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INTRODUCTION Recent clinical trials of amyloid beta (Aβ)‐targeting therapies in Alzheimer's disease (AD) have demonstrated a clinical benefit over 18 months, but their long‐term impact on disease trajectory is not yet understood. We propose a framework for evaluating realistic long‐term scenarios. METHODS Results from recent phase 3 trials of Aβ‐targeting antibodies were integrated with an estimate of the long‐term patient‐level natural history trajectory of the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) score to explore realistic long‐term efficacy scenarios. RESULTS Three distinct long‐term efficacy scenarios were examined, ranging from conservative to optimistic. These extrapolations of positive phase 3 trials suggested treatments delayed onset of severe dementia by 0.3 to 0.6 years (conservative), 1.1 to 1.9 years (intermediate), and 2.0 to 4.2 years (optimistic). DISCUSSION Our study provides a common language for long‐term impact of disease‐modifying treatments. Our work calls for studies with longer follow‐up and results from early intervention trials to provide a comprehensive assessment of these therapies' true long‐term impact. Highlights We present long‐term scenarios of the efficacy of AD therapies. In this framework, scenarios are defined relative to the natural history of AD. Long‐term projections with different levels of optimism can be compared. It provides a common language for expressing beliefs about long‐term efficacy.

Selenium (Se) biofortification improves crops' nutritional value, while nano‐selenium (nano‐Se) offers enhanced bioavailability over traditional Se fertilisers. The quality of tea (Camellia sinensis) depends critically on nitrogen (N) metabolism and amino acid balance, particularly of theanine. This study assessing growth and quality, elucidating molecular mechanisms and evaluating long‐term persistence explored the effects of nano‐Se on tea through three different experiments. The results showed that nano‐Se significantly increased the chlorophyll content, photosynthetic parameters and non‐structural carbohydrates, indicating an enhanced photosynthetic capacity. Nitrogen uptake and metabolism were promoted, along with an increased leaf nitrogen content, NO3− accumulation and upregulation of ammonium transporter genes, thus providing further evidence. Theanine significantly increased in roots and leaves and upregulated theanine transporter genes, while polyphenol and catechin contents decreased, lowering the polyphenol‐to‐amino acid ratio of tea. The benefits of nano‐Se persisted across three harvest times, with a sustained selenium content and an increased root theanine level, although leaf theanine and quality improvements varied. Overall, nano‐Se promoted theanine accumulation via a coordinated regulation of N transporters and biosynthetic genes, while concurrently enhancing photosynthesis and Se biofortification. Its long‐lasting efficacy positions nano‐Se as a sustainable strategy for producing high‐quality, Se‐enriched tea, particularly in Se‐deficient regions.

Background The 300IR (index of reactivity) 5-grass pollen tablet has favorable short-term and sustained clinical efficacy in patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation. Methods Randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial in patients aged 18–50 years with ARC. During study years 1–3, patients received a daily sublingual tablet containing either 300IR 5-grass pollen extract or placebo, according to a discontinuous pre- and coseasonal protocol. Study years 4 and 5 were treatment-free. In response to health authorities’ recommendations, the daily combined score (DCS) was assessed in a post-hoc analysis as the efficacy endpoint. Components of the DCS were daily rhinoconjunctivitis total symptom score (DRTSS) and daily rescue medication score (DRMS). Results 633 patients with ARC were randomized to placebo (n = 219) or 300IR 5-grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season’s end. During the first post-treatment year, a statistically significant difference versus placebo in least squares (LS) mean DCS was noted in patients previously receiving active treatment (300IR (2 M) point estimate: −0.16, 95% confidence interval (CI 95% ): [−0.26, −0.06], p = 0.0019; −31.1%; 300IR (4 M) point estimate: −0.13, CI 95% : [−0.23, −0.03], p = 0.0103, −25.3%). During the second post-treatment year, patients in the 300IR (4 M) group, but not the 300IR (2 M) group, showed a statistically significant difference in LS mean DCS versus placebo (point estimate: −0.11, CI 95% : [−0.21; 0.00], p = 0.0478, −28.1%). This significant efficacy seen during the post-treatment years in patients previously treated with 5-grass pollen tablet compared favorably with that during the 3 prior years of active treatment. A statistically significant difference versus placebo was also noted in secondary efficacy measures in both post-treatment years (except for DRTSS in year 5). In the absence of any active treatment, the safety profile was similar in the active groups versus placebo group during either post-treatment year. Conclusions In adults with grass pollen-associated ARC, 5-grass pollen tablet therapy beginning 4 months before the pollen season and continuing to season’s end demonstrated efficacy across all variables during active treatment, and this effect was prolonged for up to 2 years post-treatment. Trial registration ClinicalTrials.gov identifier: NCT00418379 .

