5-day Course Research Articles

Treatment Patterns and Economic Burden of Ulcerative Colitis in Japan: A Retrospective Claims Analysis.

This retrospective claims analysis characterized contemporary ulcerative colitis (UC) treatment patterns and investigated the economic burden of UC in Japan. This study used anonymized claims data in the Medical Data Vision database. Patients were included if they had a confirmed UC diagnosis and ≥ 1 claim of systemic treatment for UC (index date) between June 2018 and December 2022, in addition to continuous enrollment for ≥ 6months before and ≥ 12months after the index date. Patients were excluded if they were aged < 18years at index or if they had claimed systemic UC treatmentduring the pre-index period, had a confirmed diagnosis of Crohn's or Behçet's disease, or had a record of colectomy during the pre-index period. Outcomes of interest were treatment patterns, healthcare resource utilization (HCRU), and UC-related costs per person per month (PPPM). Further exploratory analyses were conducted to understand whether real-world treatment patterns with conventional therapy were optimally aligned with guideline recommendations. Two definitions of suboptimal treatment with conventional therapies were identified: prolonged treatment with corticosteroids (i.e., consecutive use for > 90days) and corticosteroid cycling (i.e., three or more ≥ 30-day corticosteroid courses over 1year, with a ≥ 60-day gap between courses). Overall, 15,429 patients were included. The most frequently observed class of first-line treatment was 5-aminosalicylic acid monotherapy (75.0%); treatment modification was observed in 39.7% of patients. Within 1year of follow-up, patients had a mean (SD) of 9.8 (6.8) outpatient visits, and a hospital stay was reported in 23.9% of patients. Mean total cost PPPM was ¥76,374. Of patients with ≥ 1 course of corticosteroids, 39.8% received suboptimal treatment with conventional therapies. HCRU and total costs were higher for patients with versus without suboptimal treatment with conventional therapies. Japanese patients with UC would benefit from treatment options that can reduce costs, HCRU, and suboptimal treatment with conventional therapies.

Sofosbuvir as post-exposure prophylaxis for yellow fever-associated viscerotropic disease (YEL-AVD).

Yellow fever-associated viscerotropic disease (YEL-AVD) is a rare but serious complication arising from administration of live-attenuated yellow fever vaccine to individuals with risk factors such as thymectomy. At present there is no evidence-based treatment, and case fatality rates are high. Sofosbuvir, an NS5B nucleotide inhibitor, has activity against yellow fever virus in vitro and in vivo. Here we describe clinical and virological response to use of off-licence sofosbuvir as post-exposure prophylaxis for a patient inadvertently given yellow fever vaccine despite previous thymectomy. A 14-day course of oral sofosbuvir was administered in an outpatient setting with regular clinical and biochemical monitoring. The patient remained well without developing clinical features of YEL-AVD and did not experience adverse effects from the treatment. This supports the use of sofosbuvir as post-exposure prophylaxis in patients at high risk of developing YEL-AVD. Ongoing trials of efficacy of sofosbuvir in yellow fever infection may result in stronger support for this approach in the future.

Phase I trial comparing bile acid and short-chain fatty acid alterations in stool collected from human subjects treated with omadacycline or vancomycin.

The purpose of this study was to assess bile acid and SCFA changes in stool samples obtained from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers given a 10-day oral course of omadacycline or vancomycin. Vancomycin caused a larger change in the primary bile acids and SCFA concentrations compared with omadacycline. The metabolic findings help further our understanding of the mechanistic basis for the lower-risk properties of omadacycline causing CDI and warrant phase 2 investigations using omadacycline as a CDI antibiotic. This study is registered with ClinicalTrials.gov as NCT06030219.

Acute labyrinthitis complicating a seromucous otitis: discussion based on two observations

Labyrinthitis is an inflammation of the membranous labyrinth of the inner ear caused by viruses, bacteria, or systemic diseases that presents as vertigo, nausea, vomiting, tinnitus, and/or hearing loss. Treatment depends on the cause. We present two cases of labyrinthitis presenting with vertigo, otalgia, and tinnitus. They were successfully treated with a 10-day course of amoxicillin-clavulanate and corticosteroids. Taking antibiotics and corticosteroids early gives a maximum chance of recovery from the labyrinth. Keywords : emergency, labyrinthitis, corticosteroids, amoxicillin-clavulanate.

