The Role of Pharmaceutical Innovation in Clinical Practice Guidelines for Chronic Diseases.

Background: Over the last 25 years, clinical practice guidelines have emerged as a means to standardize and improve care. As pharmaceutical innovations develop, guidelines are updated to incorporate new interventions. However, the extent to which pharmacotherapies are represented as treatment options in guideline recommendations has not been well elucidated. This study aimed to quantify the role pharmacotherapy has played in clinical practice guidelines across a range of chronic diseases over the past 20 years. Methods: Clinical practice guidelines published from 2000 to 2021 were identified for five chronic diseases: ischemic heart disease (IHD), non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD), Alzheimer's disease (AD), and type 2 diabetes (T2D). Guidelines were reviewed and data on treatment recommendations were collected, including the type of intervention, line of therapy, and, for pharmacotherapies, year of regulatory approval and year of inclusion in guidelines. Results: In total, 92 clinical practice guidelines were reviewed. Among the 184 discrete recommended interventions across the five disease areas, 146 (79.3%) were pharmacotherapies, 21 (11.4%) were behavioral modifications, 6 (3.3%) were surgical interventions, and 11 (6%) were other interventions. Across guidelines, when a line of therapy was specified, behavioral modifications and pharmacotherapies were most frequently recommended as first-line interventions, whereas surgical interventions were more often recommended for subsequent lines of treatment. The time from regulatory approval of novel pharmacotherapies to inclusion in guideline recommendations varied considerably by disease area and geography. Conclusions: Across the reviewed disease areas, behavioral interventions and pharmacotherapies are shown to be critical components of clinical practice. Over the last 20 years, novel pharmaceutical innovations have been incorporated into clinical practice guideline recommendations; however, with varying speeds of adoption. Given the increasing pace of pharmacologic innovation, timely updates of clinical practice guidelines are critical to evolving the standard of care and practicing evidence-based medicine.

Increased risk of lower limb osteoarthritis among former professional soccer (football) players.

BACKGROUND: Soccer is a high-speed contact sport with risk of injury. Despite long-standing concern, evidence to date remains inconsistent as to the association between playing professional-level soccer and lifelong musculoskeletal consequences. AIMS: The objectives were to assess risk of osteoarthritis in former professional soccer players compared to matched general population controls, and subsequently assess associated musculoskeletal disorders which may contribute to, or result from, osteoarthritis-specifically meniscal injury and joint replacement. METHODS: We conducted a retrospective cohort study using national electronic health records (EHRs) on a cohort of 7676 former professional soccer players aged 40 or over at recruitment, matched on year of birth, sex (all male) and socio-economic status with 23 028 general population controls. Outcomes of interest were obtained by utilizing individual-level record linkage to EHRs from general hospital inpatient and day-case admissions. RESULTS: Compared to controls, former soccer players showed a greater risk of hospital admission for osteoarthritis (hazard ratio [HR] 3.01; 95% confidence interval [CI] 2.80-3.25; P < 0.001). This increased risk appeared age dependant, normalizing over age 80 years and reflective of increased risk of lower limb osteoarthritis. Further, risk of hospital admissions for meniscal injury (HR 2.73; 95% CI 2.42-3.08; P < 0.001) and joint replacement (HR 2.82; 95% CI 2.23-3.57; P < 0.001) were greater among former soccer players. CONCLUSIONS: We report an increased risk of lower limb osteoarthritis in former soccer players when compared with matched population controls. The results of this research add data in support of lower limb osteoarthritis among former soccer players representing a potential industrial injury.

Additive and non-additive genetic variance in juvenile Sitka spruce (Picea sitchensis Bong. Carr).

