Longer Treatment Duration Research Articles

Omega-3 Nutrition Therapy for the Treatment of Diabetic Sensorimotor Polyneuropathy.

Despite advances in clinical and translational research, an effective therapeutic option for diabetic sensorimotor polyneuropathy (DSP) has remained elusive. The pathomechanisms of DSP are diverse, and along with hyperglycemia, the roles of inflammatory mediators and lipotoxicity in the development of microangiopathy have been well elucidated. Omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential fatty acids with a vital role in a number of physiological processes, including neural health, membrane structure integrity, anti-inflammatory processes, and lipid metabolism. Identification of n-3 PUFA derived specialised proresolving mediators (SPM), namely resolvins, neuroprotectin, and maresins which also favour nerve regeneration, have positioned n-3 PUFA as potential treatment options in DSP. Studies in n-3 PUFA treated animal models of DSP showed positive nerve benefits in functional, electrophysiological, and pathological indices. Clinical trials in humans are limited, but recent proof-of-concept evidence suggests n-3 PUFA has a positive effect on small nerve fibre regeneration with an increase in the small nerve fiber measure of corneal nerve fibre length (CNFL). Further randomized control trials with a longer duration of treatment, higher n-3 PUFA doses, and more rigorous neuropathy measures are needed to provide a definitive understanding of the benefits of n-3 PUFA supplementation in DSP.

Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03.

1000 Background: In the DESTINY-Breast03 (NCT03529110) primary analysis (data cutoff [DCO], May 21, 2021), T-DXd showed superiority over T-DM1 in pts with HER2+ mBC, with a significant improvement of progression-free survival by blinded independent central review (HR, 0.284; 95% CI, 0.217-0.373; P < 0.001), and a safety profile consistent with prior studies. This analysis provides updated safety data with longer follow-up. Methods: Pts were randomized 1:1 to T-DXd or T-DM1. Prespecified safety analysis of treatment-emergent adverse events (TEAEs) was conducted; endpoints included time to event, duration of event, and resolution. Results: At DCO (September 7, 2021), 116 (45.1%) pts vs 39 (14.9%) pts remained on treatment in the T-DXd vs T-DM1 arms; median treatment duration was 16.1 mo (range, 0.7-33.0) for T-DXd vs 6.9 mo (range, 0.7-28.5) for T-DM1. Any-grade (G), G≥3, and serious AE (SAE) rates were similar for T-DXd vs T-DM1 (99.6% vs 95.4%; 53.3% vs 49.8%; and 21.0% vs 19.2%), while exposure-adjusted incidence rates (EAIRs; per pt-year) for G≥3 and SAEs were lower for T-DXd vs T-DM1 (0.42 vs 0.70 and 0.17 vs 0.27). Median time to TEAE associated with drug discontinuation or dose reduction was longer with T-DXd vs T-DM1 (224.0 vs 147.0 d and 96.0 v 19.0 d, respectively). Most TEAEs in ≥20% of pts were hematologic or gastrointestinal. Median time to first onset of select any-G TEAEs was 70.0 vs 42.0 d for anemia, 196.0 vs 168.0 d for lymphopenia, 132.0 vs 8.0 d for thrombocytopenia, 22.0 vs 24.0 d for fatigue, 74.5 vs 92.0 d for leukopenia, and 64.0 vs 105.0 d for neutropenia, with T-DXd vs T-DM1, respectively. In both arms, most nausea and vomiting events were G1/2; while G≥3 events with T-DXd vs T-DM1 were 6.6% vs 0.4% for nausea and 1.6% vs 0.8% for vomiting, respectively. Rates of nausea, vomiting, and alopecia were highest in cycle 1 and lower in subsequent cycles for T-DXd. Rates of hematologic events were generally lower in earlier cycles vs cycle ≥8 in both arms. Rates of adjudicated, drug-related ILD/pneumonitis were 10.9% (1 G2 event since previous DCO) with T-DXd vs 1.9% with T-DM1, with no G4/5 events. Median time to first adjudicated, drug-related ILD/pneumonitis event was 5.9 vs 9.5 mo for T-DXd vs T-DM1, respectively; at DCO, most events resolved (57.1% vs 80.0%), and follow-up is ongoing. Conclusions: In this updated safety analysis, T-DXd demonstrated a tolerable safety profile consistent with prior studies. Despite longer treatment duration with T-DXd, EAIRs of G≥3 and SAEs were lower for T-DXd vs T-DM1. Rates of ILD/pneumonitis for T-DXd were similar to those in the previous DCO. Nausea, vomiting, and alopecia rates decreased over time. This longer safety update reinforces the consistent safety profile of T-DXd, supporting the clinical benefit of T-DXd over T-DM1 in patients with HER2+ mBC. Clinical trial information: NCT03529110.

