Intravesical Lactobacillus rhamnosus GG Alters Urobiome Composition and Diversity Among People With Neurogenic Lower Urinary Tract Dysfunction.

Background: Neurogenic bladder is associated with bacterial colonization and frequent urinary tract infections. Objectives: To explore the effects of one to two doses of intravesical Lactobacillus rhamnosus GG (LGG) on the urobiomes of adults with spinal cord injury/disease (SCI/D) who manage their bladders with intermittent catheterization (IC). Methods: This was a pilot substudy within an 18-month phase 1 clinical trial of self-instilled intravesical LGG for urinary symptoms as directed by the Self-Management Protocol using Probiotics (SMP-Pro). Urine samples were collected monthly when participants were asymptomatic. When SMP-Pro "trigger" symptoms (cloudier and/or more foul-smelling urine) occurred, urine samples were collected immediately pre-LGG instillation and 24 to 48 hours after LGG instillation. Urine was collected via a new catheter, immediately placed on ice/freezer, and processed within 12 hours. Genomic DNA was isolated, and the V4 region of the 16S rRNA bacterial gene was amplified and high throughput sequenced. Amplicon sequence variants were inferred and bacterial composition, community structure, and variation across clinical phenotypes were determined. Results: 126 urine samples were collected from 26 participants (SCI/D = 23; multiple sclerosis = 2; spina bifida = 1) between 20 and 57 years of age. The urobiomes were characterized by four dominant phyla (>1%): Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria, which were comprised of six dominant genera (>3%): Escherichia/Shigella (29.1%), Klebsiella (22.4%), Proteus (15.2%), Aerococcus (6.3%), Streptococcus (6.0%), and Pluralibacter (3.0%). Post-LGG samples were associated with a decline in Escherichia/Shigella predominance (p < .001) and altered bacterial diversity (p < .05). Conclusion: Among people with SCI/D who use IC, intravesical LGG alters the bacterial composition and diversity of the urine ecosystem, potentially disrupting the uropathogenic urobiome.

Urinary Symptoms Among People With Neurogenic Lower Urinary Tract Dysfunction (NLUTD) Vary by Bladder Management.

Objectives: To determine whether assessment and decision-making around urinary symptoms in people with neurogenic lower urinary tract dysfunction (NLUTD) should depend on bladder management. Methods: Three surveys of urinary symptoms associated with NLUTD (USQNBs) were designed specific to bladder management method for those who manage their bladders with indwelling catheter (IDC), intermittent catheter (IC), or voiding (V). Each was deployed one time to a national sample. Subject matter experts qualitatively assessed the wording of validated items to identify potential duplicates. Clustering by unsupervised structural learning was used to analyze duplicates. Each item was classified into mutually exclusive and exhaustive categories: clinically actionable ("fever"), bladder-specific ("suprapubic pain"), urine quality ("cloudy urine"), or constitutional ("leg pain"). Results: A core of 10 "NLUTD urinary symptoms" contains three clinically actionable, bladder-specific, and urine quality items plus one constitutional item. There are 9 (IDC), 11 (IC), and 8 (V) items unique to these instruments. One decision-making protocol applies to all instruments. Conclusion: Ten urinary symptoms in NLUTD are independent of bladder management, whereas a similar number depend on bladder management. We conclude that assessment of urinary symptoms for persons with NLUTD should be specific to bladder management method, like the USQNBs are.

Urinary Symptoms Are Unrelated to Leukocyte Esterase and Nitrite Among Indwelling Catheter Users.

