Dose Reduction Research Articles

How safe is gene therapy? : Second death after Duchenne therapy

Duchenne muscular dystrophy (DMD) is asevere monogenic hereditary disease with early manifestation and aprogressive course. Treatment options have so far been limited. Gene therapy opens up new options for DMD patients. Against the background of afurther death following DMD gene therapy, the side effects and risks of the gene therapeutics already approved or undergoing clinical trials will be evaluated and alternative gene therapeutics will be described. Based thereon, the future of DMD gene therapy will be discussed. For the first time, in June 2023, delandistrogene moxeparvovec (SRP-9001), agene replacement therapy based on an adeno-associated virus (AAV) vector, was approved in the USA for children aged 4-5years with DMD. Other promising gene therapies are in preclinical development or clinical trials, including CRISPR/Cas9-mediated strategies to restore dystrophin expression. Two deaths following DMD gene therapy with high-dose AAV vectors were attributed to AAV-mediated immune responses. The pre-existing disease underlying the therapy is most likely involved in the fatal AAV toxicity. Although gene therapy applications of AAV vectors are generally considered safe, the systemic administration of high vector doses can lead to severe side effects with apotentially fatal outcome in individual patients, especially after activation of the immune system. In the future, new methods for immunosuppression, reduction of AAV dose and alternative vectors will therefore increasingly come to the fore.

A case of IgG4-related disease associated with ulcerative colitis that was successfully treated with a JAK inhibitor.

Glucocorticoids (GC) are the standard of care for the induction and maintenance of remission in immunoglobulin G4 (IgG4)-related diseases. However, IgG4-related diseases often relapse with GC dose reduction, not only making GC dose reduction difficult but also necessitating GC dose escalation in many cases. Therefore, other immunosuppressive drugs are required to maintain remission. Here, we report a 39-year-old man with ulcerative colitis and IgG4-related disease who experienced a relapse of both diseases despite treatment with tacrolimus and 6-mercaptopurine. Following the initiation of tofacitinib, a Janus-associated kinase inhibitor, it was possible to reduce the GC dose while maintaining remission of both diseases. This case highlights the potential utility of Janus-associated kinase inhibitors in managing complex cases of IgG4-related disease, especially those with concurrent conditions such as ulcerative colitis.

Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer at a single institution: A retrospective study.

In this study, we aimed to investigate patient characteristics, efficacy, prognostic factors, and safety of olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer at our institution. Patients responding to platinum-based therapy and starting olaparib maintenance therapy for recurrent epithelial ovarian, fallopian tube, or peritoneal cancer at Kurume University Hospital between January 2018 and November 2021 were enrolled in the study. Their data were extracted retrospectively from medical records. In all, 50 patients were included. The median (range) age of the patients, follow-up time, and duration of olaparib maintenance therapy were 62 (39-87) years, 21.6 (2.2-45.9) months, and 7.2 (2-45.9) months, respectively. Among the 29 patients tested for homologous recombination (HR) status, 22 (75.9%) were positive for HR deficiency (HRD), 12 (54.5%) of whom had BRCA-positive tumors. The median progression-free survival was 8.9 months (95% confidence interval: 6.2-12.6), and the median overall survival was 27.1 months (95% confidence interval: 22.5-40.3). Multivariate analysis of prognostic factors revealed that HRD was an independent prognostic factor for both progression-free survival and overall survival. The most common adverse event was nausea (any grade, n = 30, 60%), resulting in drug interruption (n = 23, 46%), dose reduction (n = 17, 34%), and discontinuation of treatment (n = 1, 2%). Olaparib maintenance therapy for recurrent platinum-sensitive ovarian cancer at our institution was effective, with acceptable adverse events. HRD was the most significant prognostic factor for patients with recurrent platinum-sensitive ovarian cancer.

Changes in Basal and Bolus Insulin Requirements with Tirzepatide as an Adjunctive Therapy in Adults with Type 1 Diabetes Using Tandem Control-IQ.

