Omalizumab improves sleep and health status for patients with chronic rhinosinusitis with nasal polyps: An analysis of randomized clinical trials.

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have high incidence of sleep impairment. We evaluated the impact of omalizumab treatment on sleep characteristics and associated health status in patients with CRSwNP. METHODS: Prespecified exploratory analysis assessed outcomes from patients included in the POLYP 1 and POLYP 2 phase 3 clinical trials and the open-label extension. Sleep was assessed by the sleep domain of the Sino-Nasal Outcome Test-22 (SNOT-22; MCID > 4 in patients with CRS) and the Medical Outcomes Study Sleep Scale (MOS-Sleep). Health status was assessed by Healthy Days Core Module (HDCM) and sinonasal-specific Patient Global Impression of Change (PGIC). RESULTS: Omalizumab improved sleep as assessed by the SNOT-22 sleep domain. At week 24, adjusted mean (95%CI) SNOT-22 sleep scores had reduced from baseline by -8.5 (-9.9 to -7.1) with omalizumab versus -2.7 (-4.1 to -1.3) with placebo. At week 52 (all patents on OMA), adjusted mean (95%CI) SNOT-22 sleep scores had reduced from baseline by -10.1 (-11.4 to -8.7) with omalizumab. Improvements were observed in all eight items of the SNOT-22 sleep domain: difficulty falling asleep, fatigue, frustration/restlessness/irritability, lack good night's sleep, reduced concentration, reduced productivity, wake up tired, and wake up at night. In addition, omalizumab improved six of eight sleep outcomes on the MOS-Sleep scale. There were concurrent improvements in HDCM and PGIC. CONCLUSION: Omalizumab improved sleep and self-reported health status in patients with CRSwNP. This contributes to evidence that omalizumab provides value for patients beyond the reduction of sinonasal symptoms.

Omalizumab improves sinonasal outcomes in patients with chronic rhinosinusitis with nasal polyps regardless of allergic status.

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) often have atopic comorbidities, including elevated IgE levels and comorbid asthma. Omalizumab, an IgE monoclonal antibody, is an effective treatment for CRSwNP, but the impact of allergy or asthma status on response to omalizumab in patients with CRSwNP has not been well studied. OBJECTIVE: To evaluate the impact of allergy and asthma status on omalizumab treatment in patients with CRSwNP, this posthoc exploratory analysis assessed sinonasal outcomes from subgroups of patients included in POLYP 1 and POLYP 2 and the open-label extension (OLE) trials. METHODS: Patients (N = 249) were grouped by the presence/absence of comorbid allergy (≥ 1 physician-reported allergic rhinitis, allergic sinusitis, food allergy, or atopic dermatitis), presence/absence of comorbid asthma, baseline serum total IgE (≥ 150 or <150 IU/mL), and baseline blood eosinophil levels (>300 or ≤ 300 cells/µL). Sinonasal outcomes were the nasal polyps score, nasal congestion score, and sino-nasal outcome test-22. RESULTS: During POLYP 1 and POLYP 2 and the OLE, omalizumab treatment improved the nasal polyps score, nasal congestion score, and sino-nasal outcome test-22 score in patients with/without physician-reported allergic comorbidities, with/without asthma, with higher/lower total IgE levels, and with higher/lower blood eosinophil counts. In the OLE, the pattern of improvement was similar in patients who continued or switched to omalizumab. CONCLUSION: In patients with CRSwNP, omalizumab improved sinonasal outcomes independent of allergic status, which suggests that a wide range of patients with different endotypes and phenotypes of CRSwNP may benefit from omalizumab treatment. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03280550, NCT03280537, NCT03478930.

Oral bemnifosbuvir (AT-527) vs placebo in patients with mild-to-moderate COVID-19 in an outpatient setting (MORNINGSKY).

Aim: This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19. Patients & methods: Outpatient adults/adolescents with mild-to-moderate COVID-19 were randomized 2:1 to bemnifosbuvir/placebo. Time to symptom alleviation/improvement (primary outcome), risk of hospitalization/death, viral load and safety were evaluated. Results: Although the study was discontinued prematurely and did not meet its primary end point, bemnifosbuvir treatment resulted in fewer hospitalizations (71% relative risk reduction), COVID-19-related medically attended hospital visits, and COVID-19-related complications compared with placebo. No reduction in viral load was observed. The proportion of patients with adverse events was similar; no deaths occurred. Conclusion: Bemnifosbuvir showed hospitalization reduction in patients with variable disease progression risk and was well tolerated. Clinical Trial Registration: NCT04889040 (ClinicalTrials.gov).