Objectives: To explore the association between dipstick results and urinary symptoms. Method: This was a prospective 12-month observational study of real-time self-administered urine dipstick results and symptoms in a community setting that included 52 spinal cord injury/disease (SCI/D) participants with neurogenic lower urinary tract dysfunction (NLUTD) who use an indwelling catheter. Symptoms were collected using the Urinary Symptom Questionnaire for Neurogenic Bladder-Indwelling Catheter (USQNB-IDC). The USQNB-IDC includes actionable (A), bladder (B1), urine quality (B2), and other (C) symptoms; analyses focused on A, B1, and B2 symptoms. Dipstick results include nitrite (NIT +/-), and leukocyte esterase (LE; negative, trace, small, moderate, or large). Dipstick outcomes were defined as strong positive (LE = moderate/large and NIT+), inflammation positive (LE = moderate/large and NIT-), negative (LE = negative/trace and NIT-), and indeterminate (all others). Results: Nitrite positive dipsticks and moderate or large LE positive dipsticks were each observed in over 50% of the sample in every week. Strong positive dipstick results were observed in 35% to 60% of participants in every week. A, B1, or B2 symptoms co-occurred less than 50% of the time with strong positive dipsticks, but they also co-occurred with negative dipsticks. Participants were asymptomatic with a strong positive dipstick an average of 30.2% of the weeks. On average, 73% of the time a person had a negative dipstick, they also had no key symptoms (95% CI, .597-.865). Conclusion: No association was observed between A, B1, and B2 symptoms and positive dipstick. A negative dipstick with the absence of key symptoms may better support clinical decision-making.

Independence of Urinary Symptoms and Urinary Dipstick Results in Voiders With Neurogenic Bladder.

Background: Urinary symptoms and urinary tract infection (UTI) are frequent and burdensome problems associated with neurogenic lower urinary tract dysfunction. Objectives: To determine whether an association exists between urinary symptoms and urine dipstick results among individuals with spinal cord injury (SCI) or multiple sclerosis (MS). Methods: Prospective 12-month cohort study of 76 participants with SCI or MS who manage their bladders by voiding. Eligibility criteria included adults ≥18 years old, at least three UTIs since diagnosis, and residence in the United States. Participants completed the Urinary Symptoms Questionnaire for Neurogenic Bladder-Voider version (USQNB-V) biweekly (26 assessments) and tested their urine by dipstick at the same time. Symptom burden was estimated based on endorsements of USQNB-V symptoms classified as clinically actionable (9), bladder function (8), and urine quality (4). Urine dipstick results assessed were leukocyte esterase (LE) and nitrite (NIT). Results: Participants were stratified into four groups based on etiology of neurologic dysfunction and whether they ever experienced any urinary symptoms (USx): SCI+USx (n = 14), SCI+NoUSx (n = 5), MS+USx (n = 32), and MS+NoUSx (n = 25). In descending order, symptom burden was greatest for the MS+USx group, followed by both SCI groups; it was lowest for MS+NoUSx. We assessed multiple definitions of "positive" dipstick and found evidence of independence of USQNB-V symptoms and urinary dipstick results with each definition. In each group, the median (and majority) of strong positive dipsticks did not coincide with any symptoms. Conclusion: Among people with SCI or MS who void, self-administered urine dipstick results and urinary symptom reporting contribute independent information for clinical decision making.

Outcomes of patients with COVID-19 after inpatient rehabilitation.

BACKGROUND: Rehabilitation outcomes of patients with coronavirus disease 2019 (COVID-19) are unknown. OBJECTIVE: To describe patients with COVID-19 who are undergoing inpatient rehabilitation and their rehabilitation outcomes. DESIGN: Retrospective observational cohort study of all inpatients from a rehabilitation hospital between March 1 and September 30, 2020. SETTING: Inpatient rehabilitation hospital. PATIENTS: Among all inpatients, inclusion criteria are: ≥18 years of age and admission and discharge within the study time frame. The initial search yielded 920 patients; 896 met the inclusion criteria. Subjects were stratified by COVID-19 status and rehabilitation impairment. MAIN OUTCOME MEASURES: Data included age, gender, body mass index (BMI), length of stay (LOS), discharge location, and functional ability in self-care and mobility (FA-SC, FA-Mob). One-sample t-tests were used to assess the difference of age, BMI, LOS, FA-SC, FA-Mob, and FA efficiency between COVID-19+ and COVID-19- patients. RESULTS: COVID-19+ patients were younger (59.4 years vs 62.9 years; t[894] = -2.05, p = .04) with a higher mean BMI (32 vs 28; t[894] = 3.51, p < .01) than COVID-19- patients. COVID-19+ patients had equivalent or superior improvements in FA-SC and FA-Mob, functional change efficiency, and LOS relative to COVID-19- patients. When medically complex patients were compared, those with COVID-19 had greater FA-SC and FA-Mob efficiencies than COVID-19- patients. COVID-19+ patients had similar rates of return to the community. CONCLUSIONS: Patients with COVID-19 who meet the admission criteria for inpatient rehabilitation can benefit from inpatient rehabilitation similarly to their non-COVID-19 counterparts with similar rehabilitation-specific diagnoses.