Effect and Mechanism of an ACT-Based Psychological Resilience Intervention Targeting Students Failing in Postgraduate Entrance Examinations in China: A Randomized Controlled Trial.

The postgraduate entrance examination frenzy is a widespread and intense phenomenon in China. As the number of students who failed the examination surged, the ensuing mental health problems became prominent. This study aimed to evaluate the effectiveness of an online ACT-based group resilience course, which incorporated the six core components of ACT and integrated elements of Chinese culture, in alleviating psychological distress among students who failed the examination. It also explored the mechanism by which the intervention affected changes in psychological distress. A total of 61 participants were randomly assigned to the intervention group (n = 31) and the control group (n = 30). They attended an 8-day group course, with 2-h sessions each day. The study outcomes were psychological distress, resilience, psychological flexibility (PF), and psychological inflexibility (PI). These outcomes were measured at baseline, post-intervention, and 1-month follow-up. Linear mixed models (LMMs) showed significant group × time interactions for all outcome variables, except for stress, which showed a marginally significant interaction. Post hoc analyses revealed significant improvements in depression, resilience, and PF at both post-intervention and at the 1-month follow-up. Additionally, significant reductions in anxiety and a marginally significant reduction in stress were observed at the 1-month follow-up. However, no significant reduction was found in PI. The multiple mediation model showed that the intervention improved psychological distress by increasing resilience and PF. These findings suggest that online resilience group intervention is generally effective in enhancing resilience and alleviating psychological distress and is acceptable to students who have failed the postgraduate entrance examination, as evidenced by high participant engagement and satisfaction.

Impact of extended-course oral nirmatrelvir/ritonavir in established Long COVID: a case series

BackgroundPrior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir.MethodsWe documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5–30 days) of oral nirmatrelvir/ritonavir outside (n = 11) of and within (n = 2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir.ResultsAmong those who take an extended course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experience a meaningful reduction in symptoms, although not all benefits persist. Others experience no effect on symptoms. One participant stopped early due to intense stomach pain. For the two participants who took an extended course of nirmatrelvir/ritonavir within the context of an acute reinfection, both report eventually returning to their pre-re-infection baseline.ConclusionsExtended courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study how and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID.

MULTIPLE ORGAN FAILURE FOLLOWING SEVERE BATTLE INJURIES DURING RECENT CONFLICTS: A FRENCH RETROSPECTIVE COHORT STUDY.

Introduction : Improvements in combat casualty care have increased survival rates, but these patients are at particular risk of developing multiple organ failure (MOF). We investigated the incidence and severity of MOF in a cohort of severe combat casualties. Materials and Methods : This retrospective study included all on-duty French land army war casualties with a severe combat injury requiring intensive care unit admission during 2009-2023. Demographic data, advanced life support interventions, and outcomes were collected. Each organ failure was then analyzed during a 7-day trauma course according to the Sequential Organ Failure Assessment score. Results: Of the 100 patients who met the inclusion criteria, those with persistent MOF at day 4 (MOF group) represented 22% of the total population (median Sequential Organ Failure Assessment score 6.0 [5.3-8.0]). Compared to those without persistent MOF, these patients were more severely injured (median Military Injury Severity Score 38.0 [interquartile range 33.0-56.8] vs. 26.5 [20.0-34.0], P < 0.001) by an explosive mechanism (68.2%) and sustained more traumatic brain injury (40.9% vs. 14.1%, P = 0.013). The MOF group also received significantly more blood units (median 14.0 [8.3-24.8] vs. 6.0 [0.0-12.0], P < 0.001) and massive transfusions (68.2% vs. 32.1%, P = 0.002). Pulmonary and cardiovascular dysfunction were the most frequently observed trauma outcomes. A multivariable logistic regression model showed that MOF persistence at day 4 was significantly associated (odds ratios [95% confidence intervals]) with severe injuries (1.5 [1-2.3], P = 0.042). Conclusion : A high number of severe lesions significantly and independently increased risk of MOF persistence at day 4 after combat-related trauma. These findings are particularly relevant to current and anticipated large-scale combat operations that will challenge battlefield casualty care and evacuation.

Basic Bronchoscopy Competence Achieved by a Nationwide One-day Simulation-based Training.