Early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2-positive metastatic breast cancer.

1038 Background: Patients with HER2+ metastatic breast cancer (MBC) are at high risk of developing central nervous system metastases. DZD1516 is a reversible HER2-specific tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Here we report the preliminary safety and PK data from the ongoing phase 1 study (NCT04509596) in patients with HER2+ MBC who relapsed from multiple prior treatments. Methods: Eligible patients received single oral dosing of DZD1516 on C0D1 and then twice daily (BID) oral dosing from C1D1 in a continuous 21-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to investigate the safety and PK of DZD1516 as a single agent. Results: As of 17 January 2022, DZD1516 was explored in 21 HER2+ MBC patients from the USA and China. DZD1516 was well tolerated at doses < 300 mg, BID. Two DLT events were reported in the 300 mg cohort. In all cohorts, 20 (95.2%) patients reported treatment-emergent adverse events (TEAEs), and 3 (14.3%) patients reported grade 3 drug-related TEAE. Two patients had dose interruption and one patient had dose reduction due to TEAE, all in the 300 mg cohort. Majority of TEAEs were reversible. The longest treatment duration was > 3 months. In all cohorts, the most common (> 20%) TEAEs included headache (42.9%), vomiting (38.1%), nausea (23.8%) and hemoglobin decreased (23.8%). At doses < 300 mg, there is no diarrhea or rash reported. PK data showed that combined exposure of DZD1516 and its active metabolite DZ2678 increased in a dose-proportional manner across the dose ranges. Elimination half-life was about 15-19 hrs. About 2-fold accumulation of DZD1516 in AUC was observed on multiple doses. In vitro, both DZD1516 and DZ2678 showed good permeability, and were not substrates of P-gp and BCRP. In patients, Kpuu,CSF of DZD1516 and DZ2678 was around 2.13 and 0.66, respectively, suggesting good CNS penetration. At the time of data cutoff, 16 patients had at least one post treatment anti-tumor assessment. With a median of 7 lines of prior treatment, the best anti-tumor response was stable disease. Conclusions: Preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 TKI, with good safety profile. Consistent with its high selectivity, no wide type EGFR related AEs have been reported. Further evaluation of its safety and efficacy is ongoing. Clinical trial information: NCT04509596. [Table: see text]

Impact of GH administration on skeletal endpoints in adults with overweight/obesity.

Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with TP53WT Merkel cell carcinoma (MCC).

