Initial Time Point Research Articles

GhLBDs Promote Callus Initiation and Act as Selectable Markers to Increase Transformation Efficiency.

Detached organs or differentiated tissues could form a mass of pluripotent cells termed as callus on an auxin-rich medium, the underlying molecular mechanism of which remains elusive in cotton. LATERAL ORGAN BOUNDARIES DOMAIN (LBD) transcription factor is a key regulator of plant cell totipotency/pluripotency, and a number of cotton GhLBDs with high-level differential expression during the callus induction process have been identified. Their overexpression in cotton calli fostered promotions in and callus induction without exogenous auxin. Expression analysis and histological observation using paraffin sectioning suggested that the first 72 h on culture is a key time point for callus initiation, whereby the GhLBDs showed high transcript abundance and enlarged calli that were rapidly developed from procambium and cambium. GhLBDs’ expression level could be precisely modulated by the gradient concentrations of exogenous auxin, whereas auxin transport inhibitor 2,3,5-triiodobenzoic acid could severely inhibit its expression. The LBD-mediated callus formation was also dependent on the expression levels of GhLBDs. Further, a β-estradiol-inducible promoter pER8 was used to drive GhLBD18-1 expression, which led to rapid callus proliferation, suggesting that pER8/GhLBD18-1 could be used as a selectable marker system to replace the existing antibiotic/herbicide-resistance selectable markers in plant transformation. Our study provides new insights for callus initiation regulatory mechanism and strategies for improving transformation efficiency in cotton.

Modeling of Usual Care: Vasopressor Initiation for Sepsis With Hypotension.

Usual care regarding vasopressor initiation is ill-defined. We aimed to develop a quantitative “dynamic practice” model for usual care in the emergency department (ED) regarding the timing of vasopressor initiation in sepsis. In a retrospective study of 589 septic patients with hypotension in an urban tertiary care center ED, we developed a multi-variable model that distinguishes between patients who did and did not subsequently receive sustained (>24 h) vasopressor therapy. Candidate predictors were vital signs, intravenous fluid (IVF) volumes, laboratory measurements, and elapsed time from triage computed at timepoints leading up to the final decision timepoint of either vasopressor initiation or ED hypotension resolution without vasopressors. A model with six independently significant covariates (respiratory rate, Glasgow Coma Scale score, SBP, SpO2, administered IVF, and elapsed time) achieved a C-statistic of 0.78 in a held-out test set at the final decision timepoint, demonstrating the ability to reliably model usual care for vasopressor initiation for hypotensive septic patients. The included variables measured depth of hypotension, extent of disease severity and organ dysfunction. At an operating point of 90% specificity, the model identified a minority of patients (39%) more than an hour before actual vasopressor initiation, during which time a median of 2,250 (IQR 1,200–3,300) mL of IVF was administered. This single-center analysis shows the feasibility of a quantitative, objective tool for describing usual care. Dynamic practice models may help assess when management was atypical; such tools may also be useful for designing and interpreting clinical trials.

Combining frog-leg lateral view may serve as a more sensitive X-ray position in monitoring collapse in osteonecrosis of the femoral head

ABSTRACTLoad-bearing capacity of the bone structures of anterolateral weight-bearing area plays an important role in the progressive collapse in osteonecrosis of the femoral head (ONFH). The purpose of this study is to assess the efficacy of combined evaluation of anteroposterior (AP) and frog-leg lateral (FLL) view in diagnosing collapse. Between December 2016 and August 2018, a total of 478 hips from 372 patients with ONFH (268 male, 104 female; mean age 37.9 ± 11.4 years) were retrospectively evaluated. All patients received standard AP and FLL views of hip joints. Japanese Investigation Committee (JIC) classification system was used to classify necrotic lesion in AP view. Anterior necrotic lesion was evaluated by FLL view. All patients with pre-collapse ONFH underwent non-operative hip-preserving therapy. The collapse rates were calculated and compared with Kaplan–Meier survival analysis with radiological collapse as endpoints. Forty-four (44/478, 9.2%) hips were classified as type A, 65 (65/478, 13.6%) as type B, 232 (232/478, 48.5%) as type C1 and 137 (137/478, 28.7%) as type C2. Three hundred cases (300/478, 62.5%) were collapsed at the initial time point. Two hundred and twenty six (226/300, 75.3%) hips and 298 (298/300, 99.3%) hips collapse were identified with AP view and FLL view, respectively. An average follow-up of 37.0 ± 32.0 months was conducted to evaluate the occurrence of collapse in 178 pre-collapse hips. Collapses occurred in 89 hips (50.0%). Seventy-seven (77/89, 86.5%) hips were determined with AP view alone and 85 (85/89, 95.5%) hips were determined with the combination of AP and FLL views. The collapse rates at five years were reported as 0% and 0%, 16.2% and 24.3%, 58.3% and 68.1% and 100% and 100% according to AP view alone or combination of AP and FLL views for types A, B, C1 and C2, respectively. The collapse can be diagnosed more accurately by combination of AP and FLL views. Besides, JIC type A and type B ONFH can be treated with conservative hip preservation, but pre-collapse type C2 ONFH should be treated with joint-preserving surgery. Type C1 needs further study to determine which subtype has potential risk of collapse.