Long-term efficacy and safety of omalizumab for nasal polyposis in an open-label extension study.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). OBJECTIVE: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. METHODS: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. RESULTS: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. CONCLUSIONS: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.

Enhanced anti-tumor immune responses and delay of tumor development in human epidermal growth factor receptor 2 mice immunized with an immunostimulatory peptide in poly(D,L-lactic-co-glycolic) acid nanoparticles.

INTRODUCTION: Cancer vaccines have the potential to induce curative anti-tumor immune responses and better adjuvants may improve vaccine efficacy. We have previously shown that Hp91, a peptide derived from the B box domain in high-mobility group box protein 1 (HMGB1), acts as a potent immune adjuvant. METHOD: In this study, Hp91 was tested as part of a therapeutic vaccine against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. RESULTS: Free peptide did not significantly augment immune responses but, when delivered in poly(D,L-lactic-co-glycolic) acid nanoparticles (PLGA-NPs), robust activation of dendritic cells (DCs) and increased activation of HER2-specific T cells was observed in vitro. Vaccination of HER2/neu transgenic mice, a mouse breast cancer model that closely mimics the immune modulation and tolerance in some breast cancer patients, with Hp91-loaded PLGA-NPs enhanced the activation of HER2-specific cytotoxic T lymphocyte (CTL) responses, delayed tumor development, and prolonged survival. CONCLUSIONS: Taken together these findings demonstrate that the delivery of the immunostimulatory peptide Hp91 inside PLGA-NPs enhances the potency of the peptide and efficacy of a breast cancer vaccine.

TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant.

High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts as an adjuvant in vivo. Here we investigated the underlying mechanisms of Hp91-mediated DC activation. Hp91-induced secretion of IL-6 was dependent on clathrin- and dynamin-driven endocytosis of Hp91 and mediated through a MyD88- and TLR4-dependent pathway involving p38 MAPK and NFκB. Endosomal TLR4 has been shown to activate the MyD88-independent interferon pathway. Hp91-induced activation of pIRF3 and IL-6 secretion was reduced in IFNαßR knockout DCs, suggesting an amplification loop via the IFNαßR. These findings elucidate the mechanisms by which Hp91 acts as immunostimulatory peptide and may serve as a guide for the future development of synthetic Th1-type peptide adjuvants for vaccines.

Delivery of a peptide via poly(D,L-lactic-co-glycolic) acid nanoparticles enhances its dendritic cell-stimulatory capacity.

Nanoparticles (NPs) are attractive carriers for vaccines. We have previously shown that a short peptide (Hp91) activates dendritic cells (DCs), which are critical for initiation of immune responses. In an effort to develop Hp91 as a vaccine adjuvant with NP carriers, we evaluated its activity when encapsulated in or conjugated to the surface of poly(d,l-lactic-co-glycolic) acid (PLGA) NPs. We found that Hp91, when encapsulated in or conjugated to the surface of PLGA-NPs, not only activates both human and mouse DCs, but is in fact more potent than free Hp91. Hp91 packaged within NPs was about fivefold more potent than the free peptide, and Hp91 conjugated to the surface of NPs was ∼20-fold more potent than free Hp91. Because of their capacity to activate DCs, such NP-Hp91 systems are promising as delivery vehicles for subunit vaccines against infectious disease or cancer. FROM THE CLINICAL EDITOR: In this paper, nanoparticle-based dendritic cell activating vaccines are described and discussed. The authors report that the presented PLGA NP based vaccine constructs increase the potency of the studied vaccine by up to 20-fold, making them promising as delivery vehicles for subunit vaccines against infectious diseases or cancer.

The employment-related breastfeeding decisions of physician mothers.

One hundred and forty-six physician mothers responded to a survey of their personal decisions regarding employment and breastfeeding. The mean duration of breastfeeding was 18.8 weeks with a range of 1 week to 128 weeks. The three major factors contributed to the physician mother' decisions to completely wean their children were return to work (45%), diminishing milk supply (31%), and lack of time to pump (18%). Return to part-time work was positively associated with greater duration of maternity leave and breastfeeding. The relationship between breastfeeding and weeks of maternity leave was positive for first- and second-born children. It was not significant for subsequent children. Upon returning to work, space and time for milk expression were obstacles for the majority of the physician mothers. Without time, space, and workplace support, mothers who attempt to combine full time employment and breastfeeding are likely to delay or skip milk expression. This may cause them to experience breastfeeding problems, resulting in premature weaning. Flexible employment arrangements may increase duration among physician mothers and provide an atmosphere of greater acceptance. Protected time and a space for milk expression could contribute to greater frequency of pumping and fewer problems associated with incomplete emptying of the breast.

