OBJECTIVE: Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters.
METHODS: Mixed-effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase [peak]). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3-month periods. The influence of epilepsy type on cosinor parameters was also analyzed.
RESULTS: Seizure-cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12-h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24-h scale and ~07:30 on a 12-h scale. The consistent cohort was associated with increases in baseline and peak seizure-cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h.
CONCLUSIONS: This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12- and 24-h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient-centered outcomes to seizure-cluster prediction.

UNASSIGNED: The increasing antibiotic resistance is the main issue causing Helicobacter pylori (H. pylori) eradication failure. As a nutritional supplement, Egg Yolk Antibody (Ig Y) provides a new approach for H. pylori infection rescue therapy.
UNASSIGNED: In this randomized, controlled study, 100 H. pylori-positive patients with previous H. pylori eradication treatment were included. All individuals received standard bismuth-containing quadruple therapy twice daily (5 mg ilaprazole, 100 mg doxycycline, 500 mg clarithromycin or 1 g amoxicillin or 100 mg furazolidone, and 220 mg colloidal bismuth tartrate) for 14 days and were randomized to receive either twice daily 7 g Ig Y-H. pylori treatment (study group) or not (control group). 4 weeks after the end of treatment, urea breath tests were used to assess the H. pylori eradication rate. All participants scored by the Global Overall Symptom scale (GOS) and recorded adverse events during the trial.
UNASSIGNED: The H. pylori eradication rates were 84.0% (95% CI 73.5-94.5%) vs. 80.0% (95% CI 68.5-91.5%) in the study and control groups at intention-to-treat (ITT) analysis and 85.7% (95% CI 75.6-95.9%) vs. 80.0% (95% CI 68.5-91.5%) at per-protocol (PP) analysis, respectively. The number of over 80% symptom relief after treatment in the two groups was 27 (60%) and 12 (29.2%) (p < 0.05), and the incidences of adverse events were 4 (8%) and 6 (12%), respectively.
UNASSIGNED: Both groups achieved satisfactory eradication efficiency in H. pylori rescue therapy and Ig Y-H. pylori effectively alleviates the symptoms with good compliance and fewer adverse effects.

We compared the efficacy and safety of rifabutin-containing triple therapy with bismuth quadruple therapy for rescue treatment of Helicobacter pylori.
This was a noninferiority study trial of H. pylori treatment for subjects who had failed at least 2 prior treatments. Subjects were randomly assigned to receive rifabutin triple therapy with 14-day esomeprazole (20 mg), amoxicillin (1.0 g), and rifabutin (150 mg) twice a day; or bismuth quadruple therapy with esomeprazole (20 mg) and bismuth (220 mg) twice a day, plus metronidazole (400 mg) and tetracycline (500 mg) 4 times a day. Antimicrobial susceptibility was assessed by agar dilution and E-test.
From May 2021 to October 2022, a total of 364 subjects were randomized. The eradication rates by intention-to-treat, per-protocol, and modified intention-to-treat were 89.0% (162/182; 95% confidence interval [CI], 83.6%-92.8%), 94.0% (157/167; 95% CI, 89.3%-96.7%), and 93.6% (162/173; 95% CI, 89.0%-96.4%) for rifabutin triple group. For bismuth quadruple group, they were 89.6% (163/182; 95% CI, 84.3%-93.2%), 95.3% (143/150; 95% CI, 90.7%-97.7%), and 93.7% (163/174; 95% CI, 89.0%-96.4%).
The rifabutin triple therapy is an alternative to classical bismuth quadruple therapy for the rescue treatment of H. pylori with fewer side effects and higher compliance.
NCT04879992.

