, we first assessed the effect of calstabin1 depletion on resting Ca(2+) levels and transients. We found that depletion of calstabin1 with the calstabin1-dissociation compound FK506 increased the release of calcium from the SR by 14 % during tetanic stimulation (50 Hz, 300 ms) and delayed cytosolic calcium removal. However, we did not find a significant increase in resting cytosolic Ca(2+) levels. Therefore, we tested if increased SERCA activity could counterbalance calcium leakage. By measuring the energy utilization of muscle fibers with and without FK506 treatment, we observed that FK506-treatment increased oxygen consumption by 125% compared to baseline levels. Finally, we found that pretreatment of muscle fibers with the RyR1 stabilizer JTV-519 led to an almost complete normalization of calcium flux dynamics and energy utilization. We conclude that cytosolic calcium levels are mostly preserved in conditions with leaky RyR1 channels due to increased SERCA activity. Therefore, we suggest that RyR1 leakiness might lead to chronic metabolic stress, followed by cellular damage, and RyR1 stabilizers could potentially protect diseased muscle tissue.

Improved quantification of small hearts for gated myocardial perfusion imaging.

PURPOSE: In patients with a small heart, defined as an end-systolic volume (ESV) of ≤20 mL calculated using the Quantitative Gated SPECT (QGS) program, underestimation of ESV and overestimation of ejection fraction (EF) using gated myocardial perfusion imaging are considered errors caused by inappropriate delineation of the left ventricle (LV). The aim of this study was to develop a new method for delineation of the LV and to evaluate it in studies using a digital phantom, normal subjects and patients. METHODS: The active shape-based method for LV delineation, EXINI heart (ExH), was adjusted to more accurately process small hearts. In small hearts, due to the partial volume effect and the short distance to the opposite ventricular wall, the endocardial and the epicardial surfaces are shifted in the epicardial direction depending on the midventricular volume. The adjusted method was evaluated using digital XCAT phantoms with Monte Carlo simulation (8 virtual patients), a Japanese multicentre normal database (69 patients) and consecutive Japanese patients (116 patients). The LV volumes, EF and diastolic parameters derived from ExH and QGS were compared. RESULTS: The digital phantom studies showed a mean ESV of 87% ± 9% of the true volume calculated using ExH and 22 % ± 18% calculated using QGS. In the normal database, QGS gave higher EFs in women than in men (71.4 ± 6.0 % vs. 67.2 ± 6.0%, p = 0.0058), but ExH gave comparable EFs (70.7 ± 4.9% and 71.4 ± 5 % in men and women, respectively, p = ns). QGS gave higher EFs in subjects with a small heart than in those with a normal-sized heart (74.5 ± 5.1% vs. 66.1 ± 4.9%), but ExH gave comparable values (70.0 ± 5.9% vs. 71.6 ± 4.2%, respectively, p = ns). In consecutive patients, the average EFs with QGS in patients with ESV >20 mL, 11-20 mL and ≤10 mL were 57.9%, 71.9% and 83.2%, but with ExH the differences among these groups were smaller (65.2%, 67.8% and 71.5%, respectively). CONCLUSION: The volume-dependent edge correction algorithm was able to effectively reduce the effects on ESV and EF of a small heart. The uniform normal values might be applicable to both men and women and to both small and normal-sized hearts.