Effect of the Hot Streak on the Overall Cooling Performance of a Coated Rotor Blade

The influence of the HS (hot streak) and unsteady wake on the overall cooling performance of a rotor blade was studied in this paper. The results show that: (1) Both the magnitude and temperature of the HS gradually drops down as it passes downstream of the vane passage. (2) Within one stator period, the highest cooling performance of the blade can be observed at the initial time points, when the LE (leading edge) of the blade turns towards the trailing edge of the vane. (3) The lowest cooling performance of the blade can be observed at the time point 0.5 T, when the LE of the blade turns towards the center of the vane passage. (4) Surface temperatures in areas with unfavorable local heat flow are usually higher than the temperature of the coolant. The additional TBCs may exert adverse effects on heat dissipation from the substrate metal to the mainstream, which has a negative effect on the improvement of the overall cooling effectiveness of the coated blade. (5) Within a stator period, a relatively higher overall cooling effectiveness increment due to the coating can be observed at the relative location with lower cooling performance. Consequently, the additional TBCs are beneficial for decreasing the surface temperature difference and thus controlling the thermal stress under the HS inlet condition.

Real-world patient-reported outcomes of breast cancer or prostate cancer patients receiving antiresorptive therapy for bone metastases: Final results of the PROBone registry study

BackgroundIn breast cancer and prostate cancer patients, bone metastases (BM) present the main cause of morbidity and often cause debilitating pain, impaired functioning and subsequent deterioration of quality of life (QoL). The management of BM is still challenging. Maintenance or improvement in QoL is the main goal of treatment. Antiresorptive treatment, such as denosumab and bisphosphonates, can help to reduce the frequency of skeletal complications, to control bone pain and potentially to improve QoL. The optimal time point for initiation of antiresorptive therapy is still discussed controversially. In patients with BM, bone pain can be used as a surrogate measure of QoL. However, limited data exist on health-related QoL in patients with BM under antiresorptive treatment. The PROBone registry study evaluated complaints and limitations caused by BM of breast and prostate cancer patients using patient-reported outcomes (PROs) in real-world in Germany. MethodsBetween 2014 and 2019, 500patients with histological confirmation of advanced breast or prostate cancer, diagnosed with BM at start of their first antiresorptive therapy were prospectively enrolled in 65outpatient-centers specialized in medical oncology across Germany. Changes of QoL were assessed monthly from baseline until a maximum of 12 months using the validated pain score Functional Assessment of Cancer Therapy Quality of Life Measurement in patients with bone pain (FACT-BP) supplemented by questions on general pain and on the impact of time spent for treatment of illness on patients’ daily activities. Statistical analysis was performed descriptively by relative and absolute frequencies. ResultsIn total, 486 patients were eligible for final analysis, of these 310 were diagnosed with breast cancer and 176 with prostate cancer. Median age was 67 years for breast cancer and 76 years for prostate cancer patients. 79.7% of breast cancer and 59.7% of prostate patients started antiresorptive treatment within 3 months after diagnosis of BM. More than 75% of patients suffered from bone pain at study inclusion. In total 52% of breast cancer patients and 47.9% of prostate cancer patients reported to take pain medication during the observation period. In breast and prostate cancer patients an initial pain reduction after start of BTA was observed: General pain and bonepain levels as well as the median FACT-BPscore showed a constant improvement over the first months and maintained stable at a constant level afterwards. Subgroup analysis showed that patients without pain at baseline reported distinctly better FACT-BP scores throughout the whole observation period than patients with pain at baseline. Looking at time-stress(M)-scores, younger breast cancer patients (<65 years) showed highest burden especially during the first months of treatment. ConclusionsOur results indicate overall good adherence to current guideline recommendation, with most breast and prostate cancer patients starting antiresorptive therapy within the first 3 months after diagnosis of BM. This point gains even more importance as our data support current recommendations by ESMO guidelines as well as by German evidence-based S3-guidelines for diagnosis and treatment of breast and prostate cancer to initiate bone-targeted agents (BTA) as soon as BM are diagnosed, to keep pain levels at the lowest level possible, to minimize the debilitating effects of metastatic bone pain and maintain a good QoL. Bone pain management by an early use of BTA following BM diagnosis might improve patient care.