In 2020, a mandatory, nationwide 1-day bronchoscopy simulation-based training (SBT) course was implemented for novice pulmonology residents in the Netherlands. This pretest-posttest study was the first to evaluate the effectiveness of such a nationwide course in improving residents' simulated basic bronchoscopy skills. After passing a theoretical test, residents followed a 1-day SBT course, available in 7 centers, where they practiced their bronchoscopy skills step-by-step on a virtual reality simulator under pulmonologist supervision. Residents practiced scope handling efficiency (task 1) and navigational skills combined with lung anatomy knowledge (task 2). Task 1 outcome measures were navigational skill simulator metrics: percentage of time at mid-lumen, percentage of time with scope-wall contact, procedure time (PT), number of wall contacts and number of wall contacts per minute of PT. Task 2 outcome measures were PT, observational assessment scores of a validated tool with a 5-point scale (1 representing the worst and 5 the best competence) and blinded dexterity assessments. The study included 100 residents. All outcome measures of task 1 improved significantly (P<0.001), except for the number of wall contacts per minute of PT (4.3 [IQR 3.0 to 6.2] pre vs. 3.5 [IQR 2.6 to 5.3] post, P=0.07). For task 2, PT was reduced by 54% (10.3±2.7minutes pre vs. 4.7±0.9minutes post, P<0.001) with an improvement in overall-competence scores (2.0 [IQR 1.0 to 2.0] pre vs. 4.0 [IQR 4.0 to 5.0] post, P<0.001) and all dexterity parameters (P<0.001). Nationwide implementation of a SBT course led to rapid improvement of residents' basic bronchoscopy skills while halving PT.

Duration of the effect of breathing and speech training under excess oxygen pressure

This article presents the assessment of the duration of the effect of a 5-day course of breathing and speech training under excess oxygen pressure in 12 Vietnamese volunteer subjects. The follow-up assessment was conducted six months after the training, with rapid aircraft cabin depressurization being simulated with excess oxygen pressure (500 mm H2O) supplied through an oxygen mask. The training and the present study were carried out using the “BARS-GD” hardware/software system developed by the Russian company Konstel. All Vietnamese volunteer subjects were found to retain high tolerance to excess oxygen pressure, maintained speech formation abilities and work capacity. A statistically significant increase in systolic and diastolic blood pressure (by 25% and 34.2%, respectively), heart rate and respiratory rate (14.4% and 41.7%, respectively) was recorded. Analysis of psychophysiological performance at the peak of excess oxygen pressure revealed a 45.2% (p 0.01) increase in simple sensorimotor reaction time, which is 27% (p 0.01) higher than immediately after the training. No significant changes were observed in the psychological component. Therefore, the functional state of the Vietnamese volunteer subjects under simulated rapid cabin depressurization and breathing under excess oxygen pressure was considered normal, with higher involvement of the body’s adaptive mechanisms than immediately after the training. The 5-day course of training in breathing and speech under excess oxygen pressure effectively developed sustainable psychological readiness in the volunteer subjects, breathing and speech skills, and professional reliability under extreme conditions of stratospheric cabin depressurization. Overall, this training course is considered promising for inclusion in the program of psychophysiological preparation of Vietnamese pilots for stratospheric flights.

Obinutuzumab in Combination with Alternative Chlorambucil Schedules in Front-Line Treatment of Chronic Lymphocytic Leukemia: A Study by KroHem, the Croatian Cooperative Group for Hematologic Diseases.

Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks.

Assessing the impact of critical care training on pharmacy students in Egypt: a pre-post study

BackgroundTransition to independent pharmacy practice is challenging. Undergraduate and postgraduate pharmacy students in low-to-middle-income countries (LMICs) currently receive minimal experiential learning in critical care.ObjectiveTo assess the critical care training course’s impact on pharmacy students’ knowledge, self-efficacy, and self-esteem, as well as their satisfaction with the course.MethodIn a pre-post interventional study, pharmacy students took a 10-day critical care training course with experiential learning. They completed a knowledge questionnaire covering various critical care topics, the 18 questions Pharmacy Self-efficacy and Self-esteem Study Questionnaire, and a satisfaction questionnaire. Data was analyzed using IBM SPSS version 20.0.ResultsA total of 72 trainees participated in the study. The average score for pre-course self-efficacy and self-esteem significantly increased post-course, with a median (IQR) of 3.75 (3.50–3.94) compared to 3.56 (3.28–3.78) pre-course, with a p-value of less than 0.05. Furthermore, their overall knowledge score significantly increased from baseline to post-course, with the median (IQR) rising from 0.53 (0.50–0.61) to 0.98 (0.97–1.0), with a p-value of less than 0.05. Their course satisfaction average total score was 45.08 (SD ± 5.41) (on a scale of 10–50).ConclusionThe present study provides clear evidence that integrating this critical care training course into a structured curriculum for pharmacy students using experiential learning can act as a facilitator of knowledge enrichment, increase their self-esteem and self-efficacy, and make them satisfied with learning. Larger long duration studies are needed to support this evidence.

