Varma, Revati

Background: Group 1 pulmonary artery hypertension (PAH) is treated with three main drug classes: prostacyclin analogs (PCAs), endothelin receptor antagonists, and nitric oxide pathway drugs. PCAs may be administered via parenteral (intravenous (IV), subcutaneous (SQ)) or oral/inhaled routes. The role of parenteral versus non-parenteral PCAs in contemporary PH practice remains unclear. Objectives: To compare contemporary hemodynamic and survival outcomes between parenteral and non-parenteral PCA use. Methods: This retrospective study included patients with WHO Group 1 PAH, who underwent a right heart catheterization (RHC) at Mayo Clinic. Diagnosis required mPAP was ≥25 mm Hg, documented chart diagnosis and initiation of PAH therapy. Echocardiographic and repeat RHC parameters were collected and only patients started on PCA therapy were included. Patients were grouped based on intiiated PCA route: parenteral (IV/SQ) vs non-parenteral routes (oral/inhaled). Hemodynamic changes (post-pretreatment) were compared using t-tests and ANOVA for parenteral vs non-parenteral PCA. Survival was assessed using Kaplan-Meier curves, and Cox proportional hazards models. Results: Of 144 patients initiated on PCA after the first RHC, 89 (62%) received parenteral and 55 (38%) non-parenteral PCA.. At baseline, patients who started on parenteral PCA had more severe disease with higher mean PAP, RAP and PVR. On follow-up, parenteral PCAs led to greater reductions in mean PAP and RAP, with no differences in PVR, TPR, or CO changes. Survival was worse with parenteral PCA use even after adjusting for comorbidities and baseline hemodynamics (HR 1.93; 95% CI 1.17-3.18; p=0.009). Discussion: Parenteral PCAs were more often used in patients with more severe pulmonary vascular disease. Despite greater hemodynamic improvements, parenteral PCAs were associated with worse survival, likely due to more severe disease at baseline. Further research is needed to understand the role of PCA route in guiding treatment strategies.

Abstract Background Small studies suggest that constipation is a common symptom associated with a worse prognosis in patients with Parkinson's disease (PD). Objectives The aim was to compare the association between constipation, motor, and other non‐motor symptoms (NMS) in PD patients at baseline and in future. Methods Using the Fox Insight database, we compared baseline characteristics, risk of progressive motor symptoms, and incidence of NMS between PD patients with versus without constipation. Results Of 20,352 participants, 16,611 (82%) reported infrequent bowel movements and/or excessive straining, 15,594 (77%) had incomplete evacuation, and 14,165 (70%) reported both symptoms. Patients with constipation were generally older, white, women, had PD >5 years, and had higher NMS and comorbidity scores ( P < 0.001). Constipation was significantly associated with worse motor symptoms and most NMS , especially fecal incontinence (odds ratio [ OR] = 1.65; 95% confidence interval [CI], 1.49–1.82), dysphagia ( OR = 1.20; 95% CI = 1.12–1.29), talking/moving during sleep ( OR = 1.39; 95% CI = 1.30–1.48), and urinary urgency ( OR = 1.23; 95% CI = 1.16–1.32). Constipation was associated with a small, but statistically significant increased risk of some progressive motor symptoms. At a mean median follow‐up of 2.8 years, constipation was associated with an increased risk of incident gastrointestinal, autonomic, neuropsychiatric, sleep‐related, sensory NMS , such as dysphagia (hazard ratio [ HR] = 1.43; 95% CI = 1.35–1.51), fecal incontinence ( HR = 1.87; 95% CI = 1.74–2.01), falls ( HR = 1.44; 95% CI = 1.35–1.52), hallucinations ( HR = 1.65; 95% CI = 1.52–1.79), cognitive impairment ( HR = 1.38; 95% CI = 1.30–1.47), and talking/moving during sleep ( HR = 1.65; 95% CI = 1.55–1.75). Conclusions Constipation is a common symptom associated with severity of motor and other NMS and portends a worse prognosis in persons with PD.