Objective Spinal muscular atrophy (SMA) is a genetic disease caused by the degeneration of spinal motor neurons due to a deficiency in survival motor neuron protein (SMN) protein, leading to progressive muscle atrophy and weakness. nusinersen, an antisense oligonucleotide that increases SMN protein expression, has shown effectiveness in both pediatric and adult patients with SMA. While it is administrated every 4 months during the maintenance period in most countries, the dosing interval is 6 months in Japan. The impact of this dosing difference on long‐term outcomes is not fully understood. This study evaluates the long‐term efficacy of the 6‐month dosing protocol of nusinersen in adult SMA patients. Methods We assessed 14 adult patients treated with nusinersen every 6 months over a period of up to 39 months using the Hammersmith Function Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). The results were compared with those from a recent cohort study of adult SMA patients in Europe. Results For ambulatory patients, the mean changes in HFMSE scores at 15, 27, and 39 months were 6.7, 8.3, and 8.0 points, respectively. These results were similar to those observed in the European cohort. In contrast, for nonambulatory patients, the mean changes in HFSME scores were –0.3, –1.4, and –1.3 points, and the mean changes in RULM scores were 2.0, 0.5, and 1.0 points at the same time points. These results were generally less favorable compared to the European cohort but did not reach clinically meaningful deterioration. Discussion The findings of this study suggest that the 6‐month nusinersen dosing protocol provides sustained long‐term benefits for ambulatory adult SMA patients. For nonambulatory patients, the 6‐month protocol appears less effective than the 4‐month protocol. We believe that future nusinersen treatment strategies for adult SMA patients should be flexible, with adjustments based on disease severity. In particular, increasing the dosing frequency and/or dosage in nonambulatory patients may lead to greater improvements.

Psoriasis vulgaris and psoriatic arthritis are common diseases that can lead to considerable impairment of quality of life. The coexistence of alopecia universalis and psoriasis may suppose a therapeutic challenge. We report a 31‐year‐old female patient with alopecia universalis, psoriasis vulgaris and psoriatic arthritis. The patient exhibited a refractory response of psoriatic arthritis and alopecia universalis to monotherapy with methotrexate (MTX), bimekizumab, deucravacitinib and tofacitinib and to topical therapy with corticoids. A subsequent regimen including tofacitinib and MTX led to marked improvements in both joint pain and hair regrowth. Current evidence supporting the utilisation of tofacitinib and methotrexate for alopecia areata is promising. The strategic implementation of combination therapies that leverage the immunomodulatory properties of MTX alongside the targeted mechanisms of action of tofacitinib may result in enhanced therapeutic outcome. Tofacitinib in combination with MTX is a promising treatment option for patients with severe, refractory alopecia areata and psoriasis. Capsule Summary We present a case of a 31‐year‐old female with alopecia universalis, psoriasis vulgaris, and psoriatic arthritis, who showed poor response to prior treatments. Following the initiation of a combination therapy with tofacitinib and methotrexate, significant improvements in joint pain and hair regrowth were observed. This case underscores the potential efficacy of this combination therapy in managing severe, resistant forms of alopecia and associated conditions, highlighting the need for further investigation into their long‐term outcomes.

Aims As an extension of a phase 2/3 study evaluating the efficacy and safety of lisdexamfetamine dimesylate (LDX) 30, 50, or 70 mg/d for 4 weeks in Japanese patients aged 6‐17 years with attention‐deficit/hyperactivity disorder (ADHD), this study evaluated its long‐term safety and efficacy. Methods This was a multicenter, open‐label study of LDX for 53 weeks. Safety was assessed by regular medical examination for treatment‐emergent adverse events (TEAEs); regular recording of body weight, vital signs, and laboratory test values; and completion of dependence questionnaires. Efficacy was assessed using Japanese versions of the ADHD‐Rating Scale‐IV (ADHD‐RS‐IV) and Conners' 3rd edition Parent Rating Scale (Conners 3); plus Clinical Global Impression‐Improvement (CGI‐I), Clinical Global Impression‐Severity, and Parent Global Assessment (PGA) scales. Results Of 132 enrolled patients, 104 completed the trial. Most frequent treatment‐related TEAEs were decreased appetite (73.5%), initial insomnia (39.4%), and weight decrease (22.0%). Most TEAEs were mild (82.6% of patients). There were no serious or severe TEAEs or deaths. No treatment‐related TEAEs were associated with blood pressure or pulse rate, and no patient had a QTcF interval >500 ms. Statistically significant improvement from baseline to week 53 was observed in the mean ADHD‐Rating Scale‐IV total score and mean Conners 3 subscale scores. Most patients showed improvement on the CGI‐I (78%) and PGA (76.5%) scales. Conclusions No significant safety issues were observed with LDX 30, 50, or 70 mg/d administered for 1 year in Japanese children and adolescents with ADHD. LDX was associated with long‐term reductions in ADHD symptoms and severity. This multicenter, open‐label study evaluated the long‐term safety and efficacy of lisdexamfetamine dimesylate (LDX) in Japanese patients aged 6‐17 years with attention‐deficit/hyperactivity disorder. No significant safety issues were observed with LDX 30, 50, or 70 mg/d administered for 1 year. There were no serious or severe treatment‐emergent adverse events (TEAEs) or deaths. The most frequent treatment‐related TEAEs were decreased appetite, initial insomnia, and weight decrease. TEAEs were mild in 82.6% of patients.

