Efficacy Of Treatment Approaches Research Articles

Unveiling the Complexities: Exploring Mechanisms of Anthracycline-Induced Cardiotoxicity.

The coexistence of cancer and heart disease, both prominent causes of illness and death, is further exacerbated by the detrimental impact of chemotherapy. Anthracycline-induced cardiotoxicity is an unfortunate side effect of highly effective therapy in treating different types of cancer; it presents a significant challenge for both clinicians and patients due to the considerable risk of cardiotoxicity. Despite significant progress in understanding these mechanisms, challenges persist in identifying effective preventive and therapeutic strategies, rendering it a subject of continued research even after three decades of intensive global investigation. The molecular targets and signaling pathways explored provide insights for developing targeted therapies, emphasizing the need for continued research to bridge the gap between preclinical understanding and clinical applications. This review provides a comprehensive exploration of the intricate mechanisms underlying anthracycline-induced cardiotoxicity, elucidating the interplay of various signaling pathways leading to adverse cellular events, including cardiotoxicity and death. It highlights the extensive involvement of pathways associated with oxidative stress, inflammation, apoptosis, and cellular stress responses, offering insights into potential and unexplored targets for therapeutic intervention in mitigating anthracycline-induced cardiac complications. A comprehensive understanding of the interplay between anthracyclines and these complexes signaling pathways is crucial for developing strategies to prevent or mitigate the associated cardiotoxicity. Further research is needed to outline the specific contributions of these pathways and identify potential therapeutic targets to improve the safety and efficacy of anthracycline-based cancer treatment. Ultimately, advancements in understanding anthracycline-induced cardiotoxicity mechanisms will facilitate the development of more efficacious preventive and treatment approaches, thereby improving outcomes for cancer patients undergoing anthracycline-based chemotherapy.

A Multi-center Exploration of Efficacious Treatment Approaches in LGI1-Ab Encephalitis

A Multi-center Exploration of Efficacious Treatment Approaches in LGI1-Ab Encephalitis

Genetic association of SLC6A3 (dopamine transporter) gene polymorphisms with personality disorders and substance abuse disorders: a systematic review and meta-analysis.

Personality disorders (PD) are characterized by socially dysfunctional behavioral patterns that affect patients and show higher incidence rates within families. Substance abuse disorders (SAD) are exemplified by extensive and prolonged use of substances, including alcohol, nicotine, or illegal drugs. Genetic predisposition for both PD and SAD has been reported to involve gene variants regulating dopaminergic pathways. Yet, discrepancy among reported results necessitates further elucidation of potential hereditary-related risk factors. Because both disorders impose a societal burden, knowledge on the impact of certain genetic backgrounds on these diseases could help develop evidence-based strategies for efficacious treatment approaches. In the present study a systematic review was performed, and the association between dopamine transporter gene polymorphism (SLC6A3), particularly rs28363170 entailing a 40-bp variable number tandem repeat, and PD as well as SAD was investigated recruiting meta-analysis approach. Initial literature search for PD yielded 1577, from which nine fulfilled eligibility criteria to be used in a meta-analysis including 729 cases and 2113 controls. From the 934 studies retrieved for SAD, only 29 articles with 5221 cases and 4822 controls were used for meta-analysis. A statistically significant association was seen between rs28363170 (for the 9-repeat allele) and PD in European populations according to the co-dominant mode of inheritance. For SAD no statistically significant correlation under any mode of inheritance was observed. There was no indication of time-trend phenomena. Our findings demonstrate the association of SLC6A3 gene polymorphism with PD, thus underling the need to understand neurobiological mechanisms inherent to the above disorders to guide treatment strategies under the perspective of personalized medicine.

Optimizing first-line TKI treatment efficacy in PD-L1-positive EGFR-mutated NSCLC: the impact of antiangiogenic agents.