9506 Background: MCC is a rare, aggressive, neuroendocrine skin cancer with a high risk of recurrence and metastases. A median survival of about 4 mo for pts with metastatic MCC who failed anti-PD-1/L1 therapy highlights an urgent need for novel therapies. In TP53WT MCC, oncoproteins from the Merkel cell polyomavirus (MCPyV) inhibit p53 tumor suppressor functions by activating murine double minute 2 (MDM2). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Methods: The dose-finding, phase 1b/2 KRT-232-103 study (NCT03787602) evaluated navtemadlin in adult TP53WT MCC pts who failed anti-PD-1/L1 therapy. Pts were randomly assigned to oral navtemadlin once daily in 21- or 28-day cycles: 240 mg 7 days (D) on/14D off or 5D on/23D off, 180 mg 5D on/23 D off or 7D on/21D off, or 120 mg 7D on/14D off, until disease progression or unacceptable toxicity. The primary endpoint was Recommended Phase 2 Dose (RP2D); objective response rate (ORR) was assessed per RECIST v1.1. Results: As of Nov 30, 2021, 31 pts were enrolled with median age 66 y (range, 25-82); 52% had visceral disease and 71% had received ≥2 lines of prior therapy. Baseline tumor profiling of available samples showed low tumor mutation burden, MCPyV-positivity, and nonamplified MDM2 gene in 100%, 92%, and 100% of pts, respectively. Treatment-emergent adverse events (TEAEs) were observed in 100% (68% grade 3/4) of pts. The most common Grade 3/4 TEAEs were hematologic: 32% anemia, 32% lymphopenia, and 19% thrombocytopenia. Navtemadlin doses ≤180 mg were well tolerated with fewer dose reductions and longer treatment durations; subsequently the 240 mg arms were closed to further enrollment. Evaluable pts receiving 180 mg 5D on/23D off showed a 25% confirmed ORR, a 38% unconfirmed + confirmed ORR, and a 63% disease control rate (Table); median duration of response was not reached (range, 6-16.2+ mo) and median time to treatment response was 4.1 mo (range, 1.2-7). Notably, one responder, following a prolonged partial response, achieved complete metabolic remission by PET/CT after 2 y on treatment. The 120 mg arm was closed due to a low response rate. The 180 mg dose has been selected for further evaluation. Conclusions: Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/L1 therapy. This study demonstrates that upregulation of the p53 pathway is a viable therapeutic strategy in MCC. Clinical trial information: NCT03787602. [Table: see text]

Factors Associated with Long-Term COVID-19: An Observational Cross-Sectional Study in Indonesia

Long-term COVID-19 could occur in COVID-19 patients, affecting the patient's quality of life, and becoming a problem for public health. However, information is rarely on factors associated with the occurrence of long COVID-19 cases. This study analyzed factors associated with long-term COVID-19. The study was an observational cross-sectional, conducted in August 2021. The data were collected through a Google form questionnaire distributed to COVID-19 survivors in Indonesian. They must be aged more than 17 years to meet the inclusion criteria, while those with incomplete data were excluded. The data were processed by using SPSS 21 with an ordinal regression test in which an alpha level was 5%. As many as 101 from 16 men (15.8%) and 85 women (84.2%) were obtained. Comorbid status (p-value = 0.001) and duration of treatment (p-value = 0.034 and 0.015) had a significant association with the occurrence of long-term COVID-19. Meanwhile, age, gender, occupation, type of care, and vaccination status were not likely associated with long-term COVID-19. COVID-19 patients with comorbidity and a long duration of treatment are more likely to experience long-term COVID-19.&#x0D; Keywords: COVID-19, long-term COVID-19, factor, public health

The Status and Prescription Patterns of Opioid Utilization in a Large Comprehensive Teaching Hospital in China According to the Anatomical Therapeutic Chemical Classification/Defined Daily Dose Methodology.

BackgroundFew studies have analyzed opioid consumption and the average daily dose and duration for different patients in hospital settings in China. The aim of this study was to measure the status of and trends in prescribed opioids and the prescribing patterns at the Second Xiangya Hospital.MethodsThe data were obtained from the prescribed medicine database of the inpatient department. We included patients who were >18 years old and received any level of opioid analgesic between 2012 and 2017. The international Anatomical Therapeutic Chemical Classification/Defined Daily Dose (ATC/DDD) methodology was used to standardize the consumption rates. All opioid units were converted into morphine equivalents (MEs) to analyze the specific opioid usage.ResultsThe consumption of prescribed opioids increased from 3.16 to 3.74 DDD/100 bed-days (+18.3%) from 2012 to 2017. Both cancer and noncancer patients had similar administration routes and median daily dosages in MEs, but cancer patients had longer treatment durations (median: 5 days vs. 1 day, respectively). The median average daily dose and treatment duration for all patients were 15 MEs/day and 2 days, respectively, for oral administration, 100 MEs/day and 1 day for parenteral administration, and 47.14 MEs/day and 5 days for both oral and parenteral administration.ConclusionAlthough there was a tendency toward an increase in opioid consumption, the overall level of consumption in the Second Xiangya Hospital remained relatively low. Thus, it is urgently necessary to increase the availability of opioids and alter prescription habits for them in order adopt the current concept of pain management developed by the World Health Organization (WHO).

