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As the world falls apart around them, piece by piece, Abigail Fuller spends humanity's final days looking after her husband David. But that's not true, not really. Abigail isn't David's wife. She's not even human. She's a replacement, built in the image of the real Abigail, who died sixteen years ago. And in three weeks, when the law changes, Abigail will no longer have to do anything David says. She'll be free to go where she likes, do whatever she wants to do. But having never lived for herself, Abigail now faces profound questions about what she is, how she wants to live, and who she wants to love. Perhaps she should start with herself.

Abstract Purpose The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs). Methods In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures. Results Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience. Conclusions OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

There is strong evidence that wood-based products are typically associated with lower fossil-based emissions over their lifecycle than functionally equivalent products made from other materials. However, the potential impact of large-scale material substitution at the market level remains challenging to quantify and is subject to assumptions and system boundary considerations. This paper presents a systematic review covering 44 peer-reviewed studies that quantify the substitution impacts of wood use at the level of a region or sector, to assess the commonalities and differences in scopes, system boundaries and key assumptions. We estimated the average and range of market-level substitution impacts and identify the caveats and knowledge gaps for such assessments. The results indicate an average substitution factor of 0.55 tonnes of fossil C avoided per tonne of C contained in wood harvested, with a range of 0.27–1.16 tC/tC for baseline scenarios covering all wood flows. This value depicts the average efficiency of avoided fossil emissions per unit of wood used for a certain wood use structure based on published studies but is of limited practical use as it is strictly context specific. A direct comparison between studies is complicated because a notable proportion of the studies provided insufficient information to estimate substitution factors or were not transparent in their assumptions, such as specifying which wood product is assumed to substitute for which non-wood product. A growing number of studies focus on policy-relevant analyses of the climate change mitigation potential associated with marginal changes in wood use, but market dynamics are generally considered to a limited extent. To further support decision-making, future studies could focus on changes in those end uses where increased substitution impacts could realistically be expected, while considering the various market dynamics and uncertainties.

Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200–800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, “high” vs “low”), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80–125%) in the analysis population. This study is registered with ClinicalTrials.gov\\, number NCT01713777. Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98–103, Cmax 90% CI 99–105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264–0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065–0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.

A new series of trifluoromethylated pyrimido[1,2-b]indazol-4(1H)-one derivatives was synthesized with good to excellent yields through a simple condensation of 3-aminoindazole derivatives with ethyl 4,4,4-trifluoro 3-oxobutanoate. The functionalization of the corresponding chlorinated fused tricyclic scaffolds via Suzuki-Miyaura and aromatic nucleophilic substitution reactions led to the synthesis of highly diverse trifluoromethylated pyrimido[1,2-b]indazole derivatives with good yields.

RationaleMinocycline, a tetracycline antibiotic, inhibits activation of microglia. In preclinical studies, minocycline prevented development of opioid tolerance and opioid-induced hyperalgesia (OIH). The goal of this study was to determine if minocycline changes pain threshold and tolerance in individuals with opioid use disorder who are maintained on agonist treatment.MethodsIn this double-blind, randomized human laboratory study, 20 participants were randomized to either minocycline (200 mg/day) or placebo treatment for 15 days. The study had three test sessions (days 1, 8, and 15 of treatment) and one follow-up visit 1 week after the end of treatment. In each test session, participants were assessed on several subjective and cognitive measures, followed by assessment of pain sensitivity using the Cold Pressor Test (CPT). Daily surveys and cognitive measures using Ecological Momentary Assessment (EMA) were also collected four times a day on days 8 through 14 of treatment, and proinflammatory serum cytokines were assessed before and on the last day of treatment.ResultsMinocycline treatment did not change pain threshold or tolerance on the CPT. Similarly, minocycline did not change severity of pain, opioid craving, withdrawal, or serum cytokines. Minocycline treatment increased accuracy on a Go/No-Go task.ConclusionsWhile these findings do not support minocycline’s effects on OIH, minocycline may have a potential use as a cognitive enhancer for individuals with opioid use disorder, a finding that warrants further systematic studies.