An IPSO-SA algorithm based on feedback mechanism for smooth path planning of UAV

The traditional PSO algorithm has been widely used in the path planning of unmanned equipment, but its algorithm is faced with the problem of premature convergence, which is easy to fall into the local optimal solution. When the initial position is not suitable, it can’t even plan the path in complex environment. At the same time, its line trajectory does not meet the requirements of the path curvature of realistic unmanned equipment. To solve the above problems, this paper proposes a new path planning strategy for unmanned equipment, and designs a new path planning algorithm for unmanned aircraft by combining the improved particle swarm optimization (IPSO) algorithm with simulated annealing algorithm (SA). At the same time, it solves the two problems that PSO algorithm is easy to fall into local optimal solution and abandoning all possible feasible solution regions in the early stage because of an illegal path. The path planned by IPSO-SA algorithm is processed by cubic spline interpolation to solve the curvature problem of its motion path. In addition, in view of the problem that the initial point is not suitable in complex environment, this algorithm designs a feedback mechanism to correct the initial point in time. The effectiveness of the algorithm is verified by theoretical derivation and simulation experiments, that is, the algorithm only needs a small number of point sequences to plan the path of UAV in simple and complex environment, and has less search amount and space-time overhead.

Rotational thromboelastometry in critical phase of dengue infection: Association with bleeding

BackgroundThe critical phase of dengue carries a high risk of bleeding. Associations of coagulation test parameters and the risk of bleeding in the critical phase is unclear. This study examines the association of rotational thromboelastometry (ROTEM delta and ROTEM platelet) with bleeding risk of patients with dengue in the critical phase. MethodsA total of 105 patients with confirmed dengue in the critical phase were recruited, with two subsequent prospective time point analyses of ROTEM parameters and platelet count within 24 and 48 hours from the onset of the critical phase. Conventional coagulation tests were performed only at the initial time point. ResultsTwenty of 105 patients developed bleeding after onset of the critical phase. Within the first 24 hours of critical‐phase onset, platelet count, coagulation tests, and ROTEM delta were unable to differentiate patients with bleeding manifestations from those without (P < .05). Area under the curve of thrombin receptor activating peptide‐6 assay of ROTEM platelet (TRAPTEM) discriminated patients with bleeding manifestations from those without, at a cutoff value of <12.5 Ω*min at a sensitivity and specificity of 73.7%, and 60.2%. In patients who developed bleeding, the maximum lysis of extrinsic pathway of ROTEM was significantly lower in patients with severe bleeding compared to those with mild to moderate bleeding. (4.3 ± 3.4% vs 9.4 ± 7.5%; P = .01). ConclusionAn association with bleeding manifestations and TRAPTEM suggest a potential role for defective platelet aggregation in the pathogenesis of bleeding in the critical phase of dengue.

Three-Dimensional Changes in the Mandibular Proximal Segment After Using a Surgery-First Approach in Patients With Class III Malocclusion and Facial Asymmetry.

:This study was performed to evaluate condylar position and angulation after asymmetric mandibular setback between a conventional (CA) and surgery-first approach (SFA) using three-dimensional analysis. The condylar positions of 30 patients with skeletal Class III malocclusion and facial asymmetry who underwent 1-jaw (sagittal split ramus osteotomy) or 2-jaw orthognathic surgery (Le Fort I osteotomy and sagittal split ramus osteotomy) with CA (n = 18) or SFA (n = 12) from 2 university hospitals were studied. The three-dimensional assessment of condylar changes was performed using computed tomography images at the initial time point (T0) and at least 6 months after surgery (T1). Segmentation of condyles and cranial base assessment from cone-beam computed tomography images were performed using ITK-SNAP software (version 3.4.0). Condylar position and angulation changes were calculated using 3D Slicer software (version 4.10.2), and statistical analysis was performed. No significant translational or rotational condylar changes were observed between the deviated and non-deviated sides in each group or between the CA and SFA groups except yaw (p = 0.014). Linear mixed-model analysis and multi-variate analysis showed no significant difference between the CA and SFA groups. Surgery-first approach might not be associated with more harmful effects on the condylar position and angulation changes as compared with CA.