This study was aimed at investigating changes in insulin requirements and glycemic outcomes in adults with type 1 diabetes (T1D) using Control IQ (Tandem Diabetes) automated insulin delivery system (AID) over 8months of tirzepatide treatment. In this single-center, observational study, we collected demographic, A1c, weight, sensor glucose, and insulin dose data for adults with T1D who were using AID and initiated tirzepatide adjunct therapy for clinical indications (n = 11, median age 37, 64% female and mean body mass index of 39.6kg/m2). Data were compared from baseline and over 8months. Within 2months of tirzepatide treatment, there were significant reductions in total daily insulin [median (IQR) 73.9 (47.6-95.8) to 51.7 (46.7-66.8) units/day, p < 0.001], basal insulin [47 (28.2-51.8) to 32.4 (25.5-46.3) units/day, p < 0.001], and bolus insulin [31.4 (19.9-38.3) to 17.9 (14.9-22.2) units/day, p < 0.001] requirements. Insulin dose reduction from 2 to 8months was modest. The frequency of user-initiated boluses did not differ throughout the study. Despite reductions in total insulin requirement, time in range (70-180mg/dl) increased by 7%, A1c reduced by 0.5%, weight reduced by 9%, without increase in time below 70mg/dl. This pilot study provides clinical guidance on insulin titration for adults with T1D who may initiate tirzepatide therapy. Based on the findings of this study, we recommend reducing 25% of total daily insulin dose at tirzepatide initiation in adults with T1D using AID with baseline A1c of less than 7.5%. Higher doses of tirzepatide were associated with greater weight loss, however, the reduction in insulin requirement was minimal.

Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo

Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.

The significance of precise diabetes diagnosis: a case of euglycemic diabetic ketoacidosis induced by the introduction of empagliflozin with simultaneous reduction of insulin dosage

Euglycemic diabetic ketoacidosis (euDKA) is a rare but severe metabolic complication of diabetes mellitus characterised by elevated anion gap metabolic acidosis despite normal or mildly elevated blood glucose levels. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as effective antidiabetic medications, yet their use is associated with an increased risk of euDKA, especially when coupled with insulin dose reduction. We present the case of a 50-year-old male with a 20-year history of diabetes mellitus, initially managed with insulin and metformin, who developed euDKA following the introduction of empagliflozin and sitagliptin alongside a reduction in insulin therapy. Despite normoglycaemia the patient exhibited symptoms of ketoacidosis, including chronic fatigue, polydipsia, and polyuria. Diagnostic workup revealed metabolic acidosis, elevated inflammatory markers, acute kidney injury and ketonuria. Subsequent specialised laboratory tests confirmed type 1 diabetes mellitus (T1DM) with the presence of anti-glutamic acid decarboxylase (anti-GAD) antibodies and the absence of C-peptide secretion. Management involved fluid therapy, intravenous insulin and glucose administration. This case underscores the diagnostic challenges of euDKA and emphasises the importance of differentiating between T1DM and T2DM, as management strategies vary significantly. Patient education on insulin therapy and injection techniques is crucial to prevent complications such as improper insulin delivery and dose reduction, which can precipitate euDKA. In conclusion, clinicians should be vigilant for euDKA in patients on SGLT2 inhibitors, particularly when insulin dose reduction is involved. Comprehensive patient education and accurate differentiation between diabetes types are essential for timely diagnosis and optimal management, thereby reducing the risk of severe complications.

Efficacy and safety of niraparib in platinum-sensitive recurrent ovarian cancer: retrospective observational study in a tertiary hospital.

Niraparib has been authorized for maintenance treatment of epithelial ovarian cancer after first-line treatment with platinum, in partial or complete response. To evaluate the effectiveness and safety of maintenance niraparib in platinum-sensitive recurrent ovarian cancer (PSROC) patients in a tertiary hospital. This retrospective observational unicentre study included women diagnosed with ovarian adenocarcinoma who received niraparib. Eligibility criteria encompassed women with PSROC, in response to platinum chemotherapy, and not previously treated with other PARPis. Data on demographics, comorbidities, BRCA mutation status, disease stage, treatment history and adverse events were recorded. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. A total of 33 patients were included, with a median age of 63.5 years. The majority of patients received niraparib at 200 mg/day based on Research on Adverse Drug Events and Report criteria. Median OS was 30 months (95% CI: 16.76-43.23), and median PFS was 8 months (95% CI: 2.48-13.52). Adverse effects were more frequent during the initial months of treatment, with most classified as CTCAE v5 grade 1-2. Dose reductions, interruption of treatment and discontinuations were observed due to haematologic toxicities primarily. This real-world study showed that maintenance niraparib in PSROC patients had effectiveness and safety profiles consistent with clinical trials and other observational studies. Median PFS and OS were comparable to previous reports, and most adverse events were manageable with dose modifications. The results support the use of niraparib as a maintenance therapy option in this patient population.

