Impact of beta blockers on resting respiratory rate in older adults: A cross-sectional study.

[Purpose] Beta blockers, commonly prescribed for older adults, affect heart rates and blood pressure and may reduce respiratory rates, which are used to evaluate patient status and predict outcomes. However, limited clinical evidence is available on the impact of beta blockers on respiratory rates. This study aimed to investigate the impact of beta blockers on respiratory rates in older adults. [Methods] This cross-sectional study included patients aged ≥60 years who underwent an annual checkup. Patients were excluded if they had a diagnosis of severe heart failure, chronic obstructive pulmonary disease, interstitial pneumonitis, severe anemia, or neurodegenerative disease. Doubly robust estimation with inverse probability weighting was applied to estimate the mean differences between beta blocker users and non-users. The dose-response relationship between the administered beta blockers and respiratory rates was examined using multivariable regression models. [Results] Of 637 participants, 108 had received beta blockers regularly. The adjusted mean differences (95% confidence interval, CI) in respiratory rates, pulse rates, systolic blood pressure, and diastolic blood pressure between beta blocker users and non-users were 0.35 (-0.68 to 1.37), -3.56 (-6.34 to -0.78), -5.53 (-8.53 to -2.52), and -4.70 (-8.27 to -1.14), respectively. The adjusted mean differences (95% CI) in respiratory rates per 1 mg of a carvedilol equivalent dose in all beta blocker users, liposoluble beta blocker users, and carvedilol users were -0.10 (-0.18 to -0.02), -0.35 (-0.59 to -0.11), and -0.29 (-0.54 to -0.06), respectively. [Conclusions] Beta blockers may dose-dependently reduce the respiratory rates of older adults. However, in clinical settings, the impact of beta-blocker use or non-use on the respiratory rate may not occur at a clinically important level. Clinicians should note the potentially suppressive impact of beta blockers on respiratory rates according to the situation.

Bladder training for treating overactive bladder in adults.

BACKGROUND: Overactive bladder (OAB) is a common chronic and bothersome condition. Bladder training is widely prescribed as a first-line treatment for OAB, but the efficacy has been systematically evaluated for urinary incontinence rather than OAB alone. OBJECTIVES: To evaluate the benefits and harms of bladder training for treating adults with OAB compared to no treatment, anticholinergics, ß3-adrenoceptor agonists, or pelvic floor muscle training (PFMT) alone or in combination. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 6 November 2022. SELECTION CRITERIA: We included randomized controlled trials involving adults aged 18 years or older with non-neurogenic OAB. We excluded studies of participants whose symptoms were caused by factors outside the urinary tract (e.g. neurologic disorders, cognitive impairment, gynecologic diseases). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported cure or improvement, 2. symptom- and condition-related quality of life (QoL), and 3. ADVERSE EVENTS: Secondary outcomes included 4. participant-reported satisfaction, 5. number of incontinence episodes, 6. number of urgency episodes, and 7. number of micturition episodes. For the purpose of this review, we considered two time points: immediately after the treatment (early phase) and at least two months after the treatment (late phase). We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 15 trials with 2007 participants; participants in these trials were predominantly women (89.3%). We assessed the risk of bias of results for primary and secondary outcomes, which across all studies was similar and predominantly of high risk of bias, and none were at low risk of bias. The certainty of evidence was low to very low, with some moderate, across measured outcomes. Bladder training versus no treatment: three studies involving 92 participants compared bladder training to no treatment. The evidence is very uncertain about the effects of bladder training on cure or improvement at the early phase (risk ratio (RR) 17.00, 95% confidence interval (CI) 1.13 to 256.56; 1 study, 18 participants; very low-certainty evidence). Bladder training may reduce the number of incontinence episodes (mean difference (MD) -1.86, 95% CI -3.47 to -0.25; 1 study, 14 participants; low-certainty evidence). No studies measured symptom- and condition-related QoL, number of adverse events, participant-reported satisfaction, number of urgency episodes, or number of micturition episodes in the early phase. Bladder training versus anticholinergics: seven studies (602 participants) investigated the effects of bladder training versus anticholinergic therapy. Bladder training may be more effective than anticholinergics on cure or improvement at the early phase (RR 1.37, 95% CI 1.10 to 1.70; 4 studies, 258 participants; low-certainty evidence). The evidence is very uncertain about the effects of bladder training on symptom- and condition-related QoL (standardized mean difference (SMD) -0.06, 95% CI -0.89 to 0.77; 2 studies, 117 participants; very low-certainty evidence). Although the evidence is very uncertain, there were fewer adverse events in the bladder training group than in the anticholinergics group (RR 0.03, 95% CI 0.01 to 0.17; 3 studies, 187 participants; very low-certainty evidence). The evidence is very uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.36, 95% CI -0.27 to 1.00; 2 studies, 117 participants; very low-certainty evidence), the number of urgency episodes per 24 hours (MD 0.70, 95% CI -0.62 to 2.02; 2 studies, 92 participants; very low-certainty evidence), and the number of micturition episodes per 24 hours (MD -0.35, 95% CI -1.90 to 1.20; 3 studies, 175 participants; very low-certainty evidence). No studies measured participant-reported satisfaction in the early phase. Bladder training versus PFMT: three studies involving 203 participants compared bladder training to PFMT. The evidence is very uncertain about the different effects between bladder training and PFMT on symptom- and condition-related QoL at the early phase (SMD 0.10, 95% CI -0.19 to 0.40; 2 studies, 178 participants; very low-certainty evidence). There were no adverse events in either group at the early phase (1 study, 97 participants; moderate-certainty evidence). The evidence is uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.02, 95% CI -0.35 to 0.39, 1 study, 81 participants; low-certainty evidence) and very uncertain about the number of micturition episodes per 24 hours (MD 0.10, 95% CI -1.44 to 1.64; 1 study, 81 participants; very low-certainty evidence). No studies measured cure or improvement, participant-reported satisfaction, or number of urgency episodes in the early phase. Although we were interested in studies examining bladder training versus ß3-adrenoceptor agonists, in combination with ß3-adrenoceptor agonists versus ß3-adrenoceptor agonists alone, and in combination with PFMT versus PFMT alone, we did not identify any eligible studies for these comparisons. AUTHORS' CONCLUSIONS: This review focused on the effect of bladder training to treat OAB. However, most of the evidence was low or very-low certainty. Based on the low- or very low-certainty evidence, bladder training may cure or improve OAB compared to no treatment. Bladder training may be more effective to cure or improve OAB than anticholinergics, and there may be fewer adverse events. There may be no difference in efficacy or safety between bladder training and PFMT. More well-designed trials are needed to reach a firm conclusion.