Reliability of the Urinary Symptom Questionnaires for people with neurogenic bladder (USQNB) who void or use indwelling catheters.

STUDY DESIGN: This is a descriptive psychometrics study. OBJECTIVES: Neurogenic lower urinary tract dysfunction (NLUTD), also called Neurogenic Bladder (NB), is a common and disruptive condition in a variety of neurologic diagnoses. Our team developed patient-centered instruments, Urinary Symptom Questionnaires for people with neurogenic bladder (USQNB), specific to people with NLUTD who manage their bladders with intermittent catheterization (IC), indwelling catheters (IDC), or who void (V). This article reports evidence of reliability of the IDC and V instruments. SETTING: Online surveys completed by individuals in the United States with NLUTD due to spinal cord injury (SCI), or multiple sclerosis (MS) who manage their bladder with IDC (SCI, n = 306), or by voiding (SCI, n = 103; MS, n = 383). METHODS: Reliability estimates were based on endorsement of the items on the USQNB-IDC and USQNB-V. Reliability evidence was representativeness of these symptoms for a national sample (by determining if endorsement > 10%); internal consistency estimates (by Cronbach's alpha and item correlation coefficient, ICC); and interrelatedness of the items (by inferred Bayesian network, BN). We also tested whether a one-factor conceptualization of "urinary symptoms in NLUTD" was supportable for either instrument. RESULTS: All items were endorsed by >20% of our samples. Urine quality symptoms tended to be the most commonly endorsed on both instruments. Cronbach's alpha and ICC estimates were high (>0.74), but not suggestive of redundancy. BNs showed interpretable associations among the items, and did not discover uninterpretable or unexpected associations. Neither instrument fit a one-factor model, as expected. CONCLUSIONS: The USQNB-IDC and USQNB-V instruments show sufficient, multidimensional reliability for implementation and further study.

Validity of the Urinary Symptom Questionnaires for people with neurogenic bladder (USQNB) who void or use indwelling catheters.

STUDY DESIGN: Descriptive Psychometrics Study OBJECTIVES: Neurogenic lower urinary tract dysfunction (NLUTD), or "neurogenic bladder" is a common and disruptive condition for individuals with spinal cord injury (SCI) and disease (including multiple sclerosis, MS). Our team has developed patient-centered instruments of urinary symptoms specific to patients with NLUTD, across bladder management methods. Validity evidence is needed to support the use of two new instruments, Urinary Symptom Questionnaires for people with Neurogenic Bladder (USQNB) for those who manage their bladder with indwelling catheters (IDC), or who void (V). SETTING: Online surveys completed by individuals in the United States with NLUTD due to either SCI or MS who manage their bladder with indwelling catheters (SCI, n = 306; MS, n = 8), or by voiding (SCI, n = 103; MS, n = 383). A total of n = 381 USQNB-IDC respondents (five control groups), and 351 USQNB-V respondents (four control groups), contributed to our convergent and divergent validity evidence. METHODS: Data were collected online to estimate key aspects of psychometric validity (content, reflection of the construct to be measured; face, recognizability of the contents as representing the construct to be measured; structural, the extent to which the instrument captures recognizable dimensions of the construct to be measured). Divergent and convergent validity evidence was derived from multiple control groups, while evidence of criterion validity was derived from attribution of each item to their experience "with a UTI". RESULTS: Evidence of face, content, criterion, convergent, and divergent validity was compiled for each instrument. CONCLUSIONS: The instruments demonstrate adequate, multi-dimensional, validity evidence to recommend their use for decision-making by patients, clinicians, and researchers.

The association between urine neutrophil gelatinase-associated lipocalin and UTI in people with neurogenic lower urinary tract dysfunction.