Breastfeeding education, treatment, and referrals by female physicians.

The female membership of the Mississippi State Medical Association and female physician employees of the Mississippi State Department of Health were surveyed (N = 350) to examine their practice-related decisions relative to breastfeeding; 215 (61%) responded to the survey. Discussion was commonly used for educating patients, with face-to-face demonstrations used by less than half of respondents. Female physicians with breastfeeding experience were more comfortable than others in treating sore nipples, plugged ducts, infected nipples, and inadequate infant weight gain. There was no difference in the proportion of physicians with and without breastfeeding experience who treated mastitis, low milk supply, and poor latch. The largest percentages of referrals to other providers were in response to infants' poor weight gain and poor latch; the fewest were for nipple infections. Seventy percent of the respondents were not taught lactation management in medical school or residency. Better education for physicians regarding lactation management is needed.

Personal breast-feeding behaviors of female physicians in Mississippi.

BACKGROUND: In this study, we examined the personal breast-feeding behaviors of female physicians in Mississippi. METHOD: Two hundred fifteen of 350 female physicians responded to a survey inquiring of their personal breast-feeding behaviors. RESULTS: One hundred fifty-five mothers (74%) reported having biologic children, and 146 (94.2%) breast-fed at least 1 child. Approximately 21% of the responding mothers breast-fed their first-born children for at least 6 months. There was a positive relationship between the duration of breast-feeding of older children and the breast-feeding duration for younger children. The major reasons for weaning were return to work, diminishing milk supply, and lack of time to pump breast milk. CONCLUSION: The breast-feeding initiation rates among female physicians surpassed those of women in the general population, yet duration rates were comparable. Their own breast-feeding success might enhance the potential of female physicians as advocates and sources of credible information regarding breast-feeding; however, physicians need to be better educated regarding the management of breast-feeding.

Do sensor glucose levels accurately predict plasma glucose concentrations during hypoglycemia and hyperinsulinemia?

OBJECTIVE: The MiniMed Continuous Glucose Monitoring System (CGMS) measures subcutaneous interstitial glucose levels that are calibrated against three or more fingerstick glucose levels daily. The objective of the present study was to examine whether the relationship between plasma and interstitial fluid glucose is altered by changes in plasma glucose and insulin levels and how such alterations might influence CGMS performance. RESEARCH DESIGN AND METHODS: Arterialized plasma glucose, sensor glucose, and interstitial fluid glucose were measured by microdialysis in 11 healthy subjects during a 1.0 mU. kg(-1). min(-1) stepped euglycemic-hypoglycemic-hyperglycemic (plasma glucose approximately 5, 3.1, and 8.6 mmol/l, respectively) insulin clamp that raised plasma insulin to approximately 360-390 pmol/l. RESULTS: When the CGMS was calibrated versus plasma glucose levels before insulin infusion, basal sensor and plasma glucose were similar (5.0 +/- 0.3 vs. 5.2 +/- 0.3 mmol/l, respectively); dialysate glucose was 3.3 +/- 0.9 mmol/l. During the hyperinsulinemic-euglycemia study (plasma glucose 4.9 +/- 0.3 mmol/l), dialysate glucose fell by 30-35%, accompanied by a significant reduction in sensor glucose (to 3.7 +/- 0.6 mmol/l; P < 0.001 vs. plasma). Subsequently, sensor levels remained lower than plasma values during mild hypoglycemia (2.5 +/- 0.6 vs. 3.1 +/- 0.3 mmol/l; P < 0.01) and during recovery from hypoglycemia (7.3 +/- 1.2 vs. 8.6 +/- 0.6; P < 0.01). However, when the CGMS was calibrated against plasma glucose levels before and during each step of the clamp, sensor glucose levels increased throughout the study and did not differ from plasma glucose values during hypoglycemia. CONCLUSIONS: Although hyperinsulinemia may contribute to modest discrepancies between plasma and sensor glucose levels, the CGMS is able to accurately track acute changes in plasma glucose when calibrated across a range of plasma glucose and insulin levels.