Efficacy and safety of praziquantel plus artemisinin-based combinations versus praziquantel in the treatment of Kenyan children with Schistosoma mansoni infection: open-label, randomized, head-to-head, non-inferiority trial.

Praziquantel alone is insufficient for the control of schistosomiasis due to poor efficacy against juvenile worms and increasing concerns about the risk of drug resistance. We compared the efficacy and safety of praziquantel combined with four different artemisinin-based combinations to praziquantel alone in treating Schistosoma mansoni infection in Kenyan children. In this randomized, open-label, five-arm, head-to-head, non-inferiority trial, children (aged 9-15 years) with S. mansoni infection according to duplicate Kato Katz thick smears from a stool sample in the Mwea irrigation scheme of central Kenya, were enrolled. Participants were randomly assigned (1:1:1:1:1) via a computer-generated block randomization procedure to receive a single oral dose of praziquantel (PZQ) (40 mg/kg/day) alone or in combination with a 3-day course (4 mg/kg of artesunate) of artesunate plus sulfalene-pyrimethamine (As + SP), artesunate plus amodiaquine (As + AQ), artesunate plus mefloquine (As + MQ) or dihydroartemisinin-piperaquine (DHAP). Laboratory technicians were masked to treatment allocation, but participants, clinicians, and study nurses were not. The primary outcomes were the cure rate and frequency of adverse events, which were assessed 6 weeks after treatment in the available case population using a per-protocol analysis. The non-inferiority margin was set at -10% for the risk difference in cure rates between combination therapy and PZQ alone. Between 12 September 2018 and 11 January 2019, 540 participants were assigned to receive PZQ alone (n = 108), PZQ plus As + SP (n = 108), PZQ plus As + AQ (n = 108), PZQ plus As + MQ (n = 108), or PZQ plus DHAP (n = 108). Primary outcome data were available for 523 (96.9%) participants. The cure rate was 82.5% (85/103) in PZQ alone, 81.7% (85/104) in PZQ plus As + SP, 76.2% (80/105) in PZQ plus As + AQ, 88.7% (94/106) in PZQ plus As + MQ, and 85.7% (90/105) in PZQ plus DHAP arm. Non-inferiority was declared for PZQ plus As + MQ (difference 6.2 [95% confidence interval: -3.3 to 15.6]) and PZQ plus DHAP (3.2 [-6.7 to 13.1]) but not for PZQ plus As + SP (-0.8 [-11.2 to 9.6]) or PZQ plus As + AQ (-6.3 [-17.3 to 4.6]). Adverse events were reported by 26% (138/540) of participants, including abdominal pain, headache, and vomiting. There were no serious adverse events. Alternatives to praziquantel should include praziquantel plus artesunate-mefloquine or praziquantel plus dihydroartemisinin-piperaquine. However, further multicentre trials are needed in different epidemiological settings and population groups to confirm these findings.CLINICAL TRIALSThis study is registered with the Pan-African Clinical Trials Registry under PACTR202001919442161.

New immunomodulatory treatment protocol for canine leishmaniosis reduces parasitemia and proteinuria.

The current standard treatment for canine leishmaniosis (CanL), N-methylglucamine antimoniate (MGA) given with allopurinol, is not fully effective and may cause adverse effects and drug resistance. In vitro and in vivo studies have shown that nucleotides, administered alone or with AHCC, offer benefits in the treatment of CanL. This study examines the effects of a new immunomodulatory treatment protocol in which dietary nucleotides and AHCC are added to the recommended standard treatment. Out of 160 sick dogs with naturally occurring clinical leishmaniosis recruited, 97 were randomized to a supplement (n = 47) or control (n = 50) group. All dogs received an initial 28-day course of MGA and 365-day course of allopurinol. From day 0 to day 730, dogs in the control group additionally received a placebo, while dogs in the supplement group received Impromune (Bioiberica S.A.U., Esplugues de Llobregat, Spain), an oral supplement providing 32 mg/kg nucleotides and 17 mg/kg AHCC daily. After 2 years, five dogs had relapsed in the supplement group (18.5%) while seven did so in the control group (22.6%). Over time, animals in both groups showed significant improvements in body weight, LeishVet clinical stage, clinical score, and anti-Leishmania antibodies. Adding the supplement to the standard protocol resulted in further significant improvements, namely in reducing the parasite load and urinary protein/creatinine ratio, improving IRIS stage, lowering serum creatinine levels on day 30, deceasing urine turbidity on day 365, and improving weight gain on day 545. The daily intake of the supplement over two years proved safe and well tolerated. Our study confirms the efficacy of the recommended standard treatment for CanL, but also reveals that by adding Impromune additional benefits are obtained, especially reduced parasitemia and improved renal function.