Abstract P1-24-06: Risk factor modeled microenvironment effects lymphatics activity and IBC invasiveness and progression

Abstract Background. Lymphovascular invasion (LVI) and breast tumor emboli within dermal and breast lymphatic vessels are prognostic for metastatic spread and poor outcomes, and are abundant in Inflammatory breast cancer (IBC). IBC is an aggressive breast cancer that presents suddenly with breast swelling and redness due to tumor emboli in lymphatics. Lack of breast-feeding and obesity are IBC risk factors. We sought to demonstrate the combinatorial effects of a high-fat diet and nursing on lymphatic function and compare these to IBC tumor induced changes in lymphatic function. We hypothesize that risk factors for aggressive breast cancer may alter lymphatic function in the normal gland prior to tumor initiation. Methods. Following two rounds of pregnancy in 20 multiparous SCID Beige immunocompromised mice, half of the mice were force weaned while half nursed pups. Prior to forced weaning, half of each of these groups were fed a high fat diet (HFD: 60 Kcal %, N = 10) while the other half received a low-fat diet (LFD: 10 Kcal %, N = 10). Consecutive dynamic near-infrared fluorescence (NIRF) lymphatic imaging was performed at 6-7 months (covid interruption) and 14 months after initiating the diet by injecting a near-IR fluorophore into the mammary fatpad and recording lymphatic pulsing over 8 minutes using V++. Matlab and ImageJ were used to quantify pulsing rates on the ventral lymphatics in each animal. Fatpads were subsequently inoculated with SUM149 IBC cells and imaging was repeated 16 months post diet initiation. Lymphatic imaging over time by HFD vs LFD was further studied in nulliparous animals. Tissues were collected for further analyses. ResultsData analysis prior to tumor injection, demonstrated lymphatic pulsing (pulses/4 minutes) increased over time in HFD force weaned (HFFW) and HFD nursing (HFN) animals only (65.5 vs 72.6, P=0.059; 60.1 vs 76.6, P=0.0099, respectively). Comparing HFFW and HFN to matched LFD groups (LFFW and LFN), at 14 weeks HFD was associated with increased pumping after forced weaning (62.3 vs. 72.6, P=0.074), and nursing (62.5 vs 76.6, P=0.0023). There was an increase in pulsing after tumor initiation (16 months after initiation of diet) in all groups (80.1, 84.1, 83.2, 82.4, P &amp;gt; 0.05 all comparisons to initial timepoint). In a separate experiment examining HFD (N=5) vs LFD (N=5) in nulliparous mice, lymphatic contractile activity increased in all animals over. time, average ventral lymphatic contractile frequency for LFD and HFD at week 8,11 and 14 weeks after diet initiation were 5, 8.64, 15.9 pumps/4 mins vs 11.8, 18.5, 28.2 pumps/4 mins, (P = 0.01, 0.05, and 0.0005 respectively). ConclusionsHFD increased lymphatic pulsing rate over time to a significantly greater extent than LFD continuing over 14 months independent of reproductive and nursing status. Tumor initiation prompted further increased pulsing rates beyond that observed after HFD across all groups. The magnitude of the effect of HFD on lymphatic pulsing approached the rate after tumor initiation, while reproductive variables did not impact lymphatic pulsing. Further studies are warranted to demonstrate the relationship if any between lymphatic pumping pre-initiation and LVI after tumor initiation and examine the role of intervention on reducing LVI. Citation Format: Wintana Balema, Janelle Morton, Richard Larson, Fred C Velasquez, Eva Sevick-Muraca, Wendy A Woodward. Risk factor modeled microenvironment effects lymphatics activity and IBC invasiveness and progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-06.

Optimal Initial Time Point of Local Radiotherapy for Unresectable Lung Adenocarcinoma: A Retrospective Analysis on Overall Arrangement of Local Radiotherapy in Advanced Lung Adenocarcinoma.