Cytokine Profiles as Potential Prognostic and Therapeutic Markers in SARS-CoV-2-Induced ARDS.

Background. Glucocorticoids (GCs) have been shown to reduce mortality and the need for invasive mechanical ventilation (IMV) in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). It has been suggested that serum cytokines levels are markers of disease severity in ARDS, although there is only limited evidence of a relationship between the longitudinal cytokine profile and clinical outcomes in patients with SARS-CoV-2-induced ARDS treated with GC. Methods. We conducted a single-center observational study to investigate serial plasma cytokine levels in 17 patients supported with non-invasive ventilation (NIV) in order to compare the response in five patients who progressed to IMV versus 12 patients who continued with NIV alone. All patients received methylprednisolone 80 mg/day continuous infusion until clinical improvement. Results. The study groups were comparable at baseline. All patients survived. Although IL-6 was higher in the NIV group at baseline, several cytokines were significantly higher in the IMV group on day 7 (IL-6, IL-8, IL-9, G-CSF, IP-10, MCP-1, MIP-1α) and 14 (IL-6, IL-8, IL-17, G-CSF, MIP-1α, RANTES). No significant differences were observed between groups on day 28. Conclusions. Patients in the IMV group had higher inflammation levels at intubation than the NIV group, which may indicate a higher resistance to glucocorticoids. Higher GC doses or a longer treatment duration in these patients might have allowed for a better control of inflammation and a better outcome. Further studies are required to define the prognostic value of cytokine patterns, in terms of both GC treatment tailoring and timely initiation of IMV.

Long-term efficacy, prognostic factors, and safety of deep brain stimulation in patients with refractory Tourette syndrome: A single center, single target, retrospective study

BackgroundTo evaluate the long-term efficacy, prognostic factors, and safety of posteroventral globus pallidus internus deep brain stimulation (DBS) in patients with refractory Tourette syndrome (RTS). MethodsThis retrospective study recruited 61 patients with RTS who underwent posteroventral globus pallidus internus (GPi) DBS from January 2010 to December 2020 at the Chinese People's Liberation Army General Hospital. The Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (YBOCS), Beck Depression Inventory (BDI), Gilles de la Tourette Syndrome Quality-of-Life Scale (GTS-QOL) were used to evaluate the preoperative and postoperative clinical condition in all patients. Prognostic factors and adverse events following surgery were analyzed. ResultsPatient follow up was conducted for an average of 73.33 ± 28.44 months. The final postoperative YGTSS (32.39 ± 22.34 vs 76.61 ± 17.07), YBOCS (11.26 ± 5.57 vs 18.31 ± 8.55), BDI (14.36 ± 8.16 vs 24.79 ± 11.03) and GTS-QOL (39.69 ± 18.29 vs 78.08 ± 14.52) scores at the end of the follow-up period were significantly lower than those before the surgery (p < 0.05). While age and the duration of follow-up were closely related to prognosis, the disease duration and gender were not. No serious adverse events were observed and only one patient exhibited symptomatic deterioration. ConclusionsPosteroventral-GPI DBS provides long-term effectiveness, acceptable safety and can improve the quality of life in RTS patients. Moreover, DBS is more successful among younger patients and with longer treatment duration.