Many quantitative genetic models assume that all genetic variation is additive because of a lack of data with sufficient structure and quality to determine the relative contribution of additive and non-additive variation. Here the fractions of additive (fa) and non-additive (fd) genetic variation were estimated in Sitka spruce for height, bud burst and pilodyn penetration depth. Approximately 1500 offspring were produced in each of three sib families and clonally replicated across three geographically diverse sites. Genotypes from 1525 offspring from all three families were obtained by RADseq, followed by imputation using 1630 loci segregating in all families and mapped using the newly developed linkage map of Sitka spruce. The analyses employed a new approach for estimating fa and fd, which combined all available genotypic and phenotypic data with spatial modelling for each trait and site. The consensus estimate for fa increased with age for height from 0.58 at 2 years to 0.75 at 11 years, with only small overlap in 95% support intervals (I95). The estimated fa for bud burst was 0.83 (I95=[0.78, 0.90]) and 0.84 (I95=[0.77, 0.92]) for pilodyn depth. Overall, there was no evidence of family heterogeneity for height or bud burst, or site heterogeneity for pilodyn depth, and no evidence of inbreeding depression associated with genomic homozygosity, expected if dominance variance was the major component of non-additive variance. The results offer no support for the development of sublines for crossing within the species. The models give new opportunities to assess more accurately the scale of non-additive variation. Supplementary Information: The online version contains supplementary material available at 10.1007/s11295-023-01627-5.

Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide.

Introduction: Riociguat, an oral soluble guanylate cyclase stimulator, has been approved for use in adults with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. However, there is limited data on its therapeutic use in children. Case Presentation: We report the case of two infants with severe suprasystemic pulmonary hypertension who were successfully treated with riociguat after failure to wean off inhaled nitric oxide (iNO) despite combination PAH therapy. Case 1 is a 6-month-old term male with TBX4 deletion who presented with severe hypoxemic respiratory failure and severe PAH immediately after birth. Initial cardiac catheterization showed PVRi 15.5 WU*m2. Marked hypoxemia and PAH persisted despite aggressive therapy with sildenafil, bosentan, intravenous treprostinil, and milrinone. The infant required high doses of inhaled nitric oxide (60 ppm) and manifested significant post-ductal hypoxemia and hemodynamic instability with any attempt at weaning. After discontinuation of sildenafil, initiation, and very slow uptitration of riociguat, the patient was able to maintain hemodynamic stability and wean from nitric oxide over 6 weeks with persistently severe but not worsened pulmonary hypertension. Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and severe pulmonary hypertension. Initial cardiac catheterization showed PVRi 28.2 WU*m2. After uptitration of sildenafil, bosentan, and IV treprostinil, serial echocardiograms continued to demonstrate near-systemic pulmonary hypertension. He failed multiple attempts to wean off typical doses of iNO (10-20 ppm) over the following weeks with tachypnea, hypoxemia, and worsening pulmonary hypertension on echocardiogram despite continued aggressive combination targeted therapy. After a 24-h sildenafil washout, he was initiated and uptitrated on riociguat with concomitant, successful wean of nitric oxide over one week that was well tolerated. No serious adverse effects in the titration period were observed. Conclusion: Riociguat may be considered as an adjuvant therapeutic agent in selected children with severe PAH who are poorly responsive to sildenafil therapy and unable to wean from iNO.

Development of a pediatric obstructive sleep apnea triage algorithm.