Local radiotherapy (LRT) is reported to be of survival benefit for advanced non-small cell lung cancer (NSCLC) in accumulating evidence, but research on the optimal initial time point remains scarce. This IRB-approved retrospective analysis identified patients diagnosed with stage IIIb–IV unresectable lung adenocarcinoma who initiated front-line LRT at our institution between 2017 and 2020. The receiver operating characteristic (ROC) curve analyses were used to cut off the initial time of LRT (before and beyond 53 days). Patients were divided into two groups: one early to initiate radiotherapy group (≤53 days, EAR group) and one deferred radiotherapy group (>53 days, DEF group). The Kaplan–Meier method was used to estimate time-to-event endpoints; the Cox proportional hazard model was used to find out predictors of progression-free survival (PFS) and overall survival (OS). A total of 265 patients with a median age of 57 were enrolled. The median follow-up time was 26.4 months (ranging from 2.2 to 69.7 months). The mOS was 38.6 months and mPFS was 12.7 months. Age >60, bone and brain metastases, multisite metastases, and EGFR 19 mutation were independent predictors associated with OS. Early initiation of local radiotherapy within 53 days after diagnosis resulted in better PFS, but not in OS. A better OS was observed in patients with bone metastasis who underwent local radiotherapy initiated within 53 days.

Why adolescents engage in early alcohol use: A study of drinking motives.

Shortly after young adolescents initiate alcohol use, we investigated whether (1) drinking motives are associated with current alcohol use and binge drinking, (2) motives predict these alcohol outcomes 6 months later, and (3) alcohol outcomes predict motives 6 months later. Data on adolescents' drinking motives and alcohol use were drawn from a Dutch longitudinal 7-wave family study at the timepoint of alcohol use initiation (t0, N = 210, 51.4% male, Mage = 14.01 SD = 1.02) and 6 months later (t1, n = 88). Logistic and linear regressions were conducted. Results indicated that young adolescents mainly drink for social and enhancement motives rather than coping and conformity motives. Shortly after alcohol initiation, social motives were associated with alcohol use at t0 (OR = 1.52), enhancement motives with binge drinking at t0 (OR = 2.35), and coping motives with binge drinking at t0 (OR = 2.62) and at t1 (OR = 3.00). Conformity motives were inversely associated with binge drinking at t0 (OR = 0.42). Binge drinking predicted coping motives at t1 (B = 0.71, SE = -0.35), but no other associations among alcohol use, binge drinking, and drinking motives at t1 were found. Conclusively, this study shows that young adolescents drink to enjoy parties and to get drunk (social and enhancement motives) rather than to fit in (conformity motives). The study also indicates that shortly after alcohol initiation, alcohol to cope represents a reciprocal risk factor for binge drinking that may persist in the future, thus pointing to the importance of drinking motives for drinking behaviors among young adolescents. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Three-dimensional morphological characterization of colorectal pits from label-free microscopy images.

The prognosis of colorectal cancer (CRC), one of the most prevalent pathologies worldwide, is linked to early detection. Kudo's pit pattern classification states morphological pit patterns of the Lieberkühn crypts by analyzing the superficial mucosa, predicting the histology of colorectal lesions. Its use as a highly accurate two-dimensional diagnostic criterion has increased, mostly involving expert endoscopists' judgment. The processing of autofluorescence images could allow the diagnostic, bypassing staining techniques and decreasing the biopsies, resources and times involved in the inspection. That criterion could be extended by data of the pit three-dimensional (3D) morphology. Thus, this work was aimed at obtaining 3D morphological information by quantifying geometrical and shape descriptors through software processing and analysis of widefield autofluorescence microscopy image stacks acquired by fresh colon tissue samples from a murine model of CRC. Statistical analyses included pits from control mice and from the second (2nd), fourth (4th), and eighth (8th) weeks of treatment. Statistically significant differences were found for almost all parameters between the pits from control and from the 4th treated week, stating that the major morphological changes begin after the 2nd week. In particular, pits from control or initial treatment time points were more tubular, straighter and less rough than the ones from later treatment points. Therefore, they may be more associated to normal or non-neoplastic crypt lumens than linked to adenomas or even cancer crypts. These preliminary outcomes could be considered an advance in 3D pit morphology characterization.

Theoretical Explanation of Upper Limb Functional Exercise and Its Maintenance in Postoperative Patients With Breast Cancer