The effect of dialectical behavior therapy on anger and aggressive behavior: A systematic review with meta-analysis

Dysregulated anger, and its common behavioral urge, aggression, pose substantial costs to public health and society. Though some studies have shown DBT to be efficacious in treating aggression and anger dyscontrol, the overall effects of DBT on these outcomes are unknown. To address this limitation, a systematic review with meta-analysis was conducted on 34 studies (N = 2536) published in PsycINFO and PubMed between January 1994 and February 2022 assessing the effect of DBT on anger and/or aggression. Included studies were empirical research articles published in a peer-reviewed journal and assessed the delivery of DBT on quantitative outcome measures of anger or aggression. Included studies delivered the standard outpatient DBT program or DBT adapted for the population and treatment setting, though all studies included the core components of DBT. Risk of publication bias was assessed. Results demonstrated that DBT significantly reduced anger (Hedge's G = −0.21, 95% CI [-0.32, −0.11]) independent of study design and participant variables, though longer treatment duration was associated with greater reductions in anger. There was also a non-significant trend for DBT in reducing aggression (Hedge's G = −0.10, 95% CI [-0.21, 0.00]). Findings from this study suggest that DBT demonstrates efficacy in reducing dysregulated anger transdiagnostically.

Association between medical androgen deprivation therapy and long-term cardiovascular disease and all-cause mortality in nonmetastatic prostate cancer.

Studies have suggested that prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are at increased risk of developing or exacerbating cardiovascular disease (CVD). We aimed to explore the association between ADT for PCa and subsequent CVD and all‐cause mortality in this nationwide, longitudinal study. We also evaluated the role of cardiovascular risk and ADT duration to determine effect modification. Norwegian registry data were used to identify patients with PCa from 2008‐18 and who received primary ADT in the first year after diagnosis. The associations between ADT and composite cardiovascular events, and the individual components of myocardial infarction, stroke and heart failure, in addition to atrial fibrillation and all‐cause mortality, were explored using time‐varying Cox regression models. We included 30 923 PCa patients, of whom 8449 (27%) received primary ADT. Mean follow‐up was 2.9 and 3.8 years for CVD events and mortality, respectively. We found an association between ADT and composite CVD (adjusted HR 1.13: 95% CI 1.05‐1.21), myocardial infarction (1.18: 1.05‐1.32), stroke (1.21: 1.06‐1.38), heart failure (1.23: 1.13‐1.35) and all‐cause mortality (1.49: 1.39‐1.61). These associations persisted in those with low and moderate CVD risk and ADT longer than 7 months. A relationship between ADT and composite CVD and all‐cause mortality was observed, especially in those with moderate CVD risk and longer treatment duration. Future studies with more detailed cancer data are needed to verify the clinical relevance of these results, especially when considering all‐cause mortality within the context of treatment guidelines and benefits of ADT.

Factors affecting recurrence in subacute granulomatous thyroiditis.

This study aimed to evaluate the factors affecting recurrence in subacute granulomatous thyroiditis (SAT). A total of 137 patients with SAT were enrolled in the study; 98 (71.5%) were women and 39 (28.5%) were men. The patients received either steroid or nonsteroidal anti-inflammatory drug (NSAID) for eight weeks. Erythrocyte sedimentation rate (ESR), C-reactive protein, serum thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine (FT4), anti-thyroid peroxidase antibodies and thyroglobulin antibodies, neutrophil, lymphocyte, platelet, neutrophil to lymphocyte ratio, and platelet to lymphocyte ratio levels were evaluated. In addition, recurrence rates were compared between patients who received NSAID treatment and those who received steroid therapy. Treatment modality and pretreatment TSH, FT4, and ESR were significantly different between patients with and without recurrence (p = 0.011, 0.001, 0.004, and 0.026, respectively). Compared with patients without recurrence, those with recurrence had higher pretreatment TSH levels, but lower FT4 and ESR levels. On logistic regression analysis, treatment modality was found to be an independent risk factor for recurrence. The risk of recurrence was higher in those taking steroids than in those taking NSAIDs (p = 0.015). The optimal TSH cutoff value for recurrence was 0.045 µIU/mL, with a sensitivity of 83.3% and specificity of 76% (AUC 0.794, 95% CI 0.639-0.949). The risk of SAT recurrence was higher with steroid therapy than with NSAIDs. Patients who had mild thyrotoxicosis had relatively high recurrence rate and may need a relatively longer duration of treatment.