INTRODUCTION: Diagnosis and treatment of obstructive sleep apnea (OSA) in children is often delayed due to the high prevalence and limited physician and sleep testing resources. As a result, children may be referred to multiple specialties, such as pediatric sleep medicine and pediatric otolaryngology, resulting in long waitlists. METHOD: We used data from our pediatric OSA clinic to identify predictors of tonsillectomy and/or adenoidectomy (AT). Before being seen in the clinic, parents completed the Pediatric Sleep Questionnaire (PSQ) and screening questionnaires for restless leg syndrome (RLS), nasal rhinitis, and gastroesophageal reflux disease (GERD). Tonsil size data were obtained from patient charts and graded using the Brodsky-five grade scale. Children completed an overnight oximetry study before being seen in the clinic, and a McGill oximetry score (MOS) was assigned based on the number and depth of oxygen desaturations. Logistic regression, controlling for otolaryngology physician, was used to identify significant predictors of AT. Three triage algorithms were subsequently generated based on the univariate and multivariate results to predict AT. RESULTS: From the OSA cohort, there were 469 eligible children (47% female, mean age = 8.19 years, SD = 3.59), with 89% of children reported snoring. Significant predictors of AT in univariate analysis included tonsil size and four PSQ questions, (1) struggles to breathe at night, (2) apneas, (3) daytime mouth breathing, and (4) AM dry mouth. The first triage algorithm, only using the four PSQ questions, had an odds ratio (OR) of 4.02 for predicting AT (sensitivity = 0.28, specificity = 0.91). Using only tonsil size, the second algorithm had an OR to predict AT of 9.11 (sensitivity = 0.72, specificity = 0.78). The third algorithm, where MOS was used to stratify risk for AT among those children with 2+ tonsils, had the same OR, sensitivity, and specificity as the tonsil-only algorithm. CONCLUSION: Tonsil size was the strongest predictor of AT, while oximetry helped stratify individual risk for AT. We recommend that referral letters for snoring children include graded tonsil size to aid in the triage based on our findings. Children with 2+ tonsil sizes should be triaged to otolaryngology, while the remainder should be referred to a pediatric sleep specialist.

Neutron sub-micrometre tomography from scattering data.

Neutrons are valuable probes for various material samples across many areas of research. Neutron imaging typically has a spatial resolution of larger than 20 µm, whereas neutron scattering is sensitive to smaller features but does not provide a real-space image of the sample. A computed-tomography technique is demonstrated that uses neutron-scattering data to generate an image of a periodic sample with a spatial resolution of ∼300 nm. The achieved resolution is over an order of magnitude smaller than the resolution of other forms of neutron tomography. This method consists of measuring neutron diffraction using a double-crystal diffractometer as a function of sample rotation and then using a phase-retrieval algorithm followed by tomographic reconstruction to generate a map of the sample's scattering-length density. Topological features found in the reconstructions are confirmed with scanning electron micrographs. This technique should be applicable to any sample that generates clear neutron-diffraction patterns, including nanofabricated samples, biological membranes and magnetic materials, such as skyrmion lattices.

Silver Diamine Fluoride and Fluoride Varnish May Halt Interproximal Caries Progression in the Primary Dentition.

Objective: The study described the incidence of interproximal caries arrest following SDF and fluoride varnish application in the primary dentition. Study design: A retrospective analysis of dental records including radiographs was conducted for interproximal dental caries in pediatric patients treated with SDF applied with woven floss. Bitewing radiographs and ICCMS™ radiographic scoring criteria were used to assess caries depth in primary teeth at baseline and then at 12-month follow-up examination. Results: This study included 185 interproximal carious lesions in 131 patients treated with SDF. Mean baseline ICCMS™ score for all lesions was 1.50, with an average dmft of 2.9. The majority of carious lesions (n=155, 84.0%) showed radiographic evidence of non-progression at 12-month follow-up. There was no statistically significant difference in caries arrest among primary canines, primary first molars, and primary second molars (P=0.61). Furthermore, there was no statistically significant difference in caries arrest in patients with commercial insurance, Medicaid, or no insurance (P=0.27). Conclusions: SDF application with woven floss was associated with interproximal caries arrest in the primary dentition at 12-month follow-up in this sample of low caries risk children. Tooth type and insurance type were not associated with caries arrest.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Endoscopic dilatation improves long-term dysphagia following head and neck cancer therapies: a randomized control trial.

