Objectives: Demonstrate an understanding of incobotulinumtoxinA efficacy in the treatment of adductor spas-modic dysphonia (SD). Understand that incobotulinumtoxinA can successfully be used as an alternative to onabotulinumtoxinA and for secondary non-responders.Methods: We conducted a prospective open-label trial from 2016 until 2019 regarding the use of incobotuli-nimtoxinA for the treatment of adductor spasmodic dysphonia. Exclusion criteria included pregnant/nursing women, botulinum toxin for other indications, known allergy, neuromuscular or systemic diseases, use of ami-noglycoside antibiotics, substance abuse, litigation regarding prior therapy, or other confounding conditions. Sixty-four injection sessions with completed with sixteen patients who were enrolled in the study and underwent EMG-guided incobotulinumtoxinA injections to the thyroarytenoid (TA) muscle using a hollow monopolar Teflon-coated needle via a trans-cricothyroid membrane approach. Dosages to each TA muscle were recorded and patients completed a Voice Handicap Index-10 (VHI-10), a validated worksheet regarding their perceived percent of normal function (PNF) following treatment, and a side effect profile. Outcomes were analyzed using the paired t-test.Results: For primary transitioners to incobotulinimtoxinA, VHI-10 scores and best percent normal function did not significantly change. For non-responders, VHI-10 decreased from 32.5 on Botox to 19.5 on incobotuli-nimtoxinA and best PNF increased from 37.6 to 90 %, which was statistically significant. Transient side effects included breathiness.Conclusions: Our study demonstrates that incobotulinimtoxinA may be used successfully for adductor SD either as first line treatment or in secondary non-responders to onabotulinumtoxinA.

Introduction Women’s baseline knowledge of pelvic floor exercises (PFEs) and pelvic floor disorders (PFDs) is not well established, as is their knowledge regarding PFE and participation in such exercise. The aim of our study was to assess baseline PFD and PFE knowledge and to determine if knowledge in any way influenced participation in PFEs. Methods This was an institutional review board–approved, cross-sectional survey administered to women 18 years or older. We included all women who completed the survey, of which 3733 met the criteria. A survey-based questionnaire was used to query lower urinary tract symptoms, PFD, knowledge, and frequency of participation in PFEs. Results Of those who responded, the mean incontinence knowledge score was 9.2 ± 2.6, whereas the mean score for pelvic organ prolapse (POP) knowledge was 6.8 ± 3.6. Of the respondents, 92.5% reported being familiar with Kegel exercises. The majority of respondents reported that they did not participate in PFEs (57.4%). Those with POP were more likely to do daily PFEs than those without POP, 34.8% versus 16.4% (P < 0.001). Stress urinary incontinence did not influence frequency of performing PFEs. Conclusions Our study demonstrated that while baseline knowledge of POP and incontinence knowledge were high in this patient population, the majority of participants did not participate in PFE. Participants with POP were more likely to partake in daily PFE. A gap exists between knowledge and willingness to participate in PFE. Bridging this gap may be significantly impactful for women’s health.

Increasing home dialysis prevalence is an international priority. Many patients start peritoneal dialysis, then transition to hemodialysis after complications. New strategies are needed to support modality persistence. Health mindset refers to individual belief about capacity to change to improve health. Mindset was measured in a cross-section of 101 adult peritoneal dialysis patients from April 2019 to June 2020. The Health Mindset Scale was administered to characterize the continuum of fixed vs. growth mindset with respect to health. Health literacy and health self-efficacy were also assessed. Participants were 43% female, 32% African American, and 42% diabetic. Health mindset scores were skewed toward growth (range 3–18), with average (SD) 12.83 (4.2). Growth mindset was strongly associated with health self-efficacy. Adults receiving peritoneal dialysis report health mindset variation. Growth mindset and health self-efficacy correlation suggests measurement of similar constructs, demonstrating convergent validity. The Health Mindset Scale may identify individuals who could benefit from targeted interventions to improve mindset, and foster peritoneal dialysis modality persistence.