Compliance to Growth Hormone Therapy in Children and Adolescents with Growth Hormone Deficiency and Turner Syndrome and Impact on Height Velocity: A Prospective Study

Adherence to recombinant growth hormone (rGH) in children is necessary to ensure good treatment outcome. Reported non-compliance to rGH in children varied from 5-82% with little data involving Asian population. The objectives of this study are to evaluate the compliance of children and adolescents to rGH, effect of non-compliance on growth and factors affecting non-adherence. Methods: This is a prospective cohort study over 1-year aiming at all patients age less than 18 years old treated with rGH in our centre. Compliance was assessed from the number of returned medications and electronic record within device. Poor compliance was defined as utilised dose &lt;86% prescribed (equivalent to missing injection ≥1 per week). Result: Thirty-four patients were recruited including 20 (59%) patients with GH deficiency and 14 (41%) with Turner syndrome. Poor compliance was noted in 35% of patients. Poor compliance in GHD patients was significantly associated with an older age (mean 12.55 ± 3.33 vs 9.28 ± 3.20 years old, p=0.038) and longer duration of treatment (mean 5.41 ± 3.0 vs 2.93 ± 2.18 years, p=0.046). Frequent reasons for missing doses were forgetfulness and inadequate medications. Participants with poor compliance had significantly reduced height velocity (HV) and HV standard deviation score (SDS) compared to those with good compliance (p&lt;0.05). Conclusion: Poor compliance is more common in adolescents, those on longer duration of treatment and leads to significantly reduced height velocity. Regular monitoring throughout the course of rGH is important. Measures to improve compliance must address the underlying reasons.

The Effect of Spontaneous LH Surges on Pregnancy Outcomes in Patients Undergoing Letrozole-HMG IUI: A Retrospective Analysis of 6,285 Cycles.

BackgroundTo date, no consensus has been reached on whether to wait for spontaneous luteinizing hormone (LH) surge to occur or to trigger ovulation regardless of the presence of an LH surge for achieving higher success rate in intrauterine insemination (IUI) cycles. Therefore, we hope to investigate the effect of the presence of a spontaneous LH surge on pregnancy outcomes in letrozole–human menopausal gonadotropin (LE-HMG) IUI cycles.MethodsIn this retrospective cohort study, a total of 6,285 LE-HMG IUI cycles were included between January 2010 and May 2021. Cycles were categorized into three groups: the trigger + LH surge group, the trigger only group, and the LH surge only group. The primary outcome measure was the clinical pregnancy rate. A logistic regression analysis was performed to explore other risk factors affecting the clinical pregnancy rate.ResultsNo significant differences were observed in biochemical pregnancy rate (P =0.640), clinical pregnancy rate (P =0.702), ongoing pregnancy rate (P =0.842), and live birth rate (P =0.951) among the three groups. The binary logistic regression analysis also confirmed that the existence of an LH surge was not associated with clinical pregnancy. There was a difference in ectopic pregnancy rates (P =0.045), but logistic regression showed that the presence of a spontaneous LH surge has no association with ectopic pregnancy. Nonetheless, patients with lead follicles within 18.1-20.0 mm/20.1-22.0 mm and a long duration of LE treatment were less likely to get ectopic pregnant compared with patients with 14.1-16.0 mm lead follicles and shorter LE treatment (OR: 0.142, 95% CI: 0.023–0.891, P =0.037; OR: 0.142, 95% CI: 0.022–0.903, P =0.039; OR: 0.445, 95% CI: 0.235–0.840, P = 0.013).ConclusionsThe presence of a spontaneous LH surge in triggered LE-HMG IUI cycles does not appear to improve pregnancy rates. Thus, we suggest that waiting for an LH surge to occur is not necessary in triggered LE-HMG IUI cycles.