ABSTRACTBackgroundThe carbon‐13 spirulina gastric emptying breath test (GEBT) is approved to identify delayed, but not accelerated, gastric emptying (GE). We compared the utility of the GEBT to scintigraphy for diagnosing abnormal GE in patients with diabetes mellitus.MethodsTwenty‐eight patients with diabetes ate a 230‐kcal test meal labeled with technetium 99 m and 13C‐spirulina, after which 10 scintigraphic images and breath samples (baseline, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min) were collected on 2 occasions 1 week apart. We assessed the accuracy of 13C‐spirulina GEBT excretion rate (percent dose multiplied by 1000 [kPCD] min−1) values to predict scintigraphic half‐life and distinguish between normal, delayed, and accelerated GE and the intraindividual reproducibility of the GEBT.Key ResultsScintigraphy revealed normal, delayed, and accelerated GE, respectively, in 17 (30%), 29 (52%), and 10 (18%) test results. GE T½ values measured with scintigraphy and GEBT were highly concordant within individuals; the intraindividual reproducibility was 34% (scintigraphy) and 15% (GEBT). Compared to current criteria, the kPCD150 (150 min) and kPCD180 values provided equally sensitive (90%) and more specific (81% vs. 67%) approach for distinguishing between delayed versus normal/accelerated GE. A new metric (kPCD60–kPCD15 min) was 90% sensitive and 83% specific for distinguishing between accelerated versus normal/delayed GE. These findings were used to create nomograms and an algorithm for interpreting GEBT results.Conclusions and InferencesAmong patients with poorly controlled diabetes, the 13C‐spirulina GEBT can accurately and precisely assess GE and effectively distinguish between normal, delayed, and accelerated GE.

Introduction: Obesity is rising in prevalence worldwide and co-exists in patients with group 1 pulmonary hypertension (PH). Clinical and hemodynamic implications of having obesity in group 1 PH remain unknown. Hypothesis . We hypothesized that obese patients with group 1 PH would exhibit worse hemodynamic parameters including higher right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) compared to non-obese patients. Aims: To compare hemodynamic parameters obtained from right heart catheterization (RHC) and echo among group 1 PH with and without obesity. Methods: We evaluated a cohort of patients with group 1 PH who underwent RHC at Mayo Clinic Rochester between 2002 to 2021 with diagnosis adjudicated by detailed chart review and initiation of pulmonary vasodilator therapy. Patients with a mean pulmonary artery pressure (mPAP) ≥ 25 mm who were clinically diagnosed with WHO Group 1 PH and recommended pulmonary vasodilator therapy initiation were included. Results: Of 822 participants with group 1 PH, obesity was common, present in 325 patients (40%). There was no difference in survival among patients with and without obesity (HR 1.15; 95% CI 0.95-1.38; p=.15). Obese patients had higher RAP (12.8 ± 6.8 vs 10.4 ± 6.5 mm of Hg, p<.0001) and cardiac output (5.2 ± 2.2 vs 4.5 ± 1.8 L/min, p<.0001) compared to non-obese group (Table 1). Despite having group 1 PH, pulmonary capillary wedge pressure (PCWP) was higher with obesity (13.8 ± 6.3 vs 12.2 ± 6.5 mm of Hg, p=.001) compared to those without obesity. Along with higher PCWP, there was less pulmonary vascular disease severity with obese group 1 PH, with higher pulmonary artery compliance (PAC, 1.65 ± 1.06 vs 1.38 ± 0.84 mL/mm of Hg, p=.0002) and lower pulmonary vascular resistance (PVR, 7.9 ± 5.2 vs 9.4 ± 7.7 Wood Units, p=.0007). After accounting for age, gender, diabetes mellitus and systemic hypertension, the RAP, cardiac output, PAC and PCWP remained significantly higher, and PVR remained lower in obese patients (p<0.05 for all). Conclusions: Comorbid obesity is associated with higher biventricular filling pressures, higher cardiac output and lower pulmonary vascular disease severity in otherwise clinically diagnosed group 1 PH. These findings call for further study of whether targeting obesity with novel weight loss drugs such as glucagon like peptide 1 receptor agonists or other drugs can lower biventricular filling pressures and associated pulmonary hypertension in group 1 PH with obesity.

AbstractBackgroundThis study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]).MethodsWe performed a randomized, double‐blinded, placebo‐controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed.Key ResultsOf 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024).Conclusions & InferencesOndansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