In individuals receiving treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), those exhibiting positive PD-L1 expression might experience reduced progression-free survival (PFS). However, the effects on overall survival (OS) and the determination of efficacious treatment approaches are still not well-defined. In our retrospective study, we examined data from 193 NSCLC patients with advanced EGFR mutations who received first-line TKI treatments, treated at two centers of Shaw Hospital in Zhejiang, China. This analysis covered a period from 1 January 2016 to 30 April 2023. Patients with PD-L1 positivity exhibited a markedly shorter average PFS (9.5months versus 17.8months, P < 0.001) and OS (44.4months versus 65.7months, P = 0.016) relative to those without PD-L1 expression. This difference in both PFS and OS remained statistically significant even after adjusting for multiple factors (P < 0.001 for PFS and P = 0.028 for OS). In the PD-L1-positive cohort, introducing combination antiangiogenic significantly extended both PFS (from 9.1 to 25.7months, P = 0.026) and OS (from 42 to 53.5months, P = 0.03). Post-first-line TKI therapy, 39.3% of PD-L1-positive patients and 54.5% of PD-L1-negative patients developed the T790M mutation (P = 0.212), with no notable difference in PFS from second-line TKI treatments between the groups. Additionally, subsequent combination therapy with immunotherapy markedly prolonged OS in the PD-L1-positive group. However, for PD-L1-negative patients, neither combination antiangiogenic therapy nor later-line immunotherapy demonstrated significant benefits in PFS or OS. For PD-L1-positive patients, combined antiangiogenic treatments and immunotherapy can significantly improve survival outcomes. In contrast, PD-L1-negative patients show less benefit from these therapies, highlighting the greater efficacy of these treatments in PD-L1-positive individuals.

Utilizing Esophageal Motility Tests in Diagnosing and Evaluating Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD), a prevalent clinical condition, is often attributed to aberrant esophageal motility, leading to gastric content reflux and associated symptoms or complications. The rising incidence of GERD presents an escalating healthcare challenge. Endoscopic and esophageal reflux monitoring can provide a basis for the diagnosis of patients with gastroesophageal reflux disease, but when the diagnostic basis is at an inconclusive value, some additional supportive evidence will be needed. Advanced technology is the key to improving patient diagnosis, accurate assessment, and the development of effective treatment strategies. High-resolution esophageal manometry (HREM) and endoscopic functional lumen imaging probe (EndoFLIP) represent the forefront of esophageal motility assessment. HREM, an evolution of traditional esophageal manometry, is considered the benchmark for identifying esophageal motility disorders. Its widespread application in esophageal dynamics research highlights its diagnostic significance. Concurrently, EndoFLIP's emerging clinical relevance is evident in diagnosing and guiding the treatment of coexisting esophageal motility issues. This review integrates contemporary research to delineate the contributions of HREM, EndoFLIP, and novel technologies in GERD. It examines their efficacy in facilitating an accurate diagnosis, differentiating similar gastrointestinal disorders, quantifying the extent of reflux, assessing the severity of the disease, forecasting patient responsiveness to proton pump inhibitor therapy, and guiding decisions for surgical interventions. The overarching aim is to deepen the understanding of GERD's underlying mechanisms and advance the formulation of holistic, efficacious treatment approaches.

Research trends in lipid-lowering therapies for coronary heart disease combined with hyperlipidemia: a bibliometric study and visual analysis.

Cardiovascular disease (CVD) poses a significant global health and economic challenge, with atherosclerosis being a primary cause. Over the past 40years, substantial research has been conducted into the prevention and reversal of atherosclerosis, resulting in the development of lipid-lowering agents such as statins and fibrates. Despite the extensive literature and formulation of numerous therapeutic guidelines in this domain, a comprehensive bibliometric analysis of the current research landscape and trends has not been performed. This study aimed to elucidate the evolution and milestones of research into lipid-lowering treatments for coronary heart disease (CHD) in conjunction with hyperlipidemia through bibliometric analysis, offering insights into future directions for treatment strategies. This study examined publications from 1986 to 2023 retrieved from the Web of Science database (Core Collection). Utilizing tools such as VOSviewer, Pajek, and CiteSpace, we analyzed publication and citation numbers, H-indexes, contributions by countries and institutions, authorship, journal sources, and keyword usage to uncover research trajectories and areas of focus. Our analysis of 587 publications revealed a recent surge in research output, particularly post-2003. The American Journal of Cardiology published the highest number of studies, with 40 articles, whereas Circulation received the highest number of citations (6,266). Key contributors included the United States, Japan, and China, with the United States leading in citation numbers and the H-index. Harvard University and Leiden University emerged as pivotal institutions, and Professors J. Wouter Jukema and Robert P. Giugliano were identified as leading experts. Keyword analysis disclosed five thematic clusters, indicating a shift in research towards new drug combinations and strategies, signaling future research directions. The last 4decades have seen a notable rise in publications on lipid-lowering therapies for CHD and hyperlipidemia, with the United States retaining world-leading status. The increase in international collaboration aids the shift towards research into innovative lipid-lowering agents and therapeutic approaches. PCSK9 inhibitors and innovative combination therapies, including antisense oligonucleotides and angiopoietin-like protein 3 inhibitors, provide avenues for future research, intending to maximize the safety and efficacy of treatment approaches.