To compare the efficacy and tolerability of minocycline vs. tetracycline in bismuth-containing quadruple therapy for Helicobacter pylori (H. pylori) rescue treatment.
This study was a multi-center, randomized-controlled, non-inferiority trial. Refractory H. pylori-infected subjects with multiple treatment-failure were randomly (1:1) allocated to receive 14-day therapy with esomeprazole 20 mg b.i.d, bismuth 220 mg b.i.d, plus metronidazole 400 mg q.i.d and minocycline 100 mg b.i.d (minocycline group) or tetracycline 500 mg q.i.d (tetracycline group). Primary outcome was H. pylori eradication rate evaluated by 13C-urea breath test at least 6 weeks after the end of treatment. Antibiotic resistance was determined using E test method.
Three hundred and sixty-eight subjects were randomized. The eradication rates in minocycline group and tetracycline group were 88.0% (162/184, 95% CI 83.3-92.8%) and 88.6% (163/184, 95% CI 83.9-93.2%) in intention-to-treat analysis, 98.0% (149/152, 95% CI 95.8-100%) and 97.4% (150/154, 95% CI 94.9-99.9%) in per-protocol analysis, 93.1% (162/174, 95% CI 89.3-96.9%) and 93.1% (163/175, 95% CI 89.4-96.9%) in modified intention-to-treat analysis. Minocycline, tetracycline and metronidazole resistance rates were 0.7%, 1.4% and 89.6%, respectively. Non-inferiority of minocycline was confirmed (P < 0.025). Metronidazole resistance did not affect the efficacy of either therapy. The two therapies exhibited comparable frequencies of adverse events (55.4% vs. 53.3%); almost half of them were mild. Dizziness was the most common adverse events in the minocycline group.
Minocycline can be an alternative for tetracycline in bismuth-containing quadruple therapy for H. pylori empirical rescue treatment, irrespective of metronidazole resistance. However, relatively high incidence of adverse events in both regimens should be emphasized.

In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy.
Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma?
This phase 3 double-blind trial randomized patients aged ≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 μg or 180/80 μg, albuterol 180 μg, budesonide 160 μg, or placebo for 12 weeks. Dual-primary efficacy end points included change from baseline in FEV1 area under the curve from 0 to 6 h (FEV1 AUC0-6h) over 12 weeks (assessing albuterol effect) and trough FEV1 at week 12 (assessing budesonide effect).
Of 1,001 patients randomized, 989 were ≥ 12 years old and evaluable for efficacy. Change from baseline in FEV1 AUC0-6h over 12 weeks was greater with albuterol-budesonide 180/160 μg vs budesonide 160 μg (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P = .003). Change in trough FEV1 at week 12 was greater with albuterol-budesonide 180/160 and 180/80 μg vs albuterol 180 μg (LSM difference, 132.8 [95% CI, 63.6-201.9] mL and 120.8 [95% CI, 51.5-190.1] mL, respectively; both P < .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents.
Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12 weeks, with no new safety findings, supporting its use as a novel rescue therapy.
ClinicalTrials.gov; No.: NCT03847896; URL: www.
gov.

The increasing rate of drug resistance often leads to Helicobacter pylori (H. pylori) eradication failure and needs the rescue therapy. Thus, the exploration of new rescue therapeutic regimens is important. The present study was designed to test the beneficial effects of Saccharomyces boulardii (S.boulardii) prior to H. pylori rescue therapy basing on bismuth quadruple.
One hundred H. pylori-infected patients were randomly divided into two groups: study group and control group. Patients in the study group (n=50) underwent two-stages therapy: patients started with S.boulardii monotherapy for 2 weeks, and then tested for H. pylori infection after resting for 4 weeks without any therapy, patients who were still positive for H. pylori continued with bismuth quadruple eradication therapy. For the control group (n=50), all patients were observed and were not treated with any gastric drugs or antibiotics for 6 weeks, then those who were still positive for H. pylori received the same eradication therapy as the study group. Eradication rate, adverse events and the cost-effectiveness of two regimens were analyzed in this study.
The H.pylori eradication rate of ITT (intent-to-treat) analysis and PP (per-protocol) analysis in the first phase of treatment were significantly higher in the study group than the control groups respectively (28.0% vs 2.0%, p<0.001 and 30.4% vs 2.1% p<0.001). For the total treatment effect, there were no significant differences in the eradication rate of ITT analysis (78.0% vs 80.0%) or PP analysis (90.7% vs 88.9%) between the study group and the control group. The cost-effectiveness ratio of the study group was slightly higher than that of the control group (8.95 vs 8.55). There were two patients in the study group and four patients in the control group with the adverse events, respectively. There was no significant difference on the incidence of adverse events between the two groups (p=0.68).
S.boulardii may serve as a beneficial treatment option before H. pylori rescue therapy since it callowed partial patients to avoid reusing bismuth quadruple.