Background: Upper limb functional exercise (ULFE) has a positive effect on promoting the rehabilitation of upper limb function. However, little is known, about what drives postoperative patients to engage in and even maintain the advised exercises. This study integrated the health action process approach (HAPA) and the theory of planned behavior theory (TPB) to investigate the psychosocial determinants on the initiation and maintenance of ULFE in breast cancer patients. In addition, this study also tests key hypotheses relating to reasoned and implicit pathways to ULFE and its maintenance among postoperative patients with breast cancer.Methods: Purposive sampling was used to recruit patients from two breast cancer wards in a provincial hospital in Jiangsu, China. Patients (N = 430) completed self-reported questionnaire about constructs from integrated theories concerning ULFE at an initial time point (T1): task self-efficacy, positive outcome expectations, negative outcome expectations, risk perception, attitude behavior, subjective norm, perceived behavioral control, behavioral intention, and ULFE-in hospital (ULFE-IH). Three months later (T2), patients self-reported: maintenance self-efficacy, action planning, coping planning, recovery self-efficacy, and ULFE-maintenance (ULFE-M).Results: The model has a good fit (GoF = 0.48). For behavioral intention of ULFE, subjective norm (β = 0.35) and perceived behavioral control (β = 0.61) were positively directly related to behavioral intention. Regarding the initiation of ULFE, perceived behavioral control (β = 0.47) and behavioral intention (β = 0.42) had a direct positive relation to ULFE-IH. In the maintenance of ULFE, action planning (β = 0.30), coping planning (β = 0.21), maintenance self-efficacy (β = 0.32), and recovery self-efficacy (β = 0.09) all had significant positive relation on ULFE-M. In addition, maintenance self-efficacy had a significant positive association on action planning (β = 0.80), coping planning (β = 0.74), and recovery self-efficacy (β = 0.67). Coping planning was significantly predicted by behavioral intention (β = 0.07). Additionally, behavioral intention is a mediator of subjective norm (β = 0.14) and perceived behavioral control (β = 0.25) to ULFE-IH. Action planning, coping planning, and recovery self-efficacy are mediators of maintaining self-efficacy to ULFE-M (β = 0.46).Conclusions: This study presents the first attempt to integrate the health behavior model in ULFE in postoperative patients with breast cancer. The study has shown that the HAPA-TPB integrated model has good applicability and effectiveness to explain and predict ULFE initiation and maintenance. Future work can be considered to develop appropriate intervention strategies based on this integrated behavioral theory.

Integral presentations of the solution of a boundary value problem for impulsive fractional integro-differential equations with Riemann-Liouville derivatives

&lt;abstract&gt;&lt;p&gt;Riemann-Liouville fractional differential equations with impulses are useful in modeling the dynamics of many real world problems. It is very important that there are good and consistent theoretical proofs and meaningful results for appropriate problems. In this paper we consider a boundary value problem for integro-differential equations with Riemann-Liouville fractional derivative of orders from $ (1, 2) $. We consider both interpretations in the literature on the presence of impulses in fractional differential equations: With fixed lower limit of the fractional derivative at the initial time point and with lower limits changeable at each impulsive time point. In both cases we set up in an appropriate way impulsive conditions which are dependent on the Riemann-Liouville fractional derivative. We establish integral presentations of the solutions in both cases and we note that these presentations are useful for furure studies of existence, stability and other qualitative properties of the solutions.&lt;/p&gt;&lt;/abstract&gt;

Allergen Release Profiles of Fast-Dissolving Freeze-Dried Orodispersible Sublingual Allergy Immunotherapy Tablets

BackgroundSublingual allergy immunotherapy tablets (SLIT-tablets) provide a well-tolerated and clinically efficacious treatment for allergic disease such as allergic rhinitis and allergic asthma. In SLIT, uptake of allergen by immune-competent cells in the oral mucosa activates the immune system and leads to tolerance toward the sensitizing allergen. The ability to deliver the full allergen content into solution within the recommended sublingual holding time is therefore an essential quality of SLIT-tablets that must be supported by the tablet formulation for all relevant allergen sources. SLIT-tablets based on a fast-dissolving orodispersible freeze-dried formulation (Zydis) are currently available for 5 of the most prevalent allergens: tree (birch and related species from the birch-homologous group), grass, ragweed, Japanese cedar, and house dust mite.ObjectivesThe purpose of this study was to examine the allergen release properties of three freeze-dried SLIT-tablets containing tree, ragweed, and Japanese cedar extracts, respectively. The correlation between SLIT-tablet allergen release and the level of allergen-specific T-cell activation was examined for the tree SLIT-tablet.MethodsAllergen release kinetics and tablet disintegration times for the 3 freeze-dried SLIT-tablets were examined. For all 3 tablets, the magnitude of solubilized major allergen relative to time in solution was compared to external controls to achieve a measure of the total allergen release. Additional assessments of allergen release occurring after the initial timepoint (15 or 30 seconds in solution) were done independently of external controls by linear regression analyses. For the tree SLIT-tablet, the immunological potency of the released major allergen was assessed at each experimental timepoint by a Bet v-specific T-cell activation assay.ResultsAll 3 SLIT-tablets disintegrated within 1 second after contact with assay buffer without any detectible residue. Complete release of major allergens (Bet v 1, Amb a 1, and Cry j 1, respectively) was seen at the earliest experimental time points (15 or 30 seconds). For the tree SLIT-tablet, full T-cell activation was achieved at 30 seconds (earliest experimental time point).ConclusionsThe freeze-dried SLIT-tablet formulation consistently provides rapid and complete release of allergen from a wide range of species in a standardized in vitro assay. Full release of the SLIT-tablet allergen content within the sublingual holding time is a prerequisite for maximal exposure of allergens to the sublingual mucosa immune system. The freeze-dried SLIT-tablet formulation examined here supports short sublingual holding times and furthermore offers a convenient administration form of allergy immunotherapy.