A pre and post evaluation of the communication and interaction training programme for professionals in dementia care.

NICE guidelines advocate that healthcare professionals should aim to use non-pharmacological and person-centred approaches as primary strategies to reduce or prevent distress in people living with dementia who reside within care settings. However, despite these recommendations, recent studies have illustrated that there is still a requirement for healthcare professionals to have adequate opportunities to access training programmes and guidance on how to effectively use non-pharmacological approaches in dementia care settings. Communication and Interaction Training (CAIT) was developed to train healthcare professionals in dementia care on how to apply person-centred principles to effectively reduce or negate distress in people living with dementia in a non-invasive manner. This paper provides an overview of current debates regarding the use of non-pharmacological approaches in dementia care, as initial care strategies, to reduce the primary use of pharmacological interventions that may have deleterious side effects for people living with dementia. Furthermore, this paper provides a summary of an evaluation that assessed the extent to which a 2-day CAIT programme could enhance healthcare professionals in their perceived ability to communicate therapeutically with and provide care for people living with dementia. In this evaluation, 35 healthcare professionals in dementia care engaged with the 2-day CAIT programme. The Confidence in Dementia Scale, Knowledge in Dementia Scale and Compassionate Competence Scale were administered for participants to complete pre and post training. A series of parametric paired samples t-tests were completed, and the results indicated that the 2-day CAIT course was effective in enhancing healthcare professionals' perceived confidence, communication skills, sensitivity, and ability to meet the care needs of people living with dementia. However, staff' knowledge of dementia did not significantly increase following the CAIT course, which could be due to participants already having high levels of knowledge on dementia prior to training. These results indicated that engaging in CAIT could be beneficial in enhancing healthcare professionals' perceived ability to use therapeutic communication strategies in their interactions with people living with dementia. Discussion is provided on how the delivery of training programmes, such as CAIT, may assist in re-enforcing guidelines that advocate for the use of non-pharmacological and non-invasive approaches in dementia care.

P66 Perforating dermatosis in a young female patient receiving adalimumab biosimilar CTP-17 for chronic plaque psoriasis

Abstract Opportunistic infections, reactivation of latent tuberculosis, demyelinating diseases were found to be the most severe adverse events associated with adalimumab. Among TNF-a inhibitors-related cutaneous adverse reactions, paradoxical reactions are the most common, whereas sweet-like neutrophilic dermatosis or perforating dermatosis have been rarely reported. A 34-year-old Caucasian woman was referred to the outpatient clinic of the University Hospital of Verona for acute onset of diffuse erythematous plaques with concentric hyperkeratosis and ulceration localized on the right thigh, right glutaeal area and elbows bilaterally, associated with pain and difficulties in walking. The acute skin reaction occurred 3 days after the switching to adalimumab biosimilar CTP17. In particular, the patient affected by chronic plaque psoriasis and psoriatic arthritis had been successfully treated with adalimumab biosimilar GP2017 for 2 years, which was later switched to CTP17 for non-medical reasons. The patient did not report any comorbidities or known allergies and was not taking other medications apart from the adalimumab biosimilar. No other symptoms were reported. The skin lesions were biopsied, and the histological examination revealed areas of epidermal ulceration, overlaid by dendritic-granulocytic crust associated with transepidermal elimination of elastic fibres (elastin). Dermal infiltrate with a rich plasma cellular component was also present. The histological diagnosis was consistent with acquired perforating dermatosis. Fungal, bacterial and mycobacterial cultures were negative. Consequently, adalimumab biosimilar CTP17 was suspended and a 30-day course of systemic therapy with corticosteroids was prescribed. After ∼60 days the cutaneous lesions progressively improved, and the ulcers have been re-epithelized, with a residual post-inflammatory erythema. Perforating dermatosis is usually associated with conditions such as trauma, diabetes, chronic renal failure and lymphoma, but is occasionally also triggered by drugs including biologics such as adalimumab, infliximab, etanercept and risankizumab.