North American Study for the Treatment of Recurrent Epistaxis with Doxycycline: The NOSTRIL trial

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a vascular bleeding disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. A frequently debilitating symptom is spontaneous recurrent epistaxis. ObjectiveTo evaluate whether doxycycline therapy improves epistaxis in HHT by using a prospective, randomized, placebo‐controlled crossover study design. Patients/MethodsTwenty‐two eligible patients between December 2017 and July 2020 at a single center were randomized to one of two study arms: doxycycline treatment followed by placebo, or vice versa. Primary outcomes measured differences in epistaxis severity between treatments. Changes in quality of life, laboratory markers of bleeding, and number of monthly blood transfusions or iron infusions were assessed as secondary endpoints. Additional post hoc endpoints included frequency and duration of dripping epistaxis and gushing epistaxis. A post hoc longitudinal analysis assessed effects of doxycycline over time. Results/ConclusionsDoxycycline was safe and well tolerated. However, there was no reduction in the three primary outcome measures, nosebleed frequency (p = .16), nosebleed duration (p = .05), and Epistaxis Severity Score (p = .19). Quality of life, hemoglobin level, and number of blood transfusions and iron infusions did not differ between groups. Post hoc analysis demonstrated reduction in instances of gushing (p = .02) with doxycycline, although this finding is of unclear clinical significance. Post hoc longitudinal analysis showed reduction in frequency (mean estimate of coefficient = −0.19, standard error = 0.07, p = .01) and duration (mean estimate of coefficient = −2.33, standard error = 1.08, p = .03) of epistaxis over time. Post hoc findings suggest possible benefit of doxycycline but should be interpreted with caution given the overall negative study. Further investigation is needed with a larger sample size and a longer treatment duration.

PD26-12 HIVEC-E: SPANISH MULTICENTER PROSPECTIVE EXPERIENCE WITH RECIRCULANT HYPERTHERMIC MMC WITH COMBAT BRS HIVEC SYSTEM

PD26-12 HIVEC-E: SPANISH MULTICENTER PROSPECTIVE EXPERIENCE WITH RECIRCULANT HYPERTHERMIC MMC WITH COMBAT BRS HIVEC SYSTEM

The Impact of Pharmacotherapy of Childhood-Onset Psychiatric Disorders on the Development of Substance Use Disorders.

Background and Objective: Child- and adolescent-onset psychopathology is known to increase the risk for developing substance use and substance use disorders (SUDs). While pharmacotherapy is effective in treating pediatric psychiatric disorders, the impact of medication on the ultimate risk to develop SUDs in these youth remains unclear. Methods: We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review of peer-reviewed literature published on PubMed through November 2021, examining pharmacological treatments of psychiatric disorders in adolescents and young adults and their effect on substance use, misuse, and use disorder development. Results: Our search terms yielded 21 studies examining the impact of pharmacotherapy and later SUD in attention-deficit/hyperactivity disorder (ADHD), two studies on Major Depressive Disorder, and three studies on psychotic disorders. The majority of these studies reported reductions in SUD (N = 14 sides) followed by no effects (N = 10) and enhanced rates of SUD (N = 2). Studies in ADHD also reported that earlier-onset and longer-duration treatment was associated with the largest risk reduction for later SUD. Conclusions: Overall, pharmacological treatments for psychiatric disorders appear to mitigate the development of SUD, especially when treatment is initiated early and for longer durations. More studies on the development of SUD linked to the effects of psychotherapy alone and in combination with medication, medication initiation and duration, adequacy of treatment, non-ADHD disorders, and psychiatric comorbidity are necessary.

Targeted transcriptomic signature for monitoring anti-tuberculosis treatment response