Time point for transport initiation in out-of-hospital cardiac arrest cases with ongoing cardiopulmonary resuscitation: anationwide cohort study in Japan.

AimThis study aimed to investigate the time point of the decision to initiate transport with ongoing cardiopulmonary resuscitation (CPR) in Japan.MethodsWe analyzed adult out‐of‐hospital cardiac arrest (OHCA) cases that achieved return of spontaneous circulation (ROSC) before hospital arrival from the All‐Japan Utstein Registry during 2015–2017. We constructed receiver operating characteristics (ROC) curves to illustrate the ability of achieving ROSC as a predictor of neurologically favorable outcomes as a function of increasing time points of resuscitation before ROSC. Furthermore, a multivariable logistic regression analysis was carried out to identify factors associated with outcomes.ResultsOf 373,993 OHCA patients with attempted resuscitation during 2015–2017, 22,067 patients with prehospital ROSC were included in our study. Patients were divided into the shockable initial rhythm (n = 5,580) and nonshockable initial rhythm (n = 16,487) cohorts. The ROC curves showed 10 min was the best test performance time point for a neurologically favorable outcome for shockable initial rhythm patients (sensitivity, 0.78; specificity, 0.53; area under the ROC curve [AUC], 0.70) and 8 min for nonshockable initial rhythm patients (sensitivity, 0.74; specificity, 0.77; AUC, 0.83). Multivariable logistic regression analyses revealed that CPR durations using the cut‐off value were independently associated with better outcomes for both shockable initial rhythm patients (odds ratio, 2.09; 95% confidence interval, 1.81–2.42) and nonshockable initial rhythm patients (odds ratio, 3.34; 95% confidence interval, 2.92–3.82).ConclusionWhen Japanese emergency medical service (EMS) providers attend OHCA cases, the decision to initiate transport with ongoing CPR should be made at approximately 10 min after EMS providers initiate CPR for shockable initial rhythm patients and at approximately 8 min for nonshockable initial rhythm patients.

Combined training is not superior to strength and aerobic training to mitigate cardiovascular risk in adult healthy men.

Although the beneficial effects of aerobic training on cardiovascular risk factors are evident, the potential beneficial effect of strength and combined training on these risk factors is controversial. This study aimed to evaluate the effect of aerobic and strength training programmes, performed alone or in combination, on cardiovascular risk factors in sedentary, apparently healthy and non-obese adult men. The study was conducted with 37 subjects who were randomly divided into the following groups: aerobic (AG), combined (ASG), strength (SG) and control (CG). The exercise programmes were performed three times a week and lasted approximately 50 minutes. Dietary intake, anthropometry, blood pressure, muscular strength, aerobic capacity, lipid profile and glycaemic control were assessed before and after 12 weeks of the intervention. One-way analysis of variation (ANOVA) for baseline, and ANOVA for repeated measures were used to assess differences between the initial and final time points of the four groups. Changes in blood pressure and glycaemic control were not significant in any of the groups. No differences were observed in LDL-C between training groups. HDL-C increased significantly only in the AG. In conclusion, if minimal changes in the lipid profile are needed, an aerobic training programme can provide possible benefits for HDL-C in apparently healthy and non-obese adult men.

Clinical Impact of GLP-1 receptor agonists in veterans receiving basal-bolus insulin.