A Prospective Study on the Use of Deep Inspiration Breath-Hold Technique in External Beam Radiotherapy for Breast Cancer

Background Breast cancer is the most common cancer and the leading cause of death in women. The deep inspiration breath-hold (DIBH) technique helps reduce the dose received by the heart and lungs in breast cancers during adjuvant radiotherapy (RT). We present the dosimetry of heart and lungs with DIBH technique, reproducibility, and ease of execution. Materials and Methods This is a prospective study among breast cancer patients planned for adjuvant RT following either breast conservation or mastectomy. Patients received adjuvant RT to a dose of 42.5 Gy/16 Fr to the chest wall/whole breast followed by a boost of 10 Gy/5 Fr for breast conservation surgery patients with either three-dimensional conformal RT or volumetric modulated arc therapy technique. The dosimetric parameters such as lung mean dose, heart mean dose, and V25 Gy were compared between DIBH and free-breathing (FB) scans. Data were analyzed using SPSS software, and p-value &lt;0.05 was considered statistically significant. Results The study was conducted from September 2018 to August 2020, and 32 patients were included. The compliance to the DIBH technique was good. The dose received by ipsilateral lung V20 (17 vs. 25%) and mean dose (9 vs. 12 Gy) were significantly lower in DIBH compared with FB (p &lt; 0.001). The V5 (31 vs. 15%), V25 (9 vs. 2%), and mean dose (7 vs. 3.3 Gy) to the heart were much higher in FB compared with DIBH (p &lt; 0.001). Conclusion DIBH-based RT treatment delivery for breast cancer patients requiring adjuvant RT showed good compliance and offers a significant reduction in radiation dose to the heart and lung.

Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. NCT04788511 and NCT04916470.

Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?

The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.

Use of selpercatinib in a patient with &lt;i&gt;RET&lt;/i&gt;-mutated non-small cell lung cancer: case report

Background. The use of the modern targeted drugs in patients with non-small-cell lung cancer (NSCLC) with certain somatic alterations (genetic alterations in EGFR, ALK, ROS1, BRAF, RET genes, etc.) provides a significant increase in overall and disease-free survival with an acceptable toxicity profile. The use of RET inhibitors, such as selpercatinib, has significantly improved prognosis in NSCLC patients with RET gene translocation, since chemotherapy and immunotherapy in this cohort of patients are ineffective options. The RET gene translocation occurs rarely (2–3 % of cases among lung adenocarcinoma), but detection of this genetic alteration with subsequent administration of targeted therapy significantly improves the prognosis of the disease. Case report. We present a clinical case of the efficacy of targeted therapy with selpercatinib in a 60-year-old patient with RET-positive NSCLC. Methods to eliminate toxicity after selpercatinib therapy and therapy response are described. Results. Second-line selpercatinib therapy resulted in partial response in our patient with lung adenocarcinoma and the presence of translocation in RET gene. Adverse effects from targeted therapy were minimized or eliminated by the use of concomitant therapy, temporary cancellation of targeted therapy with subsequent dose reduction and gradual return to full therapeutic doses. Conclusion. This case demonstrates the high significance and importance of genetic testing in patients with lung adenocarcinoma not only for the most common mutations, but also for rarer somatic alterations, such as translocation in the RET gene. Detection of this translocation and subsequent administration of appropriate targeted therapy significantly improves the prognosis of patients.

Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review

The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 &lt; 90–95%, V20 &lt; 65–86.6% and V40 &lt; 22.8–40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies.

Gradually tapering off antipsychotics: lessons for practice from case studies and neurobiological principles.