Development and validation of prediction model for incident overactive bladder: The Nagahama study.

OBJECTIVES: We aimed to develop models to predict new-onset overactive bladder in 5 years using a large prospective cohort of the general population. METHODS: This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow-ups every 5 years. We included subjects without overactive bladder at baseline and with follow-up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics (demographics, health behaviors, comorbidities, and overactive bladder symptom scores) and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation. RESULTS: We analyzed 7218 participants (male: 2238, female: 4980). The median age was 60 and 55 years, and the number of new-onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in-sample estimates for C-statistic, calibration intercept, and slope for the best performing models were 0.77 (95% confidence interval 0.74-0.80), 0.28 and 1.15 for males, and 0.77 (95% confidence interval 0.74-0.80), 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism. CONCLUSION: We developed risk prediction models for new-onset overactive bladder among men and women with good predictive ability.

Significance of Overactive Bladder as a Predictor of Falls in Community Dwelling Older Adults: 1-Year Followup of the Sukagawa Study.

PURPOSE: Little is known about the fall risk of older adults with overactive bladder, especially in the absence of urgency incontinence. We evaluated the impacts of overactive bladder with and without urgency incontinence (overactive bladder wet and overactive bladder dry) on the fall risk in older adults, and investigated the importance of overactive bladder as a predictor of falls by using tree based models. MATERIALS AND METHODS: This prospective cohort study included 630 community dwelling, independent older adults 75 years old or older who attended a health checkup in 2017 with a 1-year followup. The associations of overactive bladder dry and overactive bladder wet with a fall history, and future fall risk compared to no overactive bladder were assessed using logistic regression models. The contribution of overactive bladder as a predictor of falls was examined using a random forest and decision tree approach. RESULTS: Of the 577 analyzed participants (median age 79 years), 273 (47%) were men. The prevalence of overactive bladder dry and overactive bladder wet at baseline was 15% and 14%, respectively. Multivariable logistic regression analysis revealed that both overactive bladder dry and overactive bladder wet were associated with a higher likelihood of prior falls (adjusted ORs vs no overactive bladder 2.03 and 2.21, respectively; 95% CI 1.23-3.37 and 1.29-3.78, respectively). Among the 363 participants without a fall history, the adjusted ORs (95% CIs) of overactive bladder dry and overactive bladder wet for the occurrence of falls during the 1-year followup were 2.74 (1.19-6.29) and 1.35 (0.47-3.87), respectively. The tree based approach used for all participants showed that overactive bladder was an important predictor of falls in adults without a fall history, and the model had 83.6% accuracy and 81.8% AUC. CONCLUSIONS: Overactive bladder, even in the absence of urgency incontinence, is an important predictor of falls in older adults with a low absolute fall risk.

