Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Remibrutinib demonstrates favorable safety profile and sustained efficacy in chronic spontaneous urticaria over 52 weeks.

BACKGROUND: Remibrutinib (LOU064), an oral, highly selective Bruton tyrosine kinase inhibitor, offers fast disease control in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite treatment with second-generation H1 antihistamines. It is currently in phase 3 development for CSU. OBJECTIVE: We sought to evaluate long-term safety and efficacy of remibrutinib in patients with CSU inadequately controlled with H1 antihistamines. METHODS: In this phase 2b extension study, patients who completed the core study and had a weekly Urticaria Activity Score (UAS7) ≥16 at the beginning of the extension study received remibrutinib 100 mg twice daily for 52 weeks. The primary objective was to assess long-term safety and tolerability. Key efficacy end points included change from baseline in UAS7 and proportion of patients with complete response to treatment (UAS7 = 0) and well-controlled disease (UAS7 ≤6) at week 4 and over 52 weeks. RESULTS: Overall, 84.3% (194/230) of patients entered the treatment period and received ≥1 doses of remibrutinib. The overall safety profile of remibrutinib was comparable between the extension and core studies. Most treatment-emergent adverse events were mild to moderate and considered unrelated to remibrutinib by investigators. The 3 most common treatment-emergent adverse events by system organ class were infections (30.9%), skin and subcutaneous tissue (26.8%), and gastrointestinal disorders (16.5%). At week 4 and 52, mean ± SD change from baseline in UAS7 was -17.6 ± 13.40 and -21.8 ± 10.70; UAS7 = 0 (as observed) was achieved in 28.2% and 55.8% and UAS7 ≤6 (as observed) was achieved in 52.7% and 68.0% of patients, respectively. CONCLUSIONS: Remibrutinib demonstrated a consistent favorable safety profile with fast and sustained efficacy for up to 52 weeks in patients with CSU.

A game theory data science-based mechanism for licensed pharmaceutical products concerning their deterioration: a case of a micro, small, and medium enterprise in Iran.

One of the main characteristics of health systems and pharmaceutical supply chains is their significant costs in the public sector, which has forced governments and companies active in this field to find ways to reduce costs. In this paper, the deterioration of imported pharmaceutical items is investigated as one of the challenges of the supply chain of pharmaceutical firms. Specifically, the micro, small medium enterprise (MSME), and a collaborative strategy to reduce its costs is presented. The technical solution of the cooperative strategy is the formation of a partnership alliance between the foreign patent holder of brand drugs and a domestic manufacturer through an exclusive license contract in the local country. This leads to a significant reduction of costs in the distribution network of the pharmaceutical supply chain. On the other hand, supply chain management techniques in the cooperative strategy provide the necessary motivation for its practical implementation by splitting fair profits between producers and other members, namely local government, distributors, and pharmacies. For these purposes, a cooperative game theory-based contract is utilized to set the parameters of the license agreement, and then a profit-sharing mechanism is introduced that splits the benefits of cooperation among the supply chain members based on their afforded costs. The most important contribution of the current research is to propose an integrated framework that combines the logistics network models, valuation methods, and profit split mechanisms that embody more facts from real-world problems than separate models in this regard in previous studies. Moreover, results of the proposed strategy in the supply chain of a drug for thalassemia patients in Iran indicate the effectiveness of the proposed strategy in reducing costs and deterioration. Further, it is shown that the higher the ordering costs of the imported drugs, the lower the market share of the patent holder, and the lower the financing expenses of the cooperative alliance, the more efficient is the proposed strategy.

Histopathological spectrum of duodenal polyps in a retrospective ten-year study.

INTRODUCTION AND AIMS:  Duodenal polyps are rare in patients undergoing upper gastrointestinal endoscopy. The present study is an experience of the histopathological spectrum of the duodenal polyps and its correlation with the clinical and endoscopic findings in a tertiary care centre. MATERIALS AND METHODS: The present study is a 10-year retrospective study from the year 2011 to 2020. All the relevant clinical, endoscopic and radiologic findings were retrieved from the hospital medical records. Old histopathology slides were restained, and wherever required, special stains and immunohistochemistry (IHC) were performed. All the cases were reviewed. The present study mainly included descriptive statistics with categorical and continuous variables. RESULTS: Total 81 cases of duodenal polyps were studied in the period of 10 years. The median age was 48 years. Male: female ratio was 2.2:1. The most common presenting system was abdominal pain. We experienced both solitary and multiple polyps. The majority of the duodenal polyps were non-neoplastic, with unremarkable mucosa or inflammatory type. Unlike previous studies the most common site for the hyperplastic polyp in the present study was the first part of the duodenum. Among the neoplastic polyps, adenomatous polyp was the most common type. Contrary to the previous studies, our study showed the first part of the duodenum as the most common site for the sporadic nonampullary adenomatous duodenal polyps. Of the rare entities, we encountered a single case each of lipomatous polyp and gangliocytic paraganglioma. Among the syndromes we encountered two cases of Peutz-Jeghers syndrome and one case of familial adenomatous polyp in our study population.CONCLUSION Duodenal polyps are a rare finding on endoscopic examinations, though most of them are non-neoplastic in nature, vigilant examination under the microcope is required to rule out any neoplastic pathology and identify the risk of malignancy.

Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is inadequately controlled in many patients and greatly affects quality of life. Remibrutinib, a highly selective, oral, novel covalent Bruton tyrosine kinase inhibitor, might be effective in CSU. OBJECTIVE: This first-in-patient trial aimed to evaluate the efficacy and safety of remibrutinib in CSU treatment and characterize the dose-response. METHODS: This randomized, double-blind, placebo-controlled, phase 2b dose-finding trial evaluated remibrutinib (12 weeks) in patients inadequately controlled with second-generation H1-antihistamines, with at least moderately active CSU, with or without prior anti-IgE treatment (NCT03926611). Patients received remibrutinib 10 mg once daily, 35 mg once daily, 100 mg once daily, 10 mg twice daily, 25 mg twice daily, 100 mg twice daily, or placebo (1:1:1:1:1:1:1 ratio). The main end points were weekly Urticaria Activity Score change from baseline at week 4 and safety. RESULTS: Overall, 311 patients were randomized. Reduced symptom score was observed for all remibrutinib doses from week 1 until week 12, with weekly Urticaria Activity Score change from baseline at week 4: -19.1 (10 mg once daily), -19.1 (35 mg once daily), -14.7 (100 mg once daily), -16.0 (10 mg twice daily), -20.0 (25 mg twice daily), -18.1 (100 mg twice daily), and -5.4 for placebo (nominal P < .0001 for all doses vs placebo). Most adverse events were mild or moderate, with no dose-dependent pattern. CONCLUSION: Remibrutinib was highly effective in the treatment of CSU over the entire dose range, with a rapid onset of action and a favorable safety profile.

COVID19 epidemic outbreak: operating rooms scheduling, specialty teams timetabling and emergency patients' assignment using the robust optimization approach.

The health care system is characterized by limited resources, including the physical facilities as well as skilled human resources. Due to the extensive fixed cost of medical facilities and the high specialization required by the medical staff, the problem of resource scarcity in a health care supply chain is much more acute than in other industries. In the pandemic of the Coronavirus, where medical services are the most important services in communities, and protective and preventive guidelines impose new restrictions on the system, the issue of resource allocation will be more complicated and significantly affect the efficiency of health care systems. In this paper, the problem of activating the operating rooms in hospitals, assigning active operating rooms to the COVID-19 and non-COVID-19 patients, assigning specialty teams to the operating rooms and assigning the elective and emergency patients to the specialty teams, and scheduling their operations is studied by considering the new constraints of protective and preventive guidelines of the Coronavirus. To address these issues, a mixed-integer mathematical programming model is proposed. Moreover, to consider the uncertainty in the surgery duration of elective and emergency patients, the stochastic robust optimization approach is utilized. The proposed model is applied for the planning of operating rooms in the cardiovascular department of a hospital in Iran, and the results highlight the role of proper management in supplying sufficient medical resources effectively to respond to patients and scheduled surgical team to overcome the pressure on hospital resources and medical staff results from pandemic conditions.

Sustainability performance evaluation of the E-waste closed-loop supply chain with the SCOR model.

From a sustainability perspective, the performance of a company's supply chain will be satisfactory when it has reached in all aspects a desirable eco-environmentally friendly level. Assessing the sustainability performance in the closed-loop e-waste supply chain becomes vital because its activities are primarily targeted towards sustainability goals related to the process of production, supply, recycling, and disposal of electrical components. This study evaluates the performance of e-waste supply chain sustainability and identifies its performance indicators as a framework for evaluating supply chain performance using the Best-Worst Method (BWM), which is a multi-criteria decision-making (MCDM) approach. For this, the supply chain operations reference (SCOR) model is considered the basic performance evaluation reference. Moreover, through reviewing the literature, the complementary indicators of this model, especially in terms of sustainability, are added to the performance evaluation indices using the Nominal Group Technique (NGT). After specifying and forming a performance evaluation hierarchy, the BWM method is used to determine the criteria score. The results of implementing the framework on some well-known supply chains in New Zealand indicate that the attributes of "Costs," "Quality," and "GreenScor" are crucial for achieving high performance, while in this developed country, there is less concern about social issues.