While paresthesia-based Spinal Cord Stimulation (SCS) has been proven effective as treatment for chronic neuropathic pain, its initial benefits may lead to the development of \"Failed SCS Syndrome\' (FSCSS) defined as decrease over time related to Loss of Efficacy (LoE) with or without Loss of Coverage (LoC). Development of technologies associating new paresthesia-free stimulation waveforms and implanted pulse generator adapters provide opportunities to manage patients with LoE. The main goal of our study was to investigate salvage procedures, through neurostimulation adapters, in patients already implanted with SCS and experiencing LoE. We retrospectively analyzed a cohort of patients who were offered new SCS programs/waveforms through an implanted adapter between 2018 and 2021. Patients were evaluated before and at 1-, 3-, 6- and 12-month follow-ups. Outcomes included pain intensity rating with a Visual Analog Scale (VAS), pain/coverage mappings and stimulation preferences. Last follow-up evaluations (N = 27) showed significant improvement in VAS (p = 0.0001), ODI (p = 0.021) and quality of life (p = 0.023). In the 11/27 patients with LoC, SCS efficacy on pain intensity (36.89%) was accompanied via paresthesia coverage recovery (55.57%) and pain surface decrease (47.01%). At 12-month follow-up, 81.3% preferred to keep tonic stimulation in their waveform portfolio. SCS conversion using adapters appears promising as a salvage solution, with an emphasis on paresthesia recapturing enabled via spatial retargeting. In light of these results, adapters could be integrated in SCS rescue algorithms or should be considered in SCS rescue.

Introduction: Noninvasive ventilation (NIV) has been used to alleviate hypoxemia and dyspnea, but there is no consensus on the application of NIV in patients with coronavirus disease 2019 (COVID-19). Some staff use NIV as the rescue therapy which might lead to the adverse outcomes. This study was to identify early factors associated with intubation to help the medical staff select appropriate patients for receiving NIV treatment. Methods: Patients with laboratory-confirmed COVID-19 who were treated with NIV in emergency department or ICU of the Third People\'s Hospital (the only designated hospital for treating COVID-19 in Shenzhen) between January 1 and August 31, 2020, were retrospectively analyzed. Results: Thirty-nine patients with COVID-19 treated with NIV were included; of them, 16 (41%) received endotracheal intubation and 3 (8%) died. Significant differences were observed between intubated and non-intubated patients in PaO2/FiO2 before NIV initiation, hospitalization duration, NIV as the rescue therapy, and PaO2/FiO2 of ≤200 mmHg after 1-2 h of NIV initiation. Notably, 1-2 h after NIV initiation, a PaO2/FiO2 of ≤200 mmHg (odds ratio [OR], 9.35; 95% confidence interval [CI], 1.84-47.62; P = 0.007) and NIV as the rescue therapy (OR, 5.43; 95% CI, 1.09-27.12; P = 0.039) were the risk factors for intubation. Conclusions: In patients with COVID-19-related acute hypoxemic respiratory failure receiving NIV, close attention should be paid to PaO2/FiO2 after 1-2 h of NIV initiation. Also, using NIV as rescue therapy should draw our awareness that it might delay escalation of respiratory support and lead to adverse outcomes.

Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray.
Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2.
A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P < 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use.
These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy.

UNASSIGNED: Acute severe ulcerative colitis (ASUC) is a potentially life-threatening disease, and the best option in cases of steroid-refractory disease is still debated. We compared the early- and long-term efficacy and safety of the 2 available \"rescue therapies\", infliximab (IFX) and cyclosporine (CYS), in this setting.
UNASSIGNED: We retrospectively evaluated patients admitted for ASUC and treated with \"rescue therapy\". The primary endpoint was early colectomy-free survival (30 days) and colectomy-free survival until the end of follow up. The secondary endpoints were predictors of colectomy and long-term maintenance of the treatment strategy over time.
UNASSIGNED: Of 129 patients admitted, 68 received rescue therapy (47 with IFX), whereas 7 underwent early colectomy (10.3%). At 30 days, fewer patients treated with IFX showed a need for colectomy (8.5% vs. 14.3%) compared to those in the CYS group, though the difference was non-significant (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.10-4.69; P=0.47). No severe side effects due to IFX and CYS were observed. During a mean follow up of 40 months, 23 additional patients (37.7%) underwent colectomy, and the rate was significantly lower in the IFX group (25.6%) than in the CYS group (66.7%) (hazard ratio 0.25, 95%CI 0.10-0.61; P=0.003). Colectomy-free survival was significantly higher in the IFX group than in the CYS group (P=0.018) at 12 months.
UNASSIGNED: In our setting, the early outcomes of IFX and CYS for ASUC were comparable. IFX was associated with significantly lower colectomy rates during the observation period and had a similar safety profile to CYS.