Long-term pharyngeal dysphagia is a common complication following head and neck cancer (HNC) therapies. High-level evidence for pharyngoesophageal junction (POJ) dilatation as a treatment in this population is lacking. We aimed to evaluate the safety and efficacy of POJ dilatation in dysphagic HNC survivors. This single-center, single-blind, placebo-controlled trial (St George Hospital, Sydney, Australia) randomly assigned (1:1) HNC survivors with long-term dysphagia (≥12 months postcompleted HNC therapies) to receive either graded endoscopic dilatations or sham dilatation (placebo). Patients were blinded to intervention types. Two strata were used for permuted randomization: (1) HNC therapies (total laryngectomy vs. chemoradiation alone); (2) Prior POJ dilatation (nil vs. previous dilatation). The primary endpoint was a short-term clinical response in swallowing function (3 months), defined as (1) a decrease in Sydney Swallow Questionnaire score by ≥200 or a score ≤ ULN; and (2) satisfactory global clinical assessment. The secondary endpoints were dysphagia relapse and serious adverse events. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000707369). Between 13 January 2013 and 16 January 2017, 41 patients were randomly assigned to endoscopic dilatation (n = 21) or placebo (n = 20). The short-term response rate in the endoscopic dilatation group was 76% (n = 16), compared with 5% (n = 1) in the placebo group (P < 0.001). There were no serious adverse events. The finding of a mucosal tear postdilatation was associated strongly with clinical response (OR 13.4, 95% CI [2.4, 74.9], P = 0.003). Kaplan-Meier estimate of dysphagia relapse is 50% by 9.6 months (95% CI [6.0, 19.2]) from completion of dilatation. Endoscopic dilatation of the POJ is a safe and efficacious therapy for the treatment of long-term dysphagia in HNC survivors. Close follow-up and repeat dilatation are necessary given the high dysphagia relapse rate.

The critical importance of pharyngeal contractile forces on the validity of intrabolus pressure as a predictor of impaired pharyngo-esophageal junction compliance.

INTRODUCTION: Restrictive defects of the pharyngo-esophageal junction (PEJ) are common in both structural and neurological disorders and are amenable to therapies aiming to reduce outflow resistance. Intrabolus pressure (IBP) acquired with high-resolution manometry and impedance (HRMI) is an indicator of resistance and a marker of reduced PEJ compliance. Constraints and limitations of IBP as well as the optimal IBP parameter remain undefined. AIMS: To determine: (i) the impact of peak pharyngeal pressure (PeakP) on the diagnostic accuracy of IBP for the detection of a restrictive defect at the PEJ and (ii) the optimal IBP parameter for this purpose. METHODS: In 52 dysphagic patients previously treated for head and neck cancer. Five candidate IBP measures and PeakP were obtained with HRMI, as well as a presence of a stricture determined by a mucosal tear after endoscopic dilatation. Predictive values of IBP measures were evaluated by receiver operating characteristic (ROC) analysis for all patients and reiterated as patients with lowest PeakP were progressively removed from the cohort. RESULTS: All IBP parameters had fair to good accuracy at predicting strictures. Intrabolus pressure measured at a discrete point of maximum admittance 1 cm above the maximal excursion of the upper esophageal sphincter had highest sensitivity (0.76) and specificity (0.78). When PeakP was at least 57 mm Hg both sensitivity and specificity improved to 0.9. CONCLUSIONS: Pharyngeal propulsive force has substantial impact on the accuracy of IBP as a predictor of a PEJ stricture. When PeakP is ≥57 mm Hg, an elevated IBP is highly predictive of a restrictive defect at the PEJ.

The effect of medication nonadherence on progression-free survival among patients with renal cell carcinoma.

OBJECTIVE: To examine how observed medication nonadherence to 2 second-line, oral anticancer medications (axitinib and everolimus) affects progression-free survival (PFS) among patients with renal cell carcinoma. METHODS: We used an adherence-exposure-outcome model to simulate the impact of adherence on PFS. Using a pharmacokinetic/pharmacodynamic (PK/PD) population model, we simulated drug exposure measured by area under the plasma concentration-time curve (AUC) and minimum blood or trough concentration (Cmin) under 2 scenarios: 1) optimal adherence and 2) real-world adherence. Real-world adherence was measured using the medication possession ratios as calculated from health insurance claims data. A population PK/PD model was simulated on individuals drawn from the Medical Expenditure Panel Survey (MEPS), a large survey broadly representative of the US population. Finally, we used previously published PK/PD models to estimate the effect of drug exposure (i.e., Cmin and AUC) on PFS outcomes under optimal and real-world adherence scenarios. RESULTS: Average adherence measured using medication possession ratios was 76%. After applying our simulation model to 2164 individuals in MEPS, drug exposure was significantly higher among adherent patients compared with nonadherent patients for axitinib (AUC: 249.5 vs. 159.8 ng×h/mL, P<0.001) and everolimus (AUC: 185.4 vs. 118.0 µg×h/L, P<0.001). Patient nonadherence in the real world decreased the expected PFS from an optimally adherent population by 29% for axitinib (8.4 months with optimal adherence vs. 6.0 months using real-world adherence, P<0.001) and by 5% (5.5 vs. 5.2 months, P<0.001) for everolimus. CONCLUSION: Nonadherence by renal cell carcinoma patients to second-line oral therapies significantly decreased the expected PFS.