Abstract Background Although diabetic gastroenteropathy (DGE) is associated with small intestinal bacterial overgrowth (SIBO), most studies have evaluated SIBO with a hydrogen breath test, which may be affected by altered transit in DGE. The risk factors for the consequences of SIBO in DGE are poorly understood. We aimed to evaluate the prevalence of, risk factors for, and gastrointestinal symptoms associated with SIBO in patients with DGE. Methods In 75 patients with DGE and dyspepsia, we tested for SIBO (≥10 5 colony forming units /mL of aerobic and/or anaerobic bacteria in a duodenal aspirate) and assessed gastric emptying (GE) of solids, symptoms during a GE study and during an enteral lipid challenge (300 kcal/2 h), and daily symptoms with a Gastroparesis Cardinal Symptom Index diary for 2 weeks. Symptoms and GE were compared in patients with versus without SIBO. Key Results Of 75 patients, 34 (45%) had SIBO, which was not associated with the use of proton pump inhibitors, daily symptoms, GE, or symptoms during a GE study. During enteral lipid challenge, severe nausea ( p = 0.006), fullness ( p = 0.02) and bloating ( p = 0.009) were each associated with SIBO. Twenty patients (59%) with versus 13 (32%) without SIBO had at least one severe symptom during the lipid challenge ( p = 0.006). Conclusions & Inferences Among patients with DGE 45% had SIBO, which was associated with symptoms during enteral lipid challenge but not with delayed GE, symptoms during a GE study, or daily symptoms. Perhaps bacterial products and even fatty acids are recognized by and activate mast cells that drive the increased lipid sensitivity in SIBO.

AbstractBackgroundHow variations predicted by pharmacogenomic testing to alter drug metabolism and therapeutic response affect outcomes for patients with disorders of gut‐ brain interaction is unclear.AimsTo assess the prevalence of pharmacogenomics‐predicted drug‐gene interactions and symptom outcomes for patients with disorders of gut‐brain interaction.MethodsPatients who were treated in our clinical practice for functional dyspepsia/bowel disorder underwent pharmacogenomic testing. The change in symptoms from baseline to 6 months was compared for patients with variations in CYP2D6 and CYP2C19, which metabolize neuromodulators, and SLC6A4, which encodes the sodium‐ dependent serotonin transporter.ResultsAt baseline, 79 of 94 participants (84%) had at least one predicted major drug‐ gene interaction, and all 94 (100%) had at least one predicted moderate interaction. For the 44 participants who completed a survey of their symptoms at 6 months, the mean (SD) irritable bowel syndrome‐symptom severity score decreased from 284 (71) at baseline to 231 (95) at 6 months (p < 0.001). Among patients taking selective serotonin reuptake inhibitors, the decrease in symptom severity (p = 0.03) and pain (p = 0.002) scores from baseline to 6 months was greater for patients with a homozygous SLC6A4 long/long genotype (n = 30) (ie, increased serotonin transporter activity) than for patients with homozygous short/short or heterozygous long/short genotypes (n = 64). Symptom outcomes were not affected by CYP2D6 or CYP2C19 variations.ConclusionsThe homozygous SLC6A4 long/long genotype confers better symptom resolution for patients with disorders of gut‐brain interaction who take selective serotonin reuptake inhibitors than do the homozygous short/short or heterozygous long/short genotypes.

AbstractBackgroundDiarrhea and rectal urgency are risk factors for fecal incontinence (FI). The effectiveness of bowel modifiers for improving FI is unclear.MethodsIn this double‐blind, parallel‐group, randomized trial, women with urge FI were randomly assigned in a 1:1 ratio to a combination of oral clonidine (0.1 mg twice daily) with colesevelam (1875 mg twice daily) or two inert tablets for 4 weeks. The primary outcome was a ≥50% decrease in number of weekly FI episodes.Key ResultsFifty‐six participants were randomly assigned to clonidine–colesevelam (n = 24) or placebo (n = 32); 51 (91%) completed 4 weeks of treatment. At baseline, participants had a mean (SD) of 7.5 (8.2) FI episodes weekly. The primary outcome was met for 13 of 24 participants (54%) treated with clonidine–colesevelam versus 17 of 32 (53%) treated with placebo (p = 0.85). The Bristol stool form score decreased significantly, reflecting more formed stools with clonidine–colesevelam treatment (mean [SD], 4.5 [1.5] to 3.2 [1.5]; p = 0.02) but not with placebo (4.2 [1.9] to 4.1 [1.9]; p = 0.47). The proportion of FI episodes for semiformed stools decreased significantly from a mean (SD) of 76% (8%) to 61% (10%) in the clonidine–colesevelam group (p = 0.007) but not the placebo group (61% [8%] to 67% [8%]; p = 0.76). However, these treatment effects did not differ significantly between groups. Overall, clonidine–colesevelam was well tolerated.Conclusions and InferencesCompared with placebo, clonidine–colesevelam did not significantly improve FI despite being associated with more formed stools and fewer FI episodes for semiformed stools.