Technology-Assisted Parenting Intervention Plus Therapist Coaching: A Pilot Randomized Trial in a Community Practice Setting

ABSTRACT Disruptive behaviors are the most common clinical presentation in children and adolescents, particularly among disadvantaged youth referred to community mental health clinics (CMHCs). When left unaddressed, disruptive behaviors can increase the risk of adverse mental health outcomes. While parenting interventions are known to be efficacious and efficient treatment approaches, there are many barriers to involvement in such programs, particularly for disadvantaged populations. This pilot randomized controlled trial evaluated a technology-assisted parenting intervention (Parenting Wisely, PW) with therapist coaching compared to treatment as usual (TAU) at a CMHC. Participants included 53 caregiver-adolescent dyads and 13 clinicians recruited from a CMHC. Dyads randomized to PW + therapist coaching received a multi-component intervention that utilized a technology-assisted parenting program alongside therapist coaching sessions. Feasibility/acceptability assessments were conducted and preliminary findings on parenting outcomes and adolescent behavior outcomes were collected at 3- and 6-months post-baseline. Qualitative and quantitative results supported the feasibility and acceptability of the parenting PW + therapist coaching intervention as evidenced by caregiver engagement, therapist adherence, lack of treatment withdrawals, and satisfaction ratings. Exploratory analyses did not show differences between treatment conditions for parenting and adolescent behavioral outcomes. PW + therapist coaching may be better suited for early adolescents, who are at a critical period when disruptive behavior patterns are not yet ingrained, and parents have more authority and opportunity to address family interactions. Next steps for further evaluation include testing the effectiveness, predictors, moderators, and mechanisms of treatment outcomes of PW + therapist coaching as an adjunct to usual care.

Identifying patient preferences for diabetes care: A protocol for implementing a discrete choice experiment in Samoa.

In Samoa, adult Type 2 diabetes prevalence has increased within the past 30 years. Patient preferences for care are factors known to influence treatment adherence and are associated with reduced disease progression and severity. However, patient preferences for diabetes care, generally, are understudied, and other patient-centered factors such as willingness-to-pay (WTP) for diabetes treatment have never been explored in this setting. Discrete Choice Experiments (DCE) are useful tools to elicit preferences and WTP for healthcare. DCEs present patients with hypothetical scenarios composed of a series of multi-alternative choice profiles made up of attributes and levels. Patients choose a profile based on which attributes and levels may be preferable for them, thereby quantifying and identifying locally relevant patient-centered preferences. This paper presents the protocol for the design, piloting, and implementation of a DCE identifying patient preferences for diabetes care, in Samoa. Using an exploratory sequential mixed methods design, formative data from a literature review and semi-structured interviews with n = 20 Samoan adults living with Type 2 diabetes was used to design a Best-Best DCE instrument. Experimental design procedures were used to reduce the number of choice-sets and balance the instrument. Following pilot testing, the DCE is being administered to n = 450 Samoan adults living with diabetes, along with associated questionnaires, and anthropometrics. Subsequently, we will also be assessing longitudinally how preferences for care change over time. Data will be analyzed using progressive mixed Rank Order Logit models. The results will identify which diabetes care attributes are important to patients (p < 0.05), examine associations between participant characteristics and preference, illuminate the trade-offs participants are willing to make, and the probability of uptake, and WTP for specific attributes and levels. The results from this study will provide integral data useful for designing and adapting efficacious diabetes intervention and treatment approaches in this setting.