Engagement in health and wellness: An online incentive-based program.

Increasingly, corporate health promotion programs are implementing wellness programs integrating principles of behavioral economics. Employees of a large firm were provided a customized online incentive program to design their own commitments to meet health goals. This study examines patterns of program participation and engagement in health promotion activities. Subjects were US-based employees of a large, nondurable goods manufacturing firm who were enrolled in corporate health benefits in 2010 and 2011. We assessed measures of engagement with the workplace health promotion program (e.g., incentive points earned, weight loss). To further examine behaviors indicating engagement in health promotion activities, we constructed an aggregate, employee-level engagement index. Regression models were employed to assess the association between employee characteristics and the engagement index, and the engagement index and spending. 4220 employees utilized the online program and made 25,716 commitments. Male employees age 18-34 had the highest level of engagement, and male employees age 55-64 had the lowest level of engagement overall. Prior year health status and prior year spending did not show a significant association with the level of engagement with the program (p > 0.05). Flexible, incentive-based behavioral health and lifestyle programs may reach the broader workforce including those with chronic conditions and higher levels of health spending.

Simultaneous 68Ga DOTATATE Positron Emission Tomography/Magnetic Resonance Imaging in Meningioma Target Contouring: Feasibility and Impact Upon Interobserver Variability Versus Positron Emission Tomography/Computed Tomography and Computed Tomography/Magnetic Resonance Imaging.

AIMS: The increasing use of highly conformal radiation techniques to treat meningioma confers a greater need for accurate targeting. Several groups have shown that positron emission tomography/computed tomography (PET/CT) information alters meningioma targets contoured by single observers, but whether this translates into improved accuracy has not been defined. As magnetic resonance imaging (MRI) is the cornerstone of meningioma target contouring, simultaneous PET/MRI may be superior to PET/CT. We assessed whether 68Ga DOTATATE PET imaging (from PET/CT and PET/MRI) reduced interobserver variability (IOV) in meningioma target volume contouring. MATERIALS AND METHODS: Ten patients with meningioma underwent simultaneous 68Ga DOTATATE PET/MRI followed by PET/CT. They were selected as it was anticipated that target volume definition in their cases would be particularly challenging. Three radiation oncologists contoured target volumes according to an agreed protocol: gross tumour volume (GTV) and clinical target volume (CTV) on CT/MRI alone, CT/MRI+PET(CT) and CT/MRI+PET(MRI). GTV/CTV Kouwenhoven conformity levels (KCL), regions of contour variation and qualitative differences between PET(CT) and PET(MRI) were evaluated. RESULTS: There was substantial IOV in contouring. GTV mean KCL: CT/MRI 0.34, CT/MRI+PET(CT) 0.38, CT/MRI+PET(MRI) 0.39 (P = 0.06). CTV mean KCL: CT/MRI 0.31, CT/MRI+PET(CT) 0.35, CT/MRI+PET(MRI) 0.35 (P = 0.04 for all groups; P > 0.05 for individual pairs). One observer consistently contoured largest and one smallest. Observers rarely decreased volumes in relation to PET. Most IOV occurred in bone followed by dural tail, postoperative bed and venous sinuses. Tumour edges were qualitatively clearer on PET(MRI) versus PET(CT), but this did not affect contouring. CONCLUSION: IOV in contouring challenging meningioma cases was large and only slightly improved with the addition of 68Ga DOTATATE PET. Simultaneous PET/MRI for meningioma contouring is feasible, but did not improve IOV versus PET/CT. Whether volumes can be safely reduced according to PET requires evaluation.