A 5-day course of repetitive transcranial magnetic stimulation before pain onset ameliorates future pain and increases sensorimotor peak alpha frequency.

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine whether (1) 5 consecutive days of rTMS delivered prior to experimentally induced prolonged jaw pain has a prophylactic effect on future pain intensity and (2) whether these effects were accompanied by increases in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from day 0 to 4, 40 healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. Peak alpha frequency and CME were assessed on day 0 (before rTMS) and day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor in the right masseter muscle after the final rTMS session. From days 5 to 25, participants completed twice-daily electronic diaries including pain on chewing and yawning (primary outcomes), as well as pain during other activities (eg, talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Furthermore, active rTMS led to an increase in PAF. This is the first study to show that rTMS delivered prior to prolonged pain onset can protect against future pain. Our findings suggest that rTMS may hold promise as a prophylactic intervention for pain.

Survival Benefit From Corticosteroids in Severe Alcohol-associated Hepatitis Attributed to Clinical and Treatment Differences in a Large Multicenter Cohort.

Corticosteroids are recommended by multiple society guidelines for the treatment of severe alcohol-associated hepatitis (AH). However, their use remains controversial due to inconsistent studies regarding their survival benefit. This was a retrospective cohort study of first-time hospitalizations for severe AH (Maddrey discriminant function ≥ 32) admitted to the Veterans Health Administration between January 3, 2005, and December 5, 2020, (i) evaluating the effect of corticosteroid therapy on all-cause survival, (ii) characterizing the clinical and psychosocial factors associated with corticosteroid use, and (iii) determining the effect of duration of corticosteroid therapy on all-cause survival among treatment-responsive patients (Lille score < 0.45). During the study period, 2,618 patients were admitted with severe AH, of whom 1,083 (41.37%) received corticosteroids. Although corticosteroids were significantly associated with improved all-cause survival in the unadjusted model ( P = 0.022), no survival benefit was observed in the adjusted model after accounting for baseline and admission characteristics (adjusted hazard ratio [aHR] = 1.01, P = 0.818). Psychiatry consultation was the only factor evaluated that was protective against mortality (aHR = 0.67, P < 0.001). Among the 428 patients (49.7%) responsive to corticosteroids, duration of therapy was not associated with overall survival on unadjusted ( P = 0.696) or adjusted models (aHR = 1.12, P = 0.710 for a ≥28-day course compared with a ≤7-day reference). Despite being recommended by clinical guidelines for severe AH, corticosteroids have low utilization with no survival benefit after accounting for differences in patient characteristics and practice patterns. Among patients with treatment response per the Lille score, no difference was observed in overall survival between shorter and longer durations of corticosteroid therapy.

Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trial

Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS. CWS-2007-HR was a multicentre, open-label, randomised controlled, phase 3 trial done at 87 centers in 5countries. Eligible patients were those aged 6 months to 21 years with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring in unfavourable sites with unfavourable age (≥10 years) and/or tumour size (>5cm); all non-metastatic alveolar rhabdomyosarcoma and those with any non-metastatic rhabdomyosarcoma with nodal involvement. A further group was also eligible: patients with non-metastatic undifferentiated sarcoma, extraskeletal Ewing sarcoma and primary unresected synovial sarcoma. Patients in complete remission at the end of standard therapy (nine cycles of ifosfamide, vincristine with doxorubicine or dactinomycin, and surgery or radiotherapy, or both) were randomised to either stop treatment (S-arm) or to receive oral maintenance therapy (M-arm) with eight 10-day courses (25 weeks) of trofosfamide (2×75mg/m2/day) and idarubicin (1×5mg/m2/day 1,4,7,10) alternating with trofosfamide and etoposide (2×25mg/m2/day). The primary outcome was event-free survival (EFS) and the secondary outcome was overall survival (OS) in the intent-to treat population. This trial is registered at ClinicalTrials.gov, NCT00876031, and, EudraCT 2007-0001478-10. Between July 1st, 2009 and June 30th, 2019, 195 patients were randomly assigned to the M-arm (n=96) or S-arm (n=99). In the intent-to-treat population, with a median follow-up of 5.2 years (IQR 3.9-6.1) for surviving patients, the 3-year EFS in the M-arm was 66.9% (95% CI 58.1-77.2) versus 75.6% (67.6-84.6) in the S-arm (hazard ratio, (HR) 1.62, 95% CI 0.98-2.69, p=0.06). 3-year OS was 82.8% (95% CI 75.4-90.8) in the M-arm versus 84.7% (95% CI 77.8-92.1) in the S-arm (HR 1.55, 95% CI 0.84-2.89, p=0.17). Grade 3-4 adverse events were haematological in 66% of patients, febrile infections in 6%, gastrointestinal in 10%, and sensory neuropathy in 1%. The addition of 25 weeks of oral maintenance therapy with trofosfamide, etoposide and idarubicin after standard therapy does not improve EFS and OS in patients with high-risk rhabdomyosarcoma and other STS. Deutsche Kinderkrebsstiftung Grant No.DKS 2009.09, DKS 2012.06, DKS 2015.13, DKS 2018.10 and DKS 2021.04.