Negative impact of being underweight on the outcomes of single-session shockwave lithotripsy in patients with upper urinary tract calculi: a retrospective cohort study.

PURPOSE: To evaluate the association between being underweight and shockwave lithotripsy outcomes. METHODS: This retrospective two-centre cohort study conducted in Japan involved 597 patients diagnosed with a single urinary tract calculus based on computed tomography and who underwent shockwave lithotripsy between 2006 and 2016. We divided the patients into four groups based on their body mass index (underweight, ≤ 18.4; normal weight, 18.5-24.9; overweight, 25-29.9; obese, ≥ 30 kg/m2). We performed multivariable logistic regression analysis and estimated the odds ratio for success of single-session shockwave lithotripsy. RESULTS: Of the 597 patients, 25 (4.2%) were underweight and 34 (5.7%) were obese. After adjusting for age, sex, calculus localisation, maximum stone length, mean stone density, and skin-to-stone distance, being underweight showed a significantly negative association with success of single-session shockwave lithotripsy (odds ratio 0.25, 95% confidence interval 0.09-0.69) compared to being normal weight. CONCLUSIONS: This study showed the negative impact of being underweight on the outcomes of shockwave lithotripsy in patients with upper urinary tract calculi. This finding provides a novel viewpoint regarding the body mass index and should aid improved treatment selection for patients with upper urinary tract calculi.

Protocol for development and validation of a prediction model for 5-year risk of incident overactive bladder in the general population: the Nagahama study.

BACKGROUND: An accurate prediction model could identify high-risk subjects of incident Overactive bladder (OAB) among the general population and enable early prevention which may save on the related medical costs. However, no efficient model has been developed for predicting incident OAB. In this study, we will develop a model for predicting the onset of OAB at 5-year in the general population setting. METHODS: Data will be obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. The baseline characteristics were measured between Nov 28, 2008 and Nov 28, 2010, and follow-up was performed every 5 years. From the total of 9,764 participants (male: 3,208, female: 6,556) at baseline, we will exclude participants who could not attend the follow-up assessment and those who were defined as having OAB at baseline. The outcome will be incident OAB defined using the Overactive Bladder Symptom Score (OABSS) at follow-up assessment. Baseline questionnaires (demographic, health behavior, comorbidities and OABSS) and blood test data will be included as predictors. We will develop a logistic regression model utilizing shrinkage methods (LASSO penalization method). Model performance will be evaluated by discrimination and calibration. Net benefit will be evaluated by decision curve analysis. We will perform an internal validation and a temporal validation of the model. We will develop a web-based application to visualize the prediction model and facilitate its use in clinical practice. DISCUSSION: This will be the first study to develop a model to predict the incidence of OAB.

Phase II Study of the Reuse of Trastuzumab with Docetaxel beyond Progression after First-Line Treatment in Second-Line Treatment for Unresectable, Metastatic Gastric Cancer (T-CORE1203).

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

A model six-month workshop for developing systematic review protocols at teaching hospitals: action research and scholarly productivity.

BACKGROUND: Research engagement contributes to the improvement of patient care. A systematic review is a suitable first scholarly activity because it entails summarization of publicly available data and usually requires neither rigorous ethical review nor research funding. METHODS: This study aimed to develop a model workshop for healthcare staff to acquire skills in creating systematic review protocols based on their own clinical questions at teaching hospitals. We used an action research method to create a model workshop at four hospitals in Japan from April 2015 to March 2017. To improve the program, we solicited reflections using participant questionnaires for each lecture and examined the quality of homework submitted by participants after each lecture. We administered a revised final version of the workshop at five hospitals from April 2016 to March 2017. We evaluated the participants' scholarly productivity related to these workshops. The observation period was a minimum of 2 years following the workshops. RESULTS: Most participants had never developed a formal clinical research protocol and voluntarily participated in the workshop. The action research was developed and implemented at nine teaching hospitals in Japan, including one university hospital. The study developed a model nine-step workshop curriculum: 1) Research question development, 2) Search strategy development, 3) Search strategy brush-up, 4) Exclusion and inclusion criteria development, 5) Risk of bias assessment planning, 6) Meta-analysis planning, 7) Subgroup and sensitivity analysis planning, 8) Planning the presentation of results, and 9) Presentation protocols. A total of 233 participants, including medical doctors and other health professionals, produced 414 research questions. Seventy-nine participants (34%) completed the workshop, and 47 review teams accomplished systematic review protocols. The participants published 13 peer-reviewed articles as a result of the workshop. CONCLUSIONS: We developed a structured scholarly productive model workshop for healthcare staff working at hospitals. We found healthcare staff with clinical subspecialties were able to develop an unexpectedly high number of research questions through this workshop. Medical teachers at hospitals with prior systematic review experience could teach how to develop systematic review protocols using this model. Further research is needed to increase the academic productivity of such workshops. TRIAL REGISTRATION: UMIN (https://www.umin.ac.jp/ctr/), UMIN000017107 (4/15/2015), UMIN000025580 (1/10/2017).