There has been an increasing focus on deprescribing in psychiatry recently, particularly of antipsychotic medication, with recognition that not all patients with psychotic disorders require lifelong medication. We summarize some empirical and theoretical papers, and examine case studies to provide instruction on this topic. Recent studies have found that slower tapering (over months or longer) of antipsychotics is associated with a lower relapse rate than quicker tapering (weeks). Case studies presented suggest that the process of reduction is associated with the precipitation or exacerbation of psychotic symptoms and that a slower process of reduction may minimize this effect. This may be because faster reductions cause greater disruption of homeostatic equilibria, provoking psychotic symptoms either as direct withdrawal symptoms or consequences of nonpsychotic withdrawal symptoms (e.g. insomnia) - although not all patients will experience withdrawal symptoms. This suggests that smaller dose reductions, especially at lower doses, made very gradually, may minimize the risk of psychotic symptoms. Slower tapering of antipsychotics may provide time for adaptations made to the presence of the medications to resolve, thus reducing the disruption to homeostatic equilibrium caused by dose reduction, potentially reducing the risk of relapse. Exacerbation of psychotic symptoms on antipsychotic reduction may not represent evidence of the need for a higher dose of antipsychotic on a long-term basis but may indicate the need for more gradual reduction. Gradual reduction of antipsychotics, especially after long-term use in clinical practice is prudent.

Synergistic anxiolytic efficacy exploring the combined effects of diazepam and zinc chloride in wistar albino rats.

Combinations of medications are frequently employed when their effects are similar. Beyond aiding in the reduction of medication dosages, this approach may yield additional positive outcomes. Studies have shown that zinc can mitigate anxiety-related behavior in laboratory animals. This study aimed to investigate the potential stabilizing effects of zinc chloride and diazepam in Wistar albino rats.Five groups, each comprising six animals. Test groups included two combinations of zinc chloride and diazepam, each with two different doses of diazepam (1 and 2 mg/kg) and 10 mg/kg of zinc chloride. Four established anxiety models-the Elevated Plus Maze (EPM), the hole board, the light and dark box, and the mirror chamber-were employed to assess the anxiolytic effects. The combination of zinc chloride and diazepam proved to be more effective than the individual doses of zinc chloride and diazepam, indicating enhanced anxiolytic effects.

The Potential Role of the Ketogenic Diet in Serious Mental Illness: Current Evidence, Safety, and Practical Advice

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that mimics the physiological state of fasting. The potential therapeutic effects in many chronic conditions have led to the gaining popularity of the KD. The KD has been demonstrated to alleviate inflammation and oxidative stress, modulate the gut microbiota community, and improve metabolic health markers. The modification of these factors has been a potential therapeutic target in serious mental illness (SMI): bipolar disorder, major depressive disorder, and schizophrenia. The number of clinical trials assessing the effect of the KD on SMI is still limited. Preliminary research, predominantly case studies, suggests potential therapeutic effects, including weight gain reduction, improved carbohydrate and lipid metabolism, decrease in disease-related symptoms, increased energy and quality of life, and, in some cases, changes in pharmacotherapy (reduction in number or dosage of medication). However, these findings necessitate further investigation through larger-scale clinical trials. Initiation of the KD should occur in a hospital setting and with strict care of a physician and dietitian due to potential side effects of the diet and the possibility of exacerbating adverse effects of pharmacotherapy. An increasing number of ongoing studies examining the KD’s effect on mental disorders highlights its potential role in the adjunctive treatment of SMI.

Abemaciclib for the Treatment of HR+HER2− Metastatic Breast Cancer: An Institutional Experience