Molecular characterization of cancer-intrinsic immune evasion genes indicates prognosis and tumour microenvironment infiltration in osteosarcoma.

Cancer-intrinsic immune evasion (IE) to cells is a critical factor in tumour growth and progression, yet the molecular characterization of IE genes (IEGs) in osteosarcoma remains underexplored. In this study, 85 osteosarcoma patients were comprehensively analyzed based on 182 IEGs, leading to the identification of two IE clusters linked to distinct biological processes and clinical outcomes. In addition, two IE clusters demonstrated diverse immune cell infiltration patterns, with IEGcluster A displaying increased levels compared to IEGcluster B. Moreover, an IE score was identified as an independent prognostic factor and nomogram may serve as a practical tool for the individual prognostic evaluation of patients with osteosarcoma. Finally, GBP1, a potential biomarker with high expression in osteosarcoma was identified. The findings of this study highlight the presence of two IE clusters, each associated with differing patient outcomes and immune infiltration properties. The IE score may serve to assess individual patient IE characteristics, enhance comprehension of immune features, and guide more efficacious treatment approaches.

Abstract P2177: Autophagy-based Drugs Can Be Used To Treat Anthracycline-induced Cardiotoxicity

Background: Anthracyclines are highly effective chemotherapeutics, but their use is limited by Anthracycline-Induced Cardiotoxicity (AIC) with notable decline in ejection fraction (EF). Recovery of cardiac function is slow and often only partial, mandating novel and more efficacious treatment approaches to AIC. Hypothesis: Based on high throughput genetic screening in zebrafish we identified autophagy activation, e.g. via Atg7, a key protein in the induction of autophagy, as a potential novel translational therapeutic approach to AIC. Methods: In a mouse model of cardiotoxicity (4 x weekly 5 mg/kg intravenous doxorubicin treatment) two approaches were tested starting one week after the last treatment: 1) AdenoAssociated Viral vector 9-mediated overexpression of Atg7 in the myocardium (AAV9-ATG7, one time injection) and 2) 3 FDA approved autophagy activating (FAA) drugs (pravastatin (40 mg/kg), spironolactone (20 mg/kg) and empagliflozin (10 mg/kg), by daily gavage). Echocardiograms were performed at baseline, before start of therapy and after 28 days before sacrifice. Results: All three FAA drugs were able to rescue AIC and Atg7 overexpression by AAV9 alone sufficed to rescue from AIC (Figure 1). All three FAA drugs were able to either restore Atg7 levels to baseline (pravastatin and empagliflozin) or 2.5 times above baseline levels (spironolactone) versus more than 60fold above baseline by an AAV9-based approach. Conclusion: Atg7 overexpression and autophagy activation suffices to rescue from AIC and can be recapitulated to different levels by pravastatin, empaglifozin and spironolactone.

Network pharmacology-based approach for exploring the biotargets and mechanisms of vitamin A for the treatment of diabetic foot ulcers

Abstract Background In some developing countries, people have little knowledge about the causes of diabetic foot ulcers. Therefore, public health education for patients on these conditions is a prerequisite for effective pharmacological treatment. Diabetic foot ulcers are a complex symptom of diabetes and are hard to cure due to the lack of efficacious medicine and alternative treatment approaches. Vitamin A (VA) is known to have potent biological functions, including skin repair and immunoregulation. However, the potential pharmacological effects and molecular mechanisms of VA on foot ulcers are still to be discovered. Methods By using bioinformatic/computational analyses, including network pharmacology, gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis, we aimed to identify and reveal the pharmacological targets, molecular mechanisms, biological functions, and signaling pathways of VA in the treatment of diabetic foot ulcers. Results A total of 66 intersection genes were identified as candidate targets of VA, which are related to diabetic foot ulcers. Therein, 18 core genes/targets, namely JUN, MAPK1, THRB, MAPK14, MTNR1B, CXCR3, ESR1, AR, HDAC1, IL-10, CNR1, DRD2, EGFR, ADRA2A, CCND1, RXRB, RARA, and RXRA, were further identified. Furthermore, the biological processes, cell components, and molecular functions which may underlie the effects of VA against diabetic foot ulcers were characterized. Conclusion Based on our findings, we concluded that the pharmacological effects of VA on diabetic foot ulcers primarily involve the promotion of cellular regeneration and proliferation and the inhibition of inflammatory response. The core genes/targets may potentially serve as promising biomarkers for the diagnosis of diabetic foot ulcers.