Impact of individual background on the unmet needs of cancer survivors and caregivers - a mixed-methods analysis.

BACKGROUND: Cancer survivors and their caregivers may have various unmet needs that are medically difficult to solve. Previous studies have suggested the relations between individuals' backgrounds and their unmet needs. We conducted a large-scale analysis to clarify the influence of individuals' backgrounds, primarily cancer type, on specific types of unmet needs. METHODS: Using a mixed-methods approach, we analyzed records of first-time callers to a cancer-focused telephone consultation service that was provided by the Kanagawa Cancer Clinical Research Information Organization from October 2006 to May 2014. The qualitative approach concerned extracting unmet needs mentioned in each consultation and classifying them into themes of specific needs, while the quantitative approach comprised multi-variated analysis of the relationships between the frequency by which the needs in each theme arose and the associated callers' backgrounds. RESULTS: A total of 1938 consultation cases were analyzed. In the qualitative analysis, the needs were classified into 16 themes. The mean number of unmet needs for each caller was 1.58 (standard deviation = 0.86). In the multi-variated analysis, caregivers for colorectal cancer survivors had a lower frequency of "emotional/mental health" needs (OR: 0.31, 95%CI: 0.11-0.88, p = 0.028) than did caregivers for breast-cancer survivors. Nevertheless, this was the only significant difference in needs frequency among callers (including survivors and their caregivers) with specific cancer types. Meanwhile, there significant difference in the frequency of occurrence of each unmet need theme was found among items concerning other background elements. Among survivors, sex was related to the frequency of needs among "physical" and "resources" themes, and "emotions/mental health"; their age group with "employment"; treatment course with "physical" and "resources" themes and "cure"; residence with "physical" themes; presence of symptom with "physical," "education/information," "resources," "emotions/mental health," and "cure" themes. CONCLUSIONS: This large-scale study suggests that cancer type is not a significant factor for specific unmet needs and that individuals' backgrounds and presence of symptoms play a more important role. Through this study, it was found that instruments to predict people's needs and a system to provide individualized cancer care across cancer types should be developed in the future.

Development and validation of a prediction model for failed shockwave lithotripsy of upper urinary tract calculi using computed tomography information: the S3HoCKwave score.

PURPOSE: To develop and validate a new clinical prediction model that accurately predicts the failure of shockwave lithotripsy (SWL) using information obtained from non-contrast-enhanced computed tomography (NCCT). METHODS: This multicentre retrospective cohort study consecutively enrolled patients diagnosed with upper urinary tract calculi by NCCT at five hospitals in Japan from January 1, 2006 to December 31, 2016. Among the candidate predictors, we selected the six most significant predictors a priori. The main outcome was SWL failure after three sessions. Model calibration was evaluated by the calibration slope and the Hosmer-Lemeshow test. Discrimination was evaluated by the receiver-operating characteristic curves and the area under the curve (AUC). A multivariable logistic regression analysis was performed; based on the estimated ß coefficients, predictive scores were generated. RESULTS: Of 2695 patients, 2271 were included. Patients were divided into the development cohort (1666 patients) and validation cohort (605 patients) according to geographical factors. We developed a clinical prediction model with scores ranging from 0 to 49 points. We named the prediction model the S3HoCKwave score based on the initials of the predictors (sex, skin-to-stone distance, size, Hounsfield units, colic, and kidney or ureter). As a result of internal validation, the optimism-corrected AUC was 0.72. In the validation cohort, the Hosmer-Lemeshow test did not show statistical significance (P = 0.33), and the AUC was 0.71 (95% confidence interval 0.65-0.76). CONCLUSIONS: The S3HoCKwave score is easy to understand, has a relatively high predictive value, and allows clinicians to make appropriate treatment selections.

Preoperative Use of Alpha-1 Receptor Blockers in Male Patients Undergoing Extracorporeal Shock Wave Lithotripsy for a Ureteral Calculus.