(1) Background: Abemaciclib combined with endocrine therapy is a standard first- or later--line of treatment for HR+/HER2− metastatic breast cancer (MBC). The aim of this retrospective cohort study was to describe the outcomes of patients treated in a real-world setting, with particular focus on elderly patients. (2) Patients and methods: Patients treated with abemaciclib between November 2019 and February 2022 were included in the study. Data were collected from electronic medical records. The primary objective was to determine real-world progression-free survival (rwPFS), and secondary objectives included median overall survival (mOS) and safety. (3) Results: Analysis included 134 patients, with a median follow-up of 42 months. Median age was 62 years, with 29.9% aged 70+ years. A total of 51.5% of patients received abemaciclib in first-line, predominantly with aromatase inhibitor (68.1%). Median rwPFS was 21 in first-line and 20 months in the second-line, with no significant difference between treatment lines (HR 0.96; p = 0.88). Patients treated in the third- or later-line had a significantly shorter rwPFS, at 7 months (HR 1.48, p = 0.003). mOS was not reached in the first-line setting. For second- and third- or later-lines, mOS was 29 and 19 months, respectively. There was no significant difference in mOS between first- or second-line (HR 1.37, p = 0.36). In the 70+ group, median rwPFS was 15 months and mOS was 25 months with no significant difference compared to younger patients (rwPFS HR 1.1; p = 0.65; OS HR 1.4; p = 0.21). Most common adverse events (AEs) were diarrhoea (68.7%), anaemia (64.9%), and increased serum creatinine (63.4%). Grade 3/4 AEs were reported in 21.6% of patients. Dose reductions occurred in 30.6% of patients and were more frequent in patients 70+ (40%) compared to younger patients (28%); the difference was not significant (p = 0.22). At study cut-off, 64.9% of patients discontinued abemaciclib, primarily due to disease progression (73.5%). (4) Conclusions: Our study provides valuable insights into the effectiveness and safety of abemaciclib for the treatment of MBC. We observed comparable outcomes in terms of rwPFS and OS between the first two lines, suggesting consistent effectiveness across treatment lines. In addition, our findings suggest that older age (70+) does not significantly impact the effectiveness and tolerability of abemaciclib, although the careful monitoring and management of AEs are warranted.

Suspected duloxetine-induced restless legs syndrome phenotypic variant: a case report

BackgroundRestless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific diagnostic criteria. When effective therapeutic agents induced RAS and symptoms persisted after briefly observation, clinicians will face the challenge of weighing efficacy against side effects.Case presentationA 67-year-old woman was admitted to a geriatric psychiatric ward with depression. Upon admission, the escitalopram dose was reduced from 15 mg to 10 mg per day, and the duloxetine dose was increased from 60 mg to 80 mg per day. The next night before bedtime, she developed itching and creeping sensations deep inside bilateral shoulders and arms, with the urge to move, worsening at rest, and alleviation after hammering. The symptoms persisted when escitalopram was discontinued. A history of RLS was confirmed. Treatment with 40 mg of duloxetine and 0.125 mg of pramipexole significantly improved depression, and the paresthesia disappeared, with no recurrence occurring 6 months after discharge.Discussion and conclusionsThis case suggests that psychiatrists should pay attention to RLS variants when increasing doses of duloxetine. Long-term improvement can be achieved through dosage reduction combined with dopaminergic drugs instead of immediate discontinuation.

Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

Efficacy of gonadal shielding in dose reduction for female pelvic radiography.

This study aimed to evaluate the dose reduction using gonad shielding (GS) during pelvic imaging. Three types of pelvic images (radiography, magnetic resonance and computed tomography) were fused to elucidate the three-dimensional relationship between the position of ovaries and GS. To estimate the dose received by the ovaries, the off-axis dose at any given depth was measured under two different imaging conditions using thermoluminescence dosemeters and a polymethyl methacrylate phantom. The mean ovarian depth was 8.4cm. The mean estimated ovarian dose without an additional filter was 0.36mGy without GS and 0.14mGy with GS. The mean estimated ovarian dose with an additional filter was 0.24mGy without GS and 0.10mGy with GS. The efficacy of ovarian dose reduction should be evaluated based on the achieved ovarian dose, considering the ovarian depth and use of additional filtration, rather than the ovarian protection rate of GS.

Futibatinib: A Review in Locally Advanced and Metastatic Cholangiocarcinoma.

Futibatinib (LYTGOBI®) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor receptor (FGFR)1-4. It is approved in the EU, Japan and the USA for the treatment of adults with locally advanced or metastatic cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy. In the phase II part (FOENIX-CCA2) of a multinational phase I/II study in this patient population, monotherapy with futibatinib 20mg once daily was associated with clinically meaningful and durable responses, sustained health-related quality of life (HR-QOL), and a manageable safety profile with supportive care and as-needed dose modifications. Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.