0489 Two Years Of Experience Managing OSA Patients Using Remote Patient Monitoring

Abstract Introduction Remote-Patient-Monitoring(RPM) is gaining implementation but to date, nightly-monitoring of OSA other than PAP devices, has not become a standard of care. We have taken the lead on OSA-RPM and developed a platform that imports data from a FDA-approved technology based on Cardiopulmonary-Coupling software linked to a ring oximeter (SleepImage) worn at night. Last year we presented on the practicality and patient adherence of our approach. Here we are presenting our experience over the past two years of using our platform to assist in the management of a wide range of OSA treatment approaches. Methods We developed software to manage the work-flow involved with nightly RPM of sleep. Patients wear a ring oximeter at night designed to provide data to a cloud-based platform for retrieval by our staff using our tracking software platform. Inclusion criteria: OSA with an abnormal baseline AHI. Also included are narcolepsy patients on oxybate, known to enhance OSA. Patient self-reported inputs regarding therapy are captured. Treatment approaches range from PAP (CPAP/BiLevel), Inspire-HGNS, Oral-Appliance-Therapy, Surgical-Interventions (i.e. MMA), orthodontics and combinations of the above. Results Since 1-1-2021, 140pts enrolled, 85 since 1/1/2022, and 87 currently monitored (12/1/2022). Ave 59yrs +/- 13, 64% Males. Discontinuation resulted for reasons ranging from clinical improvement, financial limitations, lack of compliance and other. Numerous treatment modifications have been guided without repeat NPSG/HSAT testing. OSA-RPM has influenced management of PAP, Inspire-HGNS, Oral-Appliance, orthodontics, and surgical therapies, as well as combination of the above. Detailed outcomes to be furnished. In brief, OSA-RPM with our system has provided extensive insight into efficacy of treatment approaches. Additionally, night to night variability can be better appreciated with this RPM technique, implying the limitation of single-night sleep studies. Conclusion Using this approach has allowed direct ongoing assessment of the impact of therapy modifications directed by both the clinician and the patient. There are currently no established protocols or guidelines for the use of this type of OSA-monitoring. It is important that guidelines be implemented to provide an improved level of care and not abused to just increase reimbursements with little added value, as abuse could hinder the growth of this type of care. Support (if any)

Differential Diagnosis of Trauma Spectrum Disorders and Clinical High Risk for Psychosis

Early identification of symptoms and accurate diagnoses are necessary for referrals to intervention programs, diagnostic conceptualization, treatment planning, recovery, pharmacotherapy decision-making, improvement in prognosis, functional capacity, and possible prevention of the emergence of full diagnostic disorders. Different symptom profiles have been shown to have more efficacious treatment approaches than others; however, differential diagnoses can be complicated when psychosis-like symptoms first start to emerge. Thus, learning how to differentiate between clinical high risk for psychosis, borderline personality disorder, and posttraumatic stress disorder to determine if a singular diagnosis or multiple comorbid diagnoses are necessary to improve patient care and treatment outcomes. [ Psychiatr Ann . 2023;53(5):204–208.]

Connecting DSM-5 and ICD-11 trait domains with schema therapy and dialectical behavior therapy constructs.

The DSM-5 Section III alternative model of personality disorder (AMPD) and the International Classification of Diseases - 11th Edition's (ICD-11) personality disorder classification allow clinicians to identify individual trait domains in which people score highly. However, how these domains relate to constructs associated with efficacious treatment approaches is unclear. The current study aimed to determine whether constructs from two evidence-based treatments (schema therapy [ST] and dialectical behavior therapy [DBT]) were associated with maladaptive personality traits in a way consistent with underlying theories. We examined associations between ST constructs, DBT skill use and maladaptive coping styles, and personality traits in a sample of 525 adults. Bivariate intercorrelations and a series of multiple regression analyses were conducted to investigate the associations. As hypothesized, maladaptive coping was strongly associated with all trait domains. Surprisingly, poor DBT-skill use was only associated with negative affectivity, detachment, and disinhibition trait domains. Specific schema domains were associated with each personality trait domain, supporting trait domain-schema domain specificity. The current study highlights the potential clinical utility of the AMPD and ICD-11 trait models and ultimately contributes to the dearth of evidence on their likely usefulness for treatment selection, planning, and applications.