Residual Volume Responsiveness Testing May Improve the Detection of Reversible Airway Obstruction in Asthma.

BACKGROUND: Residual volume responsiveness to bronchodilator administration has been observed in subjects with chronic obstructive pulmonary disease. However, the prevalence of residual volume (RV) responsiveness has not been formally studied in asthma. OBJECTIVE: To identify the prevalence and magnitude of RV responsiveness in asthma. METHODS: Physician-diagnosed adult subjects with asthma on treatment for >12 months were prospectively recruited to perform spirometry and measurement of lung volumes using body plethysmography before and after administration of 360 µg of albuterol. RESULTS: Among 120 subjects, 76% were women. The ethnic composition was 64% Caucasian, 32% Hispanic, and 13% African American. The mean age was 52 ± 15 years. The mean duration of asthma was 16 ± 15 years. The mean RV% responsiveness was -7.74 ± 14. Whereas patients with the lowest baseline forced expiratory volume in 1 second (FEV1) value showed the highest mean responsiveness (P = .001), the baseline RV value had minimal influence on RV responsiveness. Using -7.74% to define significant RV responsiveness, and ≥12% and ≥200 mL to define significant FEV1 responsiveness, more subjects showed isolated RV responsiveness (37%) compared with 6% with isolated FEV1 responsiveness and 14% with both FEV1 and RV responsiveness (P = .04). There was a minimal correlation between FEV1 responsiveness and RV responsiveness (r = 0.17, P = .06). The RV responsiveness was significantly associated with the wheeze score (P = .006) and dyspnea score (P = .029). CONCLUSION: The addition of RV responsiveness testing to spirometry based responsiveness testing can improve the identification of reversible airway obstruction in asthma. RV responsiveness may be useful in monitoring symptoms associated with air trapping in asthma.

Effectiveness of C1-INH therapy in angiotensin converting enzyme inhibitor induced angioedema.

INTRODUCTION: Angiotensin Converting Enzyme Inhibitors (ACEI) are a common cause of Emergency Room presentation for angioedema. Although no treatment guidelines exist, C1 esterase inhibitor concentrate (C1-INH) is used on an off label basis for management of ACEI acquired angioedema (ACEI AAE). OBJECTIVE: To evaluate the efficacy of C1-INH in management of ACEI AAE at our local centers. RESULTS: Nine patients, from 3 academic sites, were identified through Allergy Service consultation data and records from Diagnostic Services Manitoba, Canada from 2010-2020. The majority of the patients (n = 8/9) required endotracheal intubation prior to the initiation of C1-INH. Overall, approximately 56% of patients (n = 5/9) had resolution of angioedema ranging between 12 and 17 h, with a median time of 13.5 h, and no recurrence after the administration of C1-INH concentrate. One patient had transient symptom resolution in 14 h, however, recurrence of angioedema required re-intubation. The remainder of patients (n = 4/9), had resolution of angioedema between 22 and 72 h, with a median time of 33.75 h. CONCLUSION: Our findings demonstrate continued ambivalence of the efficacy and role of C1-INH concentrate in the treatment of ACEI AAE, secondary to multiple uncontrolled confounding factors. Further research into characterizing a subgroup of intubated patients in our study that responded to C1-INH concentrate needs to be completed.

Comparison of antimicrobial efficacy of aqueous ozone, green tea, and normal saline as irrigants in pulpectomy procedures of primary teeth.

AIM: Sodium hypochlorite, though considered an ideal root canal irrigant, cannot be used at required concentrations in children, due to its undesirable effects. Hence, it is imperative to search for an ideal root canal irrigant to avoid these undesirable effects which we hope to achieve with this study. The antimicrobial efficacy of aqueous ozone, green tea, and normal saline as irrigants in pulpectomy procedures of the primary teeth has been compared. MATERIALS AND METHODS: Sixty patients between 4 and 8 years of age with a single-rooted deciduous tooth indicated for pulpectomy were included. The infected teeth were randomly allocated to one of the three treatment groups based on the irrigating agents used, namely normal saline, green tea extract, or ozonated water. Specimens for anaerobic culture were collected three times from the teeth: before irrigation, after initial irrigation, and on the 3rd day after final irrigation. RESULTS AND CONCLUSION: Mean colony forming unit (CFU) count after both initial and final irrigation with ozonated water was significantly lower when compared with green tea and normal saline. Further, it was observed that the mean CFU count with green tea was significantly lower than the counts obtained with normal saline on the 3rd day after final irrigation. Hence, both ozonated water and green tea could be considered a good alternative to conventional root canal irrigants in the primary teeth. Larger sample sizes with a larger variety of irrigants are recommended.