In 2017, an estimated 7.4million Americans used insulin to treat diabetes. Insulin is proven to lower A1c but can result in hypoglycemia and weight gain. Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1-RA) may provide additional blood glucose control while limiting undesirable effects including weight gain. To characterize the clinical impact of adding a GLP-1-RA to a basal-bolus insulin regimen in patients with type 2 diabetes. This retrospective observational study used national Veteran's Health Administration data to identify patients with an existing basal-bolus insulin regimen who initiated a GLP-1-RA between January 1, 2005 and December 31, 2017. A1c, insulin total daily dose (TDD), and weight were collected at GLP-1-RA initiation (baseline), 3-, 6-, and 12-month time points and then analyzed using an intent-to-treat approach with the last observation carried forward. Decreases in A1c ≥ 0.5% and weight ≥2kg were deemed clinically significant. Among 7651 patients initiating GLP-1-RA therapy, mean A1c had a clinically significant decline at 3, 6, and 12months by -0.5%, -0.7%, and -0.7%, respectively, from a mean baseline of 9%. Patients with lower baseline A1c levels did not have clinically significant changes in A1c, whereas patients with baseline A1c ≥9% had more clinically significant declines. Insulin TDD decreased by -32, -38, and -42 units/day at 3, 6, and 12months, respectively, where the mean decrease in insulin TDD at 12months was 79 units/day among patients who discontinued bolus insulin (52.3%) compared with a mean decrease of 2 units/day among those who continued bolus insulin. Mean weight reductions at 3, 6, and 12months were -1.2, -2.3, and -2.9kg, respectively, from a mean baseline of 120.6kg. Combining a GLP-1-RA with basal-bolus insulin had a clinically significant improvement on blood glucose control, lowered insulin TDD, and reduced weight. These outcomes were achieved within 3 to 6months following GLP-1-RA initiation and were maintained through 1year.

The Role of HMG COA Reductase Inhibitors on the Progression of Coronary Artery Disease: Focus on Prediction Model

Abstract Currently, an integrated site-specific and patient-specific comprehensive predictive model of plaque progression in various CVD is not available. In this study, we considered medical records of 256 patients obtained within the EU H2020 SMARTool project which is carefully designed to collect the features from various domains relevant for disease which are used in everyday clinical practice. The database contains detailed information of patients with suspected CAD disease regarding the clinical status, risk factors, routine blood analyses, CAD morphology and progression and current therapy. Results showed that there was statistically significant difference of values of this parameter for the SMARTool patients with and without disease progression, measured at the follow-up, F(1,250)=33.39, p &lt; 0.001, while the CAD Score in the follow-up is significantly different from the score measured at the initial time point, F(1,254)=76.244, p &lt; 0.001. The significant interaction of statins is achieved with aspirin F(1,252)= 3.921, p=0.049, while interactions with other medicaments are insignificant for CAD Score. The results showed that there was no significant interaction of statins and dyslipidemia, F(1,251)=0.877, p = 0.350. Also, there was no significant interaction of statins and hypertension, F(1,245)=0.283, p=0.596. The CAD score in the baseline was significantly different among patients who were further prescribed with therapy than those who were not, and this trend remained unchanged after a given time period, i.e. those patients who were at risk had progression in addition to statins, but the combination of statins and aspirin was shown as effective in decreasing the CAD Score. The Random Forest classifier applied on 24 selected features is the most reliable among all tested ML algorithms for the prediction of CAD progress.

In vitro assessment of polyetheretherketone for an attachment component for an implant-retained overdenture

Statement of problemFrequent maintenance because of the limited lifetime of overdenture attachments with O-rings has led to the development of materials that might improve their functionality and longevity. However, testing of newly developed attachment materials is lacking. PurposeThe purpose of this in vitro study was to evaluate a newly developed attachment made of polyetheretherketone (PEEK) for an implant-retained overdenture. Material and methodsSpecimens of PEEK, polyacetal, and Teflon O-ring materials were prepared for analysis of roughness, surface hardness, and compressive strength. For the fatigue resistance test, new specimens based on acrylic resin were subjected to 2880 insertion and removal cycles. Compression and roughness data were compared with the Kruskal-Wallis and Dunn post hoc test; hardness data with ANOVA and t test; and fatigue and stereomicroscopy with ANOVA with repeated measures, t test, and Bonferroni adjustment (α=.05). ResultsPolyacetal had the lowest surface roughness (P=.038). There was a significant difference in hardness among the materials (P<.05). PEEK presented the highest compressive strength among the materials (P<.001). For the fatigue resistance, only polyacetal showed a difference between the initial time-point (P<.05) and subsequent time-points. Polyacetal had a higher fatigue resistance than Teflon (P<.001) and PEEK (P<.05). Regarding the internal deformation of the attachments, a significant difference was observed among the materials (P<.05). ConclusionsPEEK showed promising results regarding the physicomechanical properties necessary for use as an overdenture attachment when compared with other evaluated materials. In addition, the PEEK attachment showed results comparable to those in the control group (O-rings) in terms of retention.