In this retrospective single-center cohort study, we investigated the impact of preoperative use of an alpha-1 adrenergic receptor (AR) blocker on the outcome of single-session extracorporeal shock wave lithotripsy (SWL) in 193 male patients who underwent SWL for a single ureteral calculus between 2006 and 2016. We reviewed their medical records to obtain the data on the preoperative use of alpha-1 AR blockers. The primary outcome was treatment success after single-session SWL. We performed a multivariable logistic regression analysis adjusting for clinically important confounders to examine the association between preoperative use of alpha-1 AR blockers and the treatment success of SWL. Among the 193 patients, 15 (7.8%) were taking an alpha-1 AR blocker preoperatively. A multivariable analysis showed that preoperative use of an alpha-1 AR blocker was a significant negative predictor for treatment success of SWL (adjusted odds ratio 0.17; 95% confidence intervals, 0.04-0.74). Our findings suggest that the preoperative use of an alpha-1 AR blocker was a negative predictor of treatment success of SWL in male patients with a single ureteral calculus. Clinicians should pay more attention to the preoperative drug use in determining an appropriate stone therapy modality.

Highly multiplex guide RNA expression units of CRISPR/Cas9 were completely stable using cosmid amplification in a novel polygonal structure.

BACKGROUND: Genome editing using the CRISPR/Cas9 system is now well documented in basic studies and is expected to be applied to gene therapy. Simultaneous expression of multiplex guide RNA (gRNA) and Cas9/Cas9 derivative is attractive for the efficient knockout of genes and a safe double-nicking strategy. However, such use is limited because highly multiplex gRNA-expressing units are difficult to maintain stably in plasmids as a result of deletion via homologous recombination. METHODS: Lambda in vitro packaging was used instead of transformation for the construction and preparation of large, cos-containing plasmid (cosmid). Polymerase chain reaction fragments containing multiplex gRNA units were obtained using the Four-guide Tandem method. Transfection was performed by lipofection. RESULTS: We constructed novel cosmids consisting of linearized plasmid-DNA fragments containing up to 16 copies of multiplex gRNA-expressing units as trimer or tetramer (polygonal cosmids). These cosmids behaved as if they were monomer plasmids, and multiplex units could stably be maintained and amplified with a lack of deletion. Surprisingly, the deleted cosmid was removed out simply by amplifying the cosmid stock using lambda packaging. The DNA fragments containing multiplex gRNA-units and Cas9 were transfected to 293 cells and were found to disrupt the X gene of hepatitis B virus by deleting a large region between the predicted sites. CONCLUSIONS: We present a simple method for overcoming the problem of constructing plasmids stably containing multiplex gRNA-expressing units. The method may enable the production of very large amounts of DNA fragments expressing intact, highly-multiplex gRNAs and Cas9/Cas9 derivatives for safe and efficient genome-editing therapy using non-viral vectors.

Gait speed and overactive bladder in the healthy community-dwelling super elderly: The Sukagawa Study.

AIM: The objective of this study is to assess the association of muscle mass, grip strength, and gait speed with overactive bladder (OAB) in community-dwelling elderly adults. METHODS: This cross-sectional study was based on the data collected from 350 Japanese healthy community-dwelling elderly individuals aged 75 years or older from the Sukagawa Study. Muscle mass (kg) was measured by bioelectrical impedance, whereas grip strength (kg) and gait speed (m/s) were measured by performance testing. Muscle mass and grip strength were corrected for body mass index (BMI). The primary outcome was the presence of OAB, evaluated using the OAB symptom score. RESULTS: Of the 314 participants analyzed, 146 (47%) were men and 88 (28%) presented with OAB. The mean (SD) BMI, muscle mass, grip strength, and gait speed were 23.2 (3.2) kg/m 2 , 38.4 (7.5) kg, 26.6 (8.1) kg, and 1.2 (0.2) m/s, respectively. Multivariable logistic regression analysis revealed that slower gait speed was associated with a greater likelihood of OAB (adjusted odds ratio [aOR] per -1 SD, 1.47; 95% confidence interval [CI], 1.11-1.95). No significant associations between muscle mass or grip strength and OAB were noted (aOR per -1 SD, 0.75, 1.03; 95% CI, 0.41-1.37, 0.62-1.72, respectively). Slower gait speed was also associated with higher likelihood of urgency and urgency incontinence (aOR per -1 SD, 1.35, 1.40; 95% CI, 1.04-1.74, 1.06-1.84, respectively). CONCLUSIONS: In the healthy community-dwelling elderly, gait speed was associated with OAB, including urgency and urgency incontinence. Our findings may provide a new framework for OAB management with respect to functional mobility.