The molecular basis of antigenic drift was determined for the hemagglutinin (HA) of human influenza A/H3N2 virus. From 1968 to 2003, antigenic change was caused mainly by single amino acid substitutions, which occurred at only seven positions in HA immediately adjacent to the receptor binding site. Most of these substitutions were involved in antigenic change more than once. Equivalent positions were responsible for the recent antigenic changes of influenza B and A/H1N1 viruses. Substitution of a single amino acid at one of these positions substantially changed the virus-specific antibody response in infected ferrets. These findings have potentially far-reaching consequences for understanding the evolutionary mechanisms that govern influenza viruses.

Background Addicted patients undergoing methadone maintenance treatment are prone to several complications and the risk of relapse. Objective The present study aims to investigate the effect of cranial electrotherapy stimulation on depression, anxiety, and craving in addicted male people undergoing methadone maintenance treatment. Methods This randomized controlled trial study was conducted on 60 male patients referred to Persia addiction treatment center between 2021 and 2022. Patients were randomly divided into two equal treatment and placebo groups. The treatment group received cranial electrotherapy stimulation intervention for 48 sessions of 30 min. Depression and anxiety were evaluated using the Hamilton questionnaire before and after the intervention, and the level of craving was also evaluated with the Federdi 2008 questionnaire. Results Comparing the level of depression and anxiety before and after the intervention in both treatment and placebo groups did not show any significant difference ( p  < 0.05). Craving after the intervention was significantly different in both groups and was lower in the treatment group compared to the placebo group (33.43 versus 42.17, p  = 0.004). In the placebo group, the level of anxiety and depression, and in the treatment group, the level of depression, anxiety and craving for consumption decreased significantly after the intervention compared to before the intervention ( p  < 0.05). Conclusion Cranial electrotherapy stimulation did not have a significant effect on reducing the level of depression and anxiety of patients, but it is effective in the reduction of craving in addicted people undergoing methadone maintenance treatment. Trial registration This randomized clinical trial was registered on 2022/5/13 with clinical trial code of IRCT20210523051367N1.

BackgroundEmergency department (ED)-initiated buprenorphine/naloxone with continuation in primary care was found to increase engagement in addiction treatment and reduce illicit opioid use at 30 days compared to referral only or a brief intervention with referral.ObjectiveTo evaluate the long-term outcomes at 2, 6 and 12 months following ED interventions.DesignEvaluation of treatment engagement, drug use, and HIV risk among a cohort of patients from a randomized trial who completed at least one long-term follow-up assessment.ParticipantsA total of 290/329 patients (88% of the randomized sample) were included. The followed cohort did not differ significantly from the randomized sample.InterventionsED-initiated buprenorphine with 10-week continuation in primary care, referral, or brief intervention were provided in the ED at study entry.Main MeasuresSelf-reported engagement in formal addiction treatment, days of illicit opioid use, and HIV risk (2, 6, 12 months); urine toxicology (2, 6 months).Key ResultsA greater number of patients in the buprenorphine group were engaged in addiction treatment at 2 months [68/92 (74%), 95% CI 65–83] compared with referral [42/79 (53%), 95% CI 42–64] and brief intervention [39/83 (47%), 95% CI 37–58; p < 0.001]. The differences were not significant at 6 months [51/92 (55%), 95% CI 45–65; 46/70 (66%) 95% CI 54–76; 43/76 (57%) 95% CI 45–67; p = 0.37] or 12 months [42/86 (49%) 95% CI 39–59; 37/73 (51%) 95% CI 39–62; 49/78 (63%) 95% CI 52–73; p = 0.16]. At 2 months, the buprenorphine group reported fewer days of illicit opioid use [1.1 (95% CI 0.6–1.6)] versus referral [1.8 (95% CI 1.2–2.3)] and brief intervention [2.0 (95% CI 1.5–2.6), p = 0.04]. No significant differences in illicit opioid use were observed at 6 or 12 months. There were no significant differences in HIV risk or rates of opioid-negative urine results at any time.ConclusionsED-initiated buprenorphine was associated with increased engagement in addiction treatment and reduced illicit opioid use during the 2-month interval when buprenorphine was continued in primary care. Outcomes at 6 and 12 months were comparable across all groups.