Laryngeal sensory dysfunction (LSD) encompasses disorders of the vagal sensory pathways. Common manifestations include chronic refractory cough (CRC) and abnormal throat sensation (ATS). This study examined clinical characteristics and treatment outcomes of LSD using a novel approach of laryngeal supraglottic Onabotulinum toxin Type A injection (BTX). This was a retrospective review of clinical data and treatment outcomes of supraglottic BTX in patients with LSD. Between November 2019 and May 2021, 14 patients underwent 25 injection cycles of supraglottic BTX for treatment of symptoms related to LSD, including ATS and CRC. Primary outcome measures included the Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ), Cough Severity Index (CSI), Reflux Symptom Index (RSI), and Voice Handicap Index-10 (VHI-10) at baseline and within three months of treatment. Pre- and post-treatment data were compared using a linear mixed model. After supraglottic BTX, LHQ scores improved by 2.6. RSI and CSI improved by 8.0 and 5.0, respectively. VHI-10 did not change as a result of treatment. Short-term response to SLN block was significantly associated with longer term response to BTX treatment. These findings suggest that LSD presents clinically as ATS and CRC along with other upper airway symptoms. Supraglottic BTX injection is a safe and effective technique in the treatment of symptoms of LSD.

Rationale: If the risk of ventilator-induced lung injury in acute respiratory distress syndrome (ARDS) is causally determined by driving pressure rather than by Vt, then the effect of ventilation with lower Vt on mortality would be predicted to vary according to respiratory system elastance (Ers). Objectives: To determine whether the mortality benefit of ventilation with lower Vt varies according to Ers. Methods: In a secondary analysis of patients from five randomized trials of lower- versus higher-Vt ventilation strategies in ARDS and acute hypoxemic respiratory failure, the posterior probability of an interaction between the randomized Vt strategy and Ers on 60-day mortality was computed using Bayesian multivariable logistic regression. Measurements and Main Results: Of 1,096 patients available for analysis, 416 (38%) died by Day 60. The posterior probability that the mortality benefit from lower-Vt ventilation strategies varied with Ers was 93% (posterior median interaction odds ratio, 0.80 per cm H2O/[ml/kg]; 90% credible interval, 0.63-1.02). Ers was classified as low (<2 cm H2O/[ml/kg], n = 321, 32%), intermediate (2-3 cm H2O/[ml/kg], n = 475, 46%), and high (>3 cm H2O/[ml/kg], n = 224, 22%). In these groups, the posterior probabilities of an absolute risk reduction in mortality ≥ 1% were 55%, 82%, and 92%, respectively. The posterior probabilities of an absolute risk reduction ≥ 5% were 29%, 58%, and 82%, respectively. Conclusions: The mortality benefit of ventilation with lower Vt in ARDS varies according to elastance, suggesting that lung-protective ventilation strategies should primarily target driving pressure rather than Vt.

A detailed understanding of the adaptive host response to SARS-CoV-2 infection in humans is urgently needed, as questions abound regarding serologic responses and the development of antibody-mediated immunity against COVID-19. We developed a highly sensitive, high-throughput, and efficient assay using liquid bead array technology. We observed advantages over traditional indirect ELISA for the detection and quantification of binding IgG against the receptor binding domain (RBD) of SARS-CoV-2. Using this sensitive and highly reproducible assay, we sought to determine whether the severity of COVID-19 symptoms is correlated with SARS-CoV-2 binding IgG level. We measured SARS-CoV-2 RBD IgG levels from 67 subjects who had recovered from PCR-confirmed, symptomatic COVID-19. Samples were obtained approximately 6 weeks post-symptom onset. We found that COVID-19 symptom severity, assessed on an 8-point severity scale, strongly correlated with RBD IgG level (p<0.001), with and without adjustment for covariates of age, sex, and time from symptom onset. These findings have substantial implications for public policy surrounding assessments of antibody responses and possible immunity, as not all cases of COVID-19 can be assumed to generate a protective antibody response, and mild disease in particular is capable of generating very low-level anti-RBD IgG levels. These findings also have important implications for the selection of donors for convalescent plasma to be used as a therapeutic, and other scenarios where antibody level, rather than mere presence or absence, is relevant.