Objective To assess long‐term follow‐up evaluations for the treatment of femoral intertrochanteric fractures with the “three‐finger method” assisted by proximal femoral nail antirotation (PFNA). Methods From January 2010 to January 2017, 123 patients were selected and followed for the treatment of femoral intertrochanteric fractures with PFNA assisted by the “three‐finger method” (application of the index finger, middle finger, and ring finger in the process of surgery to assist PFNA). There were 56 male patients and 67 female patients aged 52–93 years with an average age of 75.6 years, and 88 cases were due to a fall and 35 due to a traffic accident injury. The femoral necks were fixed with PFNA assisted by the “three‐finger method” applying the following procedure: traction reduction, determining the incision, inserting the needle, and placing screw. The Harris hip score, postoperative complications, hip pain and function status were statistically analyzed to evaluate the surgical efficacy and to discuss the surgical technique of the “three‐finger method” assisted by PFNA. Results According to the Harris scoring criteria, patients were followed for 1, 2, 4, 6, and 8 years, and the good outcomes of patients were recorded. The excellent and good rate of 87% was the highest in the second year of follow‐up. Then, the rate decreased following the eighth year of follow‐up. The excellent and good rate of 82.7% was the lowest. The patients with incisions healed well, there were no instances of fat liquefaction or infection. There were three cases of effusion, the rate was 2.4%. The secretions were cultured, and no bacterial growth was found. After treatment of the wound, it healed, and the spiral blade used for the femoral head did not wear out. There was one case of femoral head necrosis. There was no significant correlation between hip pain and sex and age (P > 0.05), and the function of the hip joint was significantly correlated with the age of the patients (P < 0.05). Conclusion The “three‐finger method” in the process of surgery to assist PFNA for the treatment of patients with intertrochanteric fractures of the femur simplified the operation steps, reduced the operation difficulty, shortened the operation time, improved the operation efficiency, and reduced the incidence of postoperative complications.

INTRODUCTION In Clarity AD, lecanemab reduced markers of amyloid in early symptomatic Alzheimer's disease and slowed cognitive and functional decline at 18 months. Herein, we report 36‐month data from the ongoing open‐label extension (OLE). METHODS Clarity AD is an 18‐month, randomized study (Core), with an OLE where participants received open‐label lecanemab. Clinical and health‐related quality‐of‐life (HRQoL) outcomes were evaluated overall and by examining “delayed‐start” and “early‐start” cohorts. Low pathology (i.e., low baseline amyloid or tau) subgroups were analyzed. RESULTS ARIA rates were low after 6 months and not associated with long‐term progression. Across clinical and HRQoL endpoints, lecanemab‐treated participants continued to benefit through 36 months. Separation between early and delayed start was maintained between 18 and 36 months. The low pathology subgroup showed stability or improvement over 18–36 months. DISCUSSION Benefit continued to accrue with ongoing lecanemab treatment through 36 months. Results in the low pathology subgroup support early initiation of lecanemab treatment. Highlights This research evaluated the long‐term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open‐label lecanemab treatment for up to 36 months. Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long‐term lecanemab treatment. Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date. No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long‐term clinical progression. Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long‐term lecanemab therapy.

Virtual reality exposure therapy (VRET) is currently being used to treat social anxiety disorder (SAD); however, VRET's magnitude of efficacy, duration of efficacy, and impact on treatment discontinuation are still unclear. We conducted a meta-analysis of studies that investigated the efficacy of VRET for SAD. The search strategy and analysis method are registered at PROSPERO (#CRD42019121097). Inclusion criteria were: (1) studies that targeted patients with SAD or related phobias; (2) studies where VRET was conducted for at least three sessions; (3) studies that included at least 10 participants. The primary outcome was social anxiety evaluation score change. Hedges' g and its 95% confidence intervals were calculated using random-effect models. The secondary outcome was the risk ratio for treatment discontinuation. Twenty-two studies (n = 703) met the inclusion criteria and were analyzed. The efficacy of VRET for SAD was significant and continued over a long-term follow-up period: Hedges' g for effect size at post-intervention, -0.86 (-1.04 to -0.68); three months post-intervention, -1.03 (-1.35 to -0.72); 6 months post-intervention, -1.14 (-1.39 to -0.89); and 12 months post-intervention, -0.74 (-1.05 to -0.43). When compared to in vivo exposure, the efficacy of VRET was similar at post-intervention but became inferior at later follow-up points. Participant dropout rates showed no significant difference compared to in vivo exposure. VRET is an acceptable treatment for SAD patients that has significant, long-lasting efficacy, although it is possible that during long-term follow-up, VRET efficacy lessens as compared to in vivo exposure.

Approximately 10 years after vaccination with the recombinant zoster vaccine (RZV), an interim analysis of this follow-up study of the ZOE-50/70 trials demonstrated that efficacy against herpes zoster remained high. Moreover, the safety profile remained clinically acceptable, suggesting that the clinical benefit of the RZV in ≥50-year-olds is sustained up to 10 years.