STUDY DESIGN: Secondary analysis of urine samples collected from a prospective within-subject clinical trial. OBJECTIVES: Describe the baseline variation in urine neutrophil gelatinase-associated lipocalin (uNGAL) levels in adults with neurogenic lower urinary tract dysfunction (NLUTD) and determine if uNGAL levels vary according to likelihood of having a UTI. SETTING: Greater Washington D.C. region. METHODS: Urine samples were collected from a cohort of adults with NLUTD from a clinical trial. Samples were divided into groups of "Not UTI", "Unlikely UTI", and "Likely UTI" based on symptoms and urine culture results. uNGAL was compared between groups using Kruskal-Wallis and post hoc Dunn's test. Mixed effects logistic model was used to assess the association of uNGAL and Likely UTI. RESULTS: Twenty-seven participants provided a total of 104 samples. uNGAL levels were lowest for the No UTI group (n = 29; 37 ng/ml interquartile range (IQR) (15, 71)), intermediate for the Unlikely UTI group (n = 67; 95 ng/ml IQR (37, 161)) and highest for the Likely UTI group (n = 8; 187 ng/ml IQR(146, 224)). uNGAL levels were higher in those with Likely UTI compared to both Unlikely UTI (p < 0.05) and No UTI (p < 0.01). uNGAL had an association with Likely UTI (OR 1.01, 95% CI (1.00-1.02), p = 0.049). CONCLUSIONS: Adults with NLUTD have notable variation in uNGAL levels in the absence of symptoms potentially due to UTI. uNGAL levels are higher in those who are likely to have UTI have higher uNGAL levels compared to those with non-specific symptoms and/or less growth on urine culture. uNGAL may have utility as a marker of UTI in people with NLUTD. SPONSORSHIP: Patient-Centered Outcomes Research Institute (PCORI) funded this work. Bioporto provided partial salary support for SLG, IL, and OKL. NGAL ELISAs were provided by Bioporto in kind.

Clinical Profiles and Symptom Burden Estimates to Support Decision-Making Using the Urinary Symptom Questionnaire for People with Neurogenic Bladder (USQNB) using Intermittent Catheters.

OBJECTIVE: To describe the scoring approach, considering interpretability, validity, and use, of a new patient-centered patient reported outcome (PRO), the Urinary Symptom Questionnaire for Neurogenic Bladder-Intermittent Catheter version (USQNB-IC). DESIGN: Subject matter experts (researchers, clinicians, a consumer, a psychometrician) classified USQNB-IC items. Profiles were then composed based on self-management decisions made by patients; patient management decisions made by clinicians; and research-oriented decisions made by investigators. Participants in an 18-month pilot study completed the USQNB-IC every week. Differences in decisions based on traditional 'total scores' and profiles were examined. Validity was defined based on alignment of scoring method with decisions. SETTING: A new set of patient-centered PROs enable monitoring and decision-making around urinary signs and symptoms among people with neurogenic bladder (NB). PARTICIPANTS: Classifications of USQNB-IC items by subject matter experts. Utility of the classifications and profiles that were created was assessed using weekly responses from the 6-month baseline period from 103 participants in a pilot study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Classification of the 29 symptoms resulted in four categories with exchangeability within-category and nonexchangeability across categories. The burden of each symptom type is one approach to scoring the USQNB-IC. Five profiles, based on these categories, emerged based on, and supportive of, decisions to be made according to symptoms, representing a categorical approach to scoring the USQNB-IC. RESULTS: USQNB-IC items are not all exchangeable. Four symptom classifications comprise within-class exchangeable items. Five profiles emerged to summarize these items to promote decision-making and identification of change over time. Both ways to "score" the USQNB-IC are described and discussed. CONCLUSIONS: "Profiling" promotes valid and interpretable decisions by patients and clinicians, based on a patient's urinary symptoms with the USQNB-IC cross-sectionally and longitudinally. Alternatively, four subsets of the 29 USQNB-IC symptoms can be used as continuous outcomes representing "burden" in clinical management or research.

Effects of Intravesical Lactobacillus Rhamnosus GG on Urinary Symptom Burden in People with Neurogenic Lower Urinary Tract Dysfunction.