Association between sleep apnea and low bone mass in adults: a systematic review and meta-analysis.

We performed a systematic review of the literature to assess the association between sleep apnea and bone metabolism diseases including osteoporosis in adult population. Results from clinical trials suggest that the association between sleep apnea and low bone mass in adults is possible. INTRODUCTION: This study aimed to synthesize existing evidence on the potential association between sleep apnea and low bone mass in adults. METHODS: Electronic searches of five databases were performed. The inclusion criteria consisted of studies in humans that assessed potential associations between sleep apnea and bone metabolic diseases in an adult population. For diagnosis of sleep apnea overnight polysomnography, home polygraphy, or validated records from healthcare databases were considered. Reduced bone density, osteoporosis, serum/urinary levels for markers of bone formation and resorption, or risk of fractures caused without history of trauma were considered indicators of low bone mass. A random-effects model meta-analysis was applied when possible. RESULTS: Of the 963 relevant references, 12 studies met our inclusion criteria and were assessed to be of medium to low bias. Nine out of 12 studies reported an association between sleep apnea and low bone mass (increased bone resorption markers, reduced bone density, and higher risk of osteoporosis). Two studies did not report a significant association, whereas one study reported an increase of bone density in sleep apnea patients compared to non-sleep apnea patients. Meta-analysis of 2 studies (n = 112,258 patients) showed that sleep apnea was a significant risk factor for osteoporosis (odds ratio (OR), 1.92; 95%CI, 1.24 to 2.97; I2 = 66%); females only had an OR of 2.56 (95% CI, 1.96 to 3.34; I2 = 0%) while the OR in males was 2.03 (95% CI, 1.24 to 3.35; I2 = 38%). CONCLUSIONS: An association between sleep apnea and low bone mass in adults is plausible, but supporting evidence has a risk of bias and is inconsistent.

Altered breathing mechanics and ventilatory response during exercise in children born extremely preterm.

BACKGROUND: Extreme preterm birth confers risk of long-term impairments in lung function and exercise capacity. There are limited data on the factors contributing to exercise limitation following extreme preterm birth. This study examined respiratory mechanics and ventilatory response during exercise in a large cohort of children born extremely preterm (EP). METHODS: This cohort study included children 8-12 years of age who were born EP (≤28 weeks gestation) between 1997 and 2004 and treated in a large regionalised neonatal intensive care unit in western Canada. EP children were divided into no/mild bronchopulmonary dysplasia (BPD) (ie, supplementary oxygen or ventilation ceased before 36 weeks gestational age; n=53) and moderate/severe BPD (ie, continued supplementary oxygen or ventilation at 36 weeks gestational age; n=50). Age-matched control children (n=65) were born at full term. All children attempted lung function and cardiopulmonary exercise testing measurements. RESULTS: Compared with control children, EP children had lower airway flows and diffusion capacity but preserved total lung capacity. Children with moderate/severe BPD had evidence of gas trapping relative to other groups. The mean difference in exercise capacity (as measured by oxygen uptake (VO2)% predicted) in children with moderate/severe BPD was -18±5% and -14±5.0% below children with no/mild BPD and control children, respectively. Children with moderate/severe BPD demonstrated a potentiated ventilatory response and greater prevalence of expiratory flow limitation during exercise compared with other groups. Resting lung function did not correlate with exercise capacity. CONCLUSIONS: Expiratory flow limitation and an exaggerated ventilatory response contribute to respiratory limitation to exercise in children born EP with moderate/severe BPD.

Correlation of esophageal pressure-flow analysis findings with bolus transit patterns on videofluoroscopy.