Abstract Background Patients interested in participating in Ulcerative Colitis (UC) and Crohn’s Disease (CD) clinical trials must be in the flare to qualify for enrollment. Digital technology can be used to help detect flares based on patient-reported symptoms, share information electronically with their physicians, and increase the likelihood of eligibility on clinical trials. Moreover, early detection and treatment of flares is key to patient management and outcomes. Methods IQVIA utilised an electronic survey to solicit input from adult patients with UC and CD, in the USA, regarding the optimum design of an app to both detect flares for participation on clinical trials and assist physicians with patient management. Patient input was critical to designing the app with features that would help manage disease, increase communication with their physicians, and increase opportunities for participation in clinical trials. Results Data were collected for 134 patients with IBD (70% 46 years or older and 28% 26–45 years old). Only 23% of respondents had previously downloaded an app to help manage their IBD, however, 78% were interested. 85% would find capturing flares and electronically sharing symptom information with their doctors useful to monitoring and managing their IBD. And 88% would find notifications about clinical research studies useful. More than 61% would be likely to go to this app when they first have symptoms of a flare and enter symptoms every day. 55% would be likely to download an app that would monitor IBD flares to see if they may qualify for a clinical research study. Of those with an interest in participation in clinical research, 27% had already participated in a study. Of this same group, 92% would be likely to download an app if it would also track IBD symptoms. Inclusion of functionality for food, stress, mood, exercise and compliance were recommended by patients to assist in elucidating factors that may cause flares. Conclusion Patients are very interested in using an app that would help detect flares, though only a minority do so at present. They are supportive of entering symptoms and related information on a daily basis, but also expanding to inclusion of other factors which may be relevant to flares for individuals. The results of this survey were influential in the recent development of an IBD app.

Abstract Background Given the increasing costs of drug development, coupled with low success rates, there is a need to both develop better predictive models and elucidate causes of failure. However, for indications such as ulcerative colitis, a baseline does not presently exist. In this paper, we review trends in drug development and establish a baseline for ulcerative colitis. Methods We used BiomedTracker to obtain information about the number of compounds, which were in development for ulcerative colitis between 2005 and 2018. We counted the number of compounds, which had reached a particular phase, had been discontinued during this phase, had successfully passed it or had been still in this phase. Success rates were derived for the different phases of drug development for all 73 candidate drugs and divided by type of molecule and type of company. A success rate was calculated by dividing the number of drugs successfully completing a particular phase by the sum of the number of drugs which were discontinued during this phase and the number of compounds that completed positively a phase. The likelihood for approval (LOA) for each phase was calculated by multiplying the success rate for the respective phase with the success rates of next stages of development. Results The success rate in phase I was 96 %, in phase II 53 % and in phase III 76%, while the respective LOA was 0.39, 0.4 and 0.76. Table 1 demonstrates the success rates and LOA by type of compound(New molecular entity (NME), Biologic, non-NME) and type of company (big, mid-size, emerging). Conclusion The general industry success rates and LOA for phase I is 64%, for Phase 2 30%, and for phase 3 60% while the LOA from phase I is 10%. These data are published by Michael Hay and co-authors in Nature in January 2014. The success rates in UC drug development are therefore higher than the overall industry success rates.

Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study. 620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP. Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone. In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

Background Meningiomas are common intracranial tumors that often necessitate surgical intervention. There is a need for risk stratification tools that accurately predict individual patient outcomes after surgery for meningioma.

Objectives A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes. Setting Pooled data from three randomised trials in intensive care identified by a systematic review. Participants 2299 patients with acute lung injury requiring mechanical ventilation. Interventions Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy. Outcome measures Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure−PEEP)) and body mass index (BMI). Results We found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m2, we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings. Conclusions MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS. Study registration number CRD42012003129.

BACKGROUND:Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (CRS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (ΔP=VT/CRS), in which VT is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than VT or PEEP in patients who are not actively breathing.METHODS:Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined ΔP as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease.RESULTS:Among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, P=0.004 and P=0.001, respectively).CONCLUSIONS:We found that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundação de Amparo e Pesquisa do Estado de São Paulo and others.).