OBJECTIVE: To test the effectiveness of intravesical Lactobacillus rhamnosus GG (LGG) to reduce the burden of urinary symptoms for individuals with spinal cord injury and disease (SCI/D) with neurogenic lower urinary tract dysfunction (NLUTD) who manage their bladders with intermittent catheterization (IC). DESIGN: A three-phase study (6 months each in baseline, intervention, and washout). Participants self-managed following the Self-Management Protocol using Probiotics (SMP-Pro), completing the online Urinary Symptom Questionnaire for Neurogenic Bladder-IC version (USQNB-IC) weekly. SETTING: Nationwide (United States). PARTICIPANTS: Ninety-six adults and seven children with SCI/D. INTERVENTIONS: In response to one or both of the SMP-Pro trigger urinary symptoms, "cloudier" or "foul smelling" urine, participants self-administered using a clean urinary catheter an LGG+ Normal Saline instillate once or twice in a 30-hour period. MAIN OUTCOME MEASURES: Change in USQNB-IC burden was adjusted individually according to the previous phase for four symptom types. Adjusted changes in burden between the intervention and washout phases were analyzed using one-sample t-tests. Holm correction was applied for the four types of symptoms: A, clinically actionable; B1, bladder function; B2, urine quality; and C, other. RESULTS: During the intervention phase, participants met SMP-Pro instillation criteria 3.83 times on average (range 1-20). An average of 5.6 doses of LGG were instilled. For those who instilled at least once, burdens of type A and B2 symptoms were significantly improved at washout (both adjusted P < .05). CONCLUSIONS: Self-instilled LGG seemed to improve "clinically actionable" (A) and "urine quality" (B2) symptom burden. No changes were observed for those who did not instill. This first-in-human clinical trial supports ongoing research of intravesical LGG, and the SMP-Pro for urinary symptoms.

Roles of Lesioned and Nonlesioned Hemispheres in Reaching Performance Poststroke.

Background. Severe poststroke arm impairment is associated with greater activation of the nonlesioned hemisphere during movement of the affected arm. The circumstances under which this activation may be adaptive or maladaptive remain unclear. Objective. To identify the functional relevance of key lesioned and nonlesioned hemisphere motor areas to reaching performance in patients with mild versus severe arm impairment. Methods. A total of 20 participants with chronic stroke performed a reaching response time task with their affected arm. During the reaction time period, a transient magnetic stimulus was applied over the primary (M1) or dorsal premotor cortex (PMd) of either hemisphere, and the effect of the perturbation on movement time (MT) was calculated. Results. For perturbation of the nonlesioned hemisphere, there was a significant interaction effect of Site of perturbation (PMd vs M1) by Group (mild vs severe; P < .001). Perturbation of PMd had a greater effect on MT in the severe versus the mild group. This effect was not observed with perturbation of M1. For perturbation of the lesioned hemisphere, there was a main effect of site of perturbation (P < .05), with perturbation of M1 having a greater effect on MT than PMd. Conclusions. These results demonstrate that, in the context of reaching movements, the role of the nonlesioned hemisphere depends on both impairment severity and the specific site that is targeted. A deeper understanding of these individual-, task-, and site-specific factors is essential for advancing the potential usefulness of neuromodulation to enhance poststroke motor recovery.

Intravesical Lactobacillus rhamnosus GG is safe and well tolerated in adults and children with neurogenic lower urinary tract dysfunction: first-in-human trial.

BACKGROUND: Urinary symptoms are common for people with neurogenic lower urinary tract dysfunction (NLUTD). No nonprescription approach has been proven safe and effective for self-management of urinary symptoms. Our objective was to describe the safety and tolerability of Lactobacillus rhamnosus GG (LGG®) instilled intravesically for self-management of inflammatory urinary symptoms in adults and children with NLUTD due to spinal cord injury or disease (SCI/D) and who use intermittent catheterization (IC). METHODS: A total of 103 individuals with SCI/D enrolled in an 18-month study consisting of three 6-month stages: baseline (weekly observation of urinary symptoms); intervention (self-instilled intravesical LGG® in response to more cloudy or foul-smelling urine); and washout (weekly observation of urinary symptoms). Urinary symptoms were assessed using the Urinary Symptom Questionnaire for people with neurogenic bladder using intermittent catheters (USQNB-IC). Safety was based on serious adverse events and adverse events (S/AEs) and trends in symptoms. Tolerability was defined as the independence of AE experience and willingness to use/pay for this intervention. RESULTS: A total of 74 (77%) adults and 6 (86%) of children completed the study, of whom 64 instilled LGG® for a total of 357 instillations (range 1-41 per person). There were 59 S/AEs, 44% (26/59) of which were categorized as infectious genitourinary. There was no statistical relationship between S/AEs and use or dose of the intervention. CONCLUSIONS: One or two doses of self-instilled intravesical LGG® in response to more cloudy or foul-smelling urine was safe and well tolerated among this sample of adults and children with SCI/D who have NLUTD and use IC.