Abstract The long duration of anti-tuberculosis treatment is associated with poor adherence and treatment outcomes leading to higher relapse rates. Shortening treatment duration has been suggested to improve treatment outcome by increasing adherence. Sputum conversion, the gold standard for monitoring treatment, has low sensitivity and specificity for predicting relapse. Better markers are therefore needed and blood-based biomarkers have been suggested as potential alternatives. The aim of this study was to identify transcriptional signatures to predict anti-tuberculosis treatment outcomes, relapse, and treatment failure. We extracted RNA from whole blood PAXgene samples from 37 confirmed TB cases at diagnosis (baseline), 14 days and two months of treatment and measured gene expression using targeted sequencing on the NanoString nCounter MAX platform using the 799-gene host response panel. To identify genes that predict treatment response and relapse, we identified differentially expressed genes (DEGs) at Day 14 and two months of treatment and compared expression between fast (sputum converters by 2 months) and slow responders (sputum converters after 2 months). Using a cut-off of 1.5-fold change and a p value of 0.05, we observed 58 DEGs at Day 14 and 175 DEGs at two months relative to baseline. When we compared slow and fast responders, 14 genes were differentially expressed but these were not significant when adjusted for multiple comparisons. We have shown that DEGs can identify different stages of disease or treatment. Further analysis is ongoing to include other treatment timepoints (four months and six months) and importantly to include participants with known relapse.

Is humoral and cellular response to SARS-CoV-2 vaccine modified by DMT in patients with multiple sclerosis and other autoimmune diseases?

Background: The effect of disease-modifying therapies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response is unclear. Objectives: We aim to determine the immunological responses to SARS-CoV-2 in multiple sclerosis (MS) and anti-CD20-treated patients with other autoimmune diseases (AID). Methods: Humoral and cellular responses we determined before and 30-90 days after vaccination in patients with MS and anti-CD20-treated patients with other AID in two Catalan centers. Results: 457 patients were enrolled. Findings showed that humoral response decreased under anti-CD20s or sphingosine 1-phosphate receptor modulators (S1PRM) and with longer treatment duration and increased after 4.5 months from the last anti-CD20 infusion. Cellular response decreased in S1PRM-treated. Patients on anti-CD20 can present cellular responses even in the absence of antibodies. Conclusion: Anti-CD20s and S1PRM modify the immunological responses to SARS-CoV-2 vaccines.

Association Between Pharmacological Treatment of Attention-Deficit/Hyperactivity Disorder and Long-term Unemployment Among Working-Age Individuals in Sweden

Adults with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for unemployment. Pharmacological treatment is effective in reducing the core symptoms of ADHD, but whether it helps to reduce the unemployment rate among adult patients remains unclear. To investigate the association between use of ADHD medication and long-term unemployment in working-age adults with ADHD. Data for this population-based cohort study were extracted from Swedish national registers. Among 25 358 individuals with ADHD born from 1958 to 1978, 12 875 middle-aged adults among the workforce were included. The longitudinal cohort was followed up from January 1, 2008, to December 31, 2013. Data were analyzed from March 1, 2020, through May 31, 2021. Use of medication for ADHD during the previous 2 years was the main exposure, as both categorical and continuous variables. Yearly accumulated unemployed days were derived from the Public Employment Service, and long-term unemployment was defined as 90 or more days of unemployment per year. Overall and sex-specific relative risks (RRs) with 95% CIs were estimated using generalized estimating equations. Among 12 875 individuals with ADHD (5343 women [41.50%] and 7532 men [58.50%]; mean [SD] age, 37.9 [5.6] years), the use of ADHD medications during the previous 2 years was associated with a 10% lower risk of long-term unemployment in the following year (adjusted RR, 0.90 [95% CI, 0.87-0.95]). An association between use of ADHD medications and long-term unemployment was found among women (RR, 0.82 [95% CI, 0.76-0.89]) but not men (RR, 0.96 [95% CI, 0.91-1.01]). Longer treatment duration was associated with a lower risk of subsequent long-term unemployment among women (RR for use of 1-6 months, 0.86 [95% CI, 0.78-0.95]; RR for use of 18-24 months, 0.72 [95% CI, 0.58-0.90]; P < .001 for trend). Within-individual comparisons showed that the long-term unemployment rate was lower during periods of ADHD medication treatment compared with nontreatment periods (RR, 0.89; 95% CI, 0.85-0.94). The findings of this cohort study suggest that the use of ADHD medication is associated with a lower risk of subsequent long-term unemployment for middle-aged women. These findings should be considered together with the existing knowledge of risks and benefits of ADHD medication when developing treatment plans for working-age adults.