Pressure-flow analysis quantifies the interactions between bolus transport and pressure generation. We undertook a pilot study to assess the interrelationships between pressure-flow metrics and fluoroscopically determined bolus clearance and bolus transport across the esophagogastric junction (EGJ). We hypothesized that findings of abnormal pressure-flow metrics would correlate with impaired bolus clearance and reduced flow across the EGJ. Videofluoroscopic images, impedance, and pressure were recorded simultaneously in nine patients with dysphagia (62-82 years, seven male) tested with liquid barium boluses. A 3.6 mm diameter solid-state catheter with 25 × 1 cm pressure/12 × 2 cm impedance was utilized. Swallowed bolus clearance was assessed using a validated 7-point radiological bolus transport scale. The cumulative period of bolus flow across the EGJ was also fluoroscopically measured (EGJ flow time). Pressure only parameters included the length of breaks in the 20 mmHg iso-contour and the 4 second integrated EGJ relaxation pressure (IRP4s). Pressure-flow metrics were calculated for the distal esophagus, these were: time from nadir impedance to peak pressure (TNadImp to PeakP) to quantify bolus flow timing; pressure flow index (PFI) to integrate bolus pressurization and flow timing; and impedance ratio (IR) to assess bolus clearance. When compared with controls, patients had longer peristaltic breaks, higher IRs, and higher residual EGJ relaxation pressures (break length of 8 [2, 13] vs. 2 [0, 2] cm, P = 0.027; IR 0.5 ± 0.1 vs. 0.3 ± 0.0, P = 0.019; IRP4s 11 ± 2 vs. 6 ± 1 mmHg, P = 0.070). There was a significant positive correlation between higher bolus transport scores and longer peristaltic breaks (Spearman correlation r = 0.895, P < 0.001) and with higher IRs (r = 0.661, P < 0.05). Diminished EGJ flow times correlated with a shorter TNadImp to PeakP (r = -0.733, P < 0.05) and a higher IR (r = -0.750, P < 0.05). Longer peristaltic breaks and higher IR correlate with failed bolus clearance on videofluoroscopy. The metric TNadImp to PeakP appears to be a marker of the period of time over which the bolus flows across the EGJ.

Inter-rater reliability and validity of automated impedance manometry analysis and fluoroscopy in dysphagic patients after head and neck cancer radiotherapy.

BACKGROUND: Pharyngeal automated impedance manometry (AIM) analysis is a novel non-radiological method to analyze swallowing function based on impedance-pressure recordings. In dysphagic head and neck cancer patients, we evaluated the reliability and validity of the AIM-derived swallow risk index (SRI) and a novel measure of postswallow residue (iZn/Z) by comparing it against videofluoroscopy as the gold standard. METHODS: Three blinded experts classified 88 videofluoroscopic swallows from 16 patients for aspiration and degree of postswallow residue. Pressure-impedance recordings of the patient and age-matched control swallows were analyzed using AIM by three observers who derived the SRI and iZn/Z. Intra-class correlation coefficients (ICC) were calculated for videofluoroscopic and AIM measures. Patient pressure/impedance measurements were compared with videofluoroscopy scores and control subjects to determine validity for detecting clinically relevant swallowing dysfunction. KEY RESULTS: Agreement among observers assessing presence of penetration and aspiration was modest (ICC 0.57) for videofluoroscopy and good (ICC 0.71, 0.82) for AIM-derived SRI and iZn/Z. When compared with age-matched controls, the SRI was higher in patients with aspiration (mean diff. 28.6, 95% CI [55.85, 1.355], p < 0.05). The iZn/Z had moderate positive correlation with bolus residue on fluoroscopy (BRS score) (rs (86) = 0.4120, p < 0.0001) and was increased in both patients with aspiration (∆244 [419.7, 69.52; p < 0.05]) and penetration (∆240 [394.3, 85.77]; p < 0.05) compared to controls. CONCLUSIONS & INFERENCES: AIM-based measures of swallowing function have better inter-rater reliability than comparable fluoroscopically derived measures. These measures are easily determined and objective markers of clinically relevant features of disordered swallowing following radiotherapy.