Preliminary validation of a Urinary Symptom Questionnaire for individuals with Neuropathic Bladder using Intermittent Catheterization (USQNB-IC): A patient-centered patient reported outcome.

BACKGROUND: We developed a Urinary Symptom Questionnaire for individuals with neurogenic bladder due to spinal cord injury (SCI) and spina bifida (SB) who manage their bladders with intermittent catheterization, the USQNB-IC. This project followed an approach to patient-centered patient reported outcomes development that we created and published in 2017, specifically to ensure the primacy of the patient's perspective and experience. PARTICIPANTS: Two sets of responses were collected from individuals with neurogenic bladder due to either SCI (n = 336) and SB (patients, n = 179; and caregivers of patients with NB, n = 66), and three sets of "controls", individuals with neurogenic bladder who do not have a history of UTIs (n = 49) individuals with chronic mobility impairments (neither SCI nor SB) and without neurogenic bladder (n = 46), and those with no mobility impairment, no neurogenic bladder, and no history of UTIs (n = 64). METHOD: Data were collected from all respondents to estimate these psychometric or measurement domains characterizing a health related PRO: Reliability (minimization of measurement error; internal consistency or interrelatedness of the items; and maximization of variability that is due to "true" difference between levels of the symptoms across patients), and validity (content, reflection of the construct to be measured; face, recognizability of the contents as representing the construct to be measured; structural, the extent to which the instrument captures recognizable dimensions of the construct to be measured; and criterion, association with a gold standard). RESULTS: Evidence from these five groups of respondents suggest the instrument has face, content, criterion, convergent, and divergent validity, as well as reliability. The items were all more descriptive of our patient (focus) groups and were only weakly endorsed by the control groups. CONCLUSIONS: The instrument is unique in its emphasis on, and origination from, the lived experiences of patients with neurogenic bladder who use intermittent catheterization; this preliminary psychometric evidence suggests the instrument could be useful for research and in the clinic. These results justify further development of the instrument, including formal exploration of the scoring and estimation of responsivity of these items to clinical interventions as well as patient-directed self care.

Nivolumab for second-line treatment of metastatic squamous non-small-cell lung cancer.

PURPOSE: The pharmacokinetics, pharmacodynamics, efficacy, toxicity, and place in therapy of nivolumab, a novel immunotherapy agent for the treatment of advanced non-small-cell lung cancer (NSCLC) of the squamous cell subtype are reviewed. SUMMARY: Nivolumab is a novel programmed cell death 1 (PD-1) immune checkpoint inhibitor indicated as a second-line treatment for patients with NSCLC whose tumors exhibit squamous cell histology. Nivolumab has high affinity for the PD-1 receptor, and durable responses to treatment have been reported in clinical trials. In a Phase II study evaluating the drug's safety and efficacy in patients who had disease progression despite treatment with platinum-based doublet chemotherapy and at least one additional systemic therapy, nivolumab-treated patients had an objective response rate of 14.5%, with a 17% rate of grade 3 or 4 treatment-related adverse events; overall survival at one year was 40.8%. A head-to-head comparison of docetaxel and nivolumab for second-line treatment of squamous cell NSCLC demonstrated superior overall survival and reduced grade 3 or 4 adverse effects in nivolumab-treated patients. CONCLUSION: Nivolumab is a novel PD-1 immune checkpoint inhibitor that is effective for treating advanced squamous NSCLC in patients previously treated with platinum-based doublet chemotherapy or alternative first-line agents. Based on its improved efficacy and lower toxicity relative to docetaxel, nivolumab should be considered standard second-line therapy for this population.