Evaluation of Novel Concentrated Interdisciplinary Group Rehabilitation for Patients With Chronic Illnesses: Protocol for a Nonrandomized Clinical Intervention Study.

BackgroundAn aging population with a growing burden of chronic complex illnesses will seriously challenge the public health care system. Consequently, novel and efficacious treatment approaches are highly warranted. Based on our experiences with concentrated treatment formats for other health challenges, we developed a highly concentrated interdisciplinary group rehabilitation approach for chronic illnesses.ObjectiveWe aim to explore the acceptability of the intervention and describe potential changes in functional impairment at follow-up.MethodsThe cornerstones of the intervention are as follows: (1) prepare the patient for change prior to treatment, (2) focus on health promoting microchoices instead of symptoms, and (3) expect the patient to integrate the changes in everyday living with limited hands-on follow-up. The intervention will be delivered to patients with highly diverse primary symptoms, namely patients with low back pain, post–COVID-19 symptoms, anxiety and depression, and type 2 diabetes.ResultsRecruitment started between August 2020 and January 2021 (according to the illness category). For initial 3-month results, recruitment is expected to be completed by the end of 2021.ConclusionsIf successful, this study may have a substantial impact on the treatment of low back pain, post–COVID-19 symptoms, anxiety and depression, and type 2 diabetes, which together constitute a major socioeconomic cost. Further, the study may widen the evidence base for the use of the concentrated treatment format in a diverse group of medical conditions.International Registered Report Identifier (IRRID)DERR1-10.2196/32216

Ageing with schizophrenia: an update.

The aim of this review was to summarize the recent literature on the clinical symptoms, functioning, outcomes and treatments for older adults with chronic schizophrenia. The number and proportion of older adults with schizophrenia is rapidly increasing. Schizophrenia is a heterogeneous disorder and older adults with schizophrenia display significant variability in symptom severity, quality of life and overall outcomes. Many achieve stable disease remission, some display persistent nonremission and others experience fluctuating symptoms. Depression is commonly reported, and although rates of suicide are higher when compared with age-matched peers, the excess mortality seen in this population is mainly attributed to natural causes of death. Cognitive decline and reduced illness awareness have important implications for functional status and quality of life. Antipsychotics remain essential in the treatment regimen, although elderly patients with chronic disease may be good candidates for gradual dose reduction. Interdisciplinary treatment approaches as well as nonpharmacologic psychosocial interventions play a critical adjunctive role in the treatment of older adults with schizophrenia. Research focusing on schizophrenia in late life is sparse. Too often, older patients are eliminated from research studies or averaged in with all age groups. Thus, there continues to be gaps in our understanding of modifiable predictors of remission and recovery, and the most efficacious and safest treatment approaches for this age group.

Treatment intensification in type 2 diabetes management after the failure of two oral hypoglycemic agents: A non-interventional comparative study.

The safety and efficacy of treatment approaches in patients with type 2 diabetes mellitus (T2DM) after the failure of two oral hypoglycemic agents (OHAs) was studied. A combination of the ambispective study was conducted between June 2013 to June 2014 at the Asir Diabetes Center, Abha, Kingdom of Saudi Arabia (KSA). Patients with poorly controlled T2DM who were administered two OHAs for at least 6months and had HbA1c levels greater than 7.0% were included. Subjects were treated with three OHAs (Group I), biphasic insulin and metformin (Group II), two existing OHAs and basal insulin (Group III), and insulin monotherapy (Group IV). Relevant data were collected at baseline at the interval of 3months for one year. Amongst 255 patients enrolled, 20.8, 29.8, 32.5, and 16.8% were in Groups I, II, III, and IV, respectively. The mean (Glycated hemoglobin) HbA1c levels were decreased significantly in the groups where insulin was an add-on therapy with the OHAs. Acceptable level of HbA1C (7 %) was significantly higher amongst patients in groups II and III, whereas hypoglycemic events were higher in Group IV. Insulin as add-on therapy with OHAs is an option for the management of T2DM where glycemic control is insufficient with two OHAs.