Reducing Tobacco-Related Disability in Chronic Smokers.

Tobacco consumption (predominantly cigarettes) is the leading preventable cause of mortality worldwide. Although the major focus of strategies to reduce mortality from tobacco must include prevention of future generations from initially gaining access, some smokers are unwilling or unable to quit. Can the higher risk chronic smoker be identified and can their risk be reduced? The risk of adverse events in cigarette smokers is influenced by the intensity and duration of cigarette smoking or secondhand exposure, associated conventional risk factors, environmental stressors, and certain genetic variants and epigenetic modifiers. Recent data suggest that inflammatory markers such as high-sensitivity C-reactive protein (hs CRP) and targeted imaging can identify some smokers at higher risk. As smoking is prothrombotic, aspirin initiation and expanded statin use might reduce cardiovascular risk in those who do not presently meet criteria for these therapies, but further study is required. Thus, although advocacy for smoking cessation should always be the primary approach, increased efforts are needed to identify and potentially treat those who are unable or unwilling to quit.

Air Trapping Correlates With Increased Frequency of Albuterol Use and Severity of Wheeze in Persistent Asthma.

BACKGROUND: Symptoms of asthma have been shown to correlate poorly with spirometric variables of obstruction. We hypothesized that lung volume measurements might correlate with symptoms and frequency of rescue inhaler use in asthma. METHODS: Patients with persistent asthma on treatment for ≥12 months were enrolled from university-based clinics. The association between lung volumes, spirometry, asthma symptoms, and rescue inhaler use were explored by using linear modeling. RESULTS: Among the 120 subjects, 76% were women. The mean age ± SD was 52 ± 15 y. With regard to ethnicity, 64% of the subjects were caucasian, 23% were Hispanic, and 13% were African-American. Twenty-one percent of the subjects reported chest pain. There was no significant correlation between asthma symptoms or rescue inhaler use to spirometry indices of obstruction. The residual volume percent of predicted showed a significant association with the wheeze score (r = 0.32, P = .001) and frequency of rescue inhaler use (r = 0.35, P ≤ .001). Linear contrast analysis showed that the mean wheeze score (P = .003) and frequency of rescue inhaler (P = .007) use increased linearly from the lowest to the highest quartiles of residual volume. Furthermore, multiple regression analysis showed an association only to the residual volume percent predicted value to the pressurized metered-dose inhaler score and the wheeze score. CONCLUSIONS: Frequent albuterol use and wheezing may be a sign of unrelieved air trapping. Chest pain is a unique symptom in persistent asthma, and the pathogenesis requires further studies. Lung volume measurement added to routine spirometry can help identify patients with asthma and with air trapping.

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Ability of Exhaled Nitric Oxide to Discriminate for Airflow Obstruction Among Frequent Exacerbators of Clinically Diagnosed Asthma.

OBJECTIVE: Fraction of exhaled nitric oxide (FENO) has been proposed as a non-invasive biomarker for allergic inflammation seen in asthma. Many asthmatics in clinical practice have never had spirometry and recent data report misdiagnoses in patients with physician diagnosed (PD) asthma. The aim of this study was to assess the ability of FENO to discriminate between those with and without airflow obstruction (AO) among patients with PD-asthma. METHODS: Frequent exacerbators of PD-asthma (with 2 or more asthma exacerbations leading to emergency room visit or hospitalization within last 12 months) were enrolled. All patients underwent diagnostic evaluations including spirometry, FENO testing and serum immunoglobulin (IgE) and eosinophils. Serial spirometry and methacholine challenge testing (MCT) were performed as indicated. AO was defined by a decreased FEV1/FVC ratio (< 70% and/or < LLN), or a positive MCT. RESULTS: Of the 222 patients with PD-asthma, AO was found in 136 (vs. 86 without AO). 81.6% of patients with AO and 66.2% without AO completed FENO testing. There was no significant difference in the mean FENO levels among patients with or without AO (40.8 vs. 30.4 ppb, P = 0.10). Likewise, there was no difference in the serum IgE levels and serum eosinophils. CONCLUSIONS: Our analyses suggest that FENO levels do not help discriminate between those with and without AO in patients with PD-asthma. Patients who experience symptoms of asthma may have elevated FENO levels above the suggested cut points of 20-25 ppb. Objective confirmation of AO should be considered in all patients with PD-asthma, irrespective of FENO levels.