Comparative Analysis of Calcium Dynamics in Regular-Set Versus Fast-Set Bioceramics: Impact on Cytotoxicity and Apatite Formation.

The objective of this study is to assess the calcium ion (Ca2+) release, pH shift, bioactivity, and cytotoxicity of both forms of EndoSequence Root Repair Material: regular set (ES) and fast set (ESF). ES (n=10) and ESF (n=10) forms were tested for their bioactivity. Elemental analysis was done on the fresh material and material immersed in phosphate buffered saline (PBS) for 30 days. The surface crystal formation was studied. Cytotoxicity was evaluated at different material concentrations using a human hepatocellular cancer cell line (Huh-7). Both materials contain Ca, P, Ta, Zr, and Si as major elements. Both ES and ESF have a limited percentage of Ytterbium and Neodymium. In the fresh material, the ES had a higher Ca2+ concentration with a homogenous surface distribution than ESF. However, ESF released significantly more Ca2+ (p<0.05) and had a higher pH over the 7-day course. When the material was immersed in PBS, the ESF exhibited a significantly higher Ca/P ratio of 2.95, while ES had 2.16 Ca/P ratio (p<0.05). The ESF had a greater capacity to precipitate and grow hydroxyapatite (HA) than ES, resulting in more mature crystals forming on the surface. Both SE and ESF demonstrated low cytotoxicity against Huh-7 cells. When ES and ESF were submerged in simulated bodily fluid, both forms produced apatite crystals at the dentin material interface, releasing high Ca2+ and displaying a prolonged high pH with high bioactivity potential. Both forms had comparable low cytotoxicity. A higher Ca2+ release in ESF indicates dynamic bioactivity, which should be aligned with the clinical requirements.

A dual phase biologic augmentation of rotator cuff healing in a preclinical rat model using IL-17F and low-dose lithium

BackgroundRotator cuff tendon tears are a common cause of shoulder dysfunction in adults. Yet, impaired healing continues to result in higher failures rates after surgical repair resulting in patient dysfunction and prolonged recovery. This has spurred increased investigation of biologic augmentation to improve tendon healing. This study examines the outcome of peritendinous IL-17F administration and oral low-dose lithium carbonate on rotator cuff healing following acute surgical repair in a rat model. MethodsTreatment group included an open supraspinatus peel and repair followed by a local injection of IL-17F at the bone-tendon interface and a 7-day course of oral lithium carbonate. Control rats received no additional intervention prior to surgical closure. Evaluation of healing was then preformed using MRI imaging, biomechanical testing, and histological analysis at the bone-tendon interface. ResultsEighteen rats (9 control, 9 experimental) underwent complete testing. Combined treatment of peri-tendinous IL-17F and oral low-dose lithium carbonate after rotator cuff repair improved rotator cuff healing in all outcomes when compared to controls. MRI imaging in the treatment group showed complete healing of all supraspinatus tendons across the anatomic footprint after repair. We also found significant increases in biomechanical stiffness compared to controls (p <0.01). At the histological level, treatment groups also had decreased osteoclasts (p<0.001), and increased histologic organization of fibroblasts compared to controls. These findings are consistent with an increase in biomechanical stiffness. ConclusionWe demonstrated that the combined treatment of IL-17F and oral low-dose lithium improved rotator cuff tendon healing quality following acute surgical repair in a rat model.