Treating male partners of women with bacterial vaginosis (StepUp): a protocol for a randomised controlled trial to assess the clinical effectiveness of male partner treatment for reducing the risk of BV recurrence

BackgroundBacterial vaginosis (BV) is estimated to affect 1 in 3 women globally and is associated with obstetric and gynaecological sequelae. Current recommended therapies have good short-term efficacy but 1 in 2 women experience BV recurrence within 6 months of treatment. Evidence of male carriage of BV-organisms suggests that male partners may be reinfecting women with BV-associated bacteria (henceforth referred to as BV-organisms) and impacting on the efficacy of treatment approaches solely directed to women. This trial aims to determine the effect of concurrent male partner treatment for preventing BV recurrence compared to current standard of care.MethodsStepUp is an open-label, multicentre, parallel group randomised controlled trial for women diagnosed with BV and their male partner. Women with clinical-BV defined using current gold standard diagnosis methods (≥3 Amsel criteria and Nugent score (NS) = 4–10) and with a regular male partner will be assessed for eligibility, and couples will then be consented. All women will be prescribed oral metronidazole 400 mg twice daily (BID) for 7 days, or if contraindicated, a 7-day regimen of topical vaginal 2% clindamycin. Couples will be randomised 1:1 to either current standard of care (female treatment only), or female treatment and concurrent male partner treatment (7 days of combined antibiotics - oral metronidazole tablets 400 mg BID and 2% clindamycin cream applied topically to the glans penis and upper shaft [under the foreskin if uncircumcised] BID). Couples will be followed for up to 12 weeks to assess BV status in women, and assess the adherence, tolerability and acceptability of male partner treatment. The primary outcome is BV recurrence defined as ≥3 Amsel criteria and NS = 4–10 within 12 weeks of enrolment. The estimated sample size is 342 couples, to detect a 40% reduction in BV recurrence rates from 40% in the control group to 24% in the intervention group within 12 weeks.DiscussionCurrent treatments directed solely to women result in unacceptably high rates of BV recurrence. If proven to be effective the findings from this trial will directly inform the development of new treatment strategies to impact on BV recurrence.Trial registrationThe trial was prospectively registered on 12 February 2019 on the Australian and New Zealand Clinical Trial Registry (ACTRN12619000196145, Universal Trial Number: U1111–1228-0106, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376883&isReview=true).

Lipophilic dye-compatible brain clearing technique allowing correlative magnetic resonance/high-resolution fluorescence imaging in rat models of glioblastoma

In this work we optimized a novel approach for combining in vivo MRI and ex vivo high-resolution fluorescence microscopy that involves: (i) a method for slicing rat brain tissue into sections with the same thickness and spatial orientation as in in vivo MRI, to better correlate in vivo MRI analyses with ex-vivo imaging via scanning confocal microscope and (ii) an improved clearing protocol compatible with lipophilic dyes that highlight the neurovascular network, to obtain high tissue transparency while preserving tissue staining and morphology with no significant tissue shrinkage or expansion. We applied this methodology in two rat models of glioblastoma (GBM; U87 human glioma cells and patient-derived human glioblastoma cancer stem cells) to demonstrate how vital the information retrieved from the correlation between MRI and confocal images is and to highlight how the increased invasiveness of xenografts derived from cancer stem cells may not be clearly detected by standard in vivo MRI approaches. The protocol studied in this work could be implemented in pre-clinical GBM research to further the development and validation of more predictive and translatable MR imaging protocols that can be used as critical diagnostic and prognostic tools. The development of this protocol is part of the quest for more efficacious treatment approaches for this devastating and still uncurable disease. In particular, this approach could be instrumental in validating novel MRI-based techniques to assess cellular infiltration beyond the macroscopic tumor margins and to quantify neo-angiogenesis.

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.