Parallel Study Research Articles

Factors associated with the Indonesian workforce’ Pneumonia Vaccination Intention: A Convergent Parallel Study

Pneumonia is part of Acute Respiratory Infections (ARI) that has high disease burden not only in the infants but also among Indonesian adult workforce. Following data from Indonesia medical trend by marsh mercer in 2023, Acute Respiratory Infections (ARI) and Pneumonia showed significant burden in the workplace and recognized as one of highest cases, medical claim, productivity loss and hospitalization. Despite the availability of the vaccine to prevent Pneumonia, the vaccination utilization remains very low in Indonesia workforce and adult in general (Utomo, 2023). This study is aiming to understand better what are the factors that associated with the workforce’ Pneumonia vaccination intention especially after COVID-19 pandemic. This study adopts (Ajzen, 1991) Theory of Planned Behavior (TPB) in explaining the variables (Attitude, Subjective Norm, Perceived Behavior Control and knowledge) that influencing the vaccination intention among Indonesian workforce. This study applies a convergent parallel study with quantitative data analysis and qualitative data analysis are performed parallelly, followed with data integration as summary. The quantitative data is collected through online survey with non-probability sampling & purposive method. Total 151 adult respondents provided their response. The qualitative data is collected through semi-structured interview with total 5 respondents of key identified stakeholders. This study utilized Partial Least Square Structural Equation Modelling (PLS SEM) as data analysis method for quantitative and Thematic Analysis for qualitative method. The results show that attitude, perceived behavior control and knowledge of Acute Respiratory Infections are positively influenced the Pneumonia vaccination intention while subjective norm is not. This study also found the underlying cause of low preventive measurement like vaccination are due to several reasons like the belief of curative is the basic medical needs in the workplace, providing vaccination coverage is part of talent retain/attract strategy, additional cost burden in providing vaccination coverage. Lower awareness on vaccination benefit in general, diseases burden & Prevention of Pneumonia & ARI are the key blockers of the lower vaccination acceptance as preventive measurement in the workplace setting in Indonesia. Lastly, Influenza Vaccination and mask wearing is the most common preventive measurement that embraced by the employer and the employee. This study contributes the application of Extended Theory Planned Behaviour towards vaccination intention among Indonesia workforce for Pneumonia Vaccine and provide extensive insights and recommendation to the multi stakeholders on the strategy to put prevention through vaccination to tackle the high burden of Acute Respiratory Infection Especially Pneumonia among Indonesia workforce.

Closed-loop oxygen control for critically ill patients--A systematic review and meta-analysis.

The impact of closed-loop control systems to titrate oxygen flow in critically ill patients, including their effectiveness, efficacy, workload and safety, remains unclear. This systematic review investigated the utilization of closed-loop oxygen systems for critically ill patients in comparison to manual oxygen titration systems focusing on these topics. A search was conducted across several databases including MEDLINE, CENTRAL, EMBASE, LILACS, CINAHL, LOVE, ClinicalTrials.gov, and the World Health Organization on March 3, 2022, with subsequent updates made on June 27, 2023. Evidence databases were searched for randomized clinical parallel or crossover studies investigating closed-loop oxygen control systems for critically ill patients. This systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. The analysis was conducted using Review Manager software, adopting the mean difference or standardized mean difference with a 95% confidence interval (95% CI) for continuous variables or risk ratio with 95% CI for dichotomous outcomes. The main outcome of interest was the percentage of time spent in the peripheral arterial oxygen saturation target. Secondary outcomes included time for supplemental oxygen weaning, length of stay, mortality, costs, adverse events, and workload of healthcare professional. A total of 37 records from 21 studies were included in this review with a total of 1,577 participants. Compared with manual oxygen titration, closed-loop oxygen control systems increased the percentage of time in the prescribed SpO2 target, mean difference (MD) 25.47; 95% CI 19.7, 30.0], with moderate certainty of evidence. Current evidence also shows that closed-loop oxygen control systems have the potential to reduce the percentage of time with hypoxemia (MD -0.98; 95% CI -1.68, -0.27) and healthcare workload (MD -4.94; 95% CI -7.28, -2.61) with low certainty of evidence. Closed-loop oxygen control systems increase the percentage of time in the preferred SpO2 targets and may reduce healthcare workload. PROSPERO: CRD42022306033.

Assessing the association between quantity and quality of family caregiver participation in decision-making clinical encounters on patient activation in the metastatic breast cancer setting

ObjectiveCaregivers support individuals undergoing cancer treatment by assisting with activities, managing care, navigating healthcare systems, and communicating with care teams. We explored the quality and quantity of caregiver participation during recorded decision-making clinical appointments in women with metastatic breast cancer.MethodsThis was a convergent parallel mixed methods study that utilized qualitative and quantitative data collection and analysis. Caregiver participation quality was operationalized using a summative thematic content analysis to identify and sum caregiver actions performed during appointments. Performance of a greater number of actions was considered greater quality of participation. Caregiver participation quantity was measured by calculating the proportion of speaking time. Participation quality and quantity were compared to patient activation, assessed using the Patient Activation Measure 1-month post decision-making appointment.ResultsFifty-three clinical encounters between patients with MBC, their caregivers, and oncologists were recorded. Identified caregiver actions included: General Support; Management of Treatment or Medication; Treatment History; Decision-Making; Insurance or Money; Pharmacy; Scheduling; Travel Concerns; General Cancer Understanding; Patient Specific Cancer Understanding; Caregiver-Initiated or Emphasis on Symptom Severity; and Caregiver Back-Up of Patient Symptom Description. Caregivers averaged 5 actions (SD 3): 48% of patient’s caregivers had low quality (< 5 actions) and 52% had high quality (> 6 actions) participation. Regarding quantity, caregivers spoke on average for 4% of the encounter, with 60% of caregivers speaking less than 4% of the encounter (low quantity) and 40% of caregivers speaking more than 4% (high quantity). Greater quality and quantity of caregiver participation was associated with greater patient activation.ConclusionsCaregivers perform a variety of actions during oncological decision-making visits aiding both patient and provider. Greater participation in terms of quantity and quality by the caregiver was associated with greater patient activism, indicating a need for better integration of the caregiver in clinical decision-making environments.

Impact of coenzyme Q10 as an adjuvant therapy to letrozole on spermiogram results and sex hormone levels in Iraqi men with infertility; randomized open label comparative study.

Background: Worldwide, infertility affects about 15% of reproductive-age couples. In many cases, infertility can't be treated, however new treatment options with promising value have been involved in recent clinical trials. The aim of this clinical trial was to evaluate the impacts of adding coenzyme Q10 (CoQ10) to letrozole on the results of spermiogram and sex hormone tests in men diagnosed with idiopathic oligoasthenoteratozoospermia (iOAT) syndrome, which is a type of male defective spermatogenesis of unknown etiology. Methods: This randomized, open-label, parallel two-arm interventional study included 67 adult male patients aged 18-60 years with a confirmed diagnosis of iOAT syndrome recruited from The High Institute for Infertility Diagnosis & Assisted Reproduction Technologies/Nahrain University. Patients were randomly separated into two groups, Group A included 29 patients treated with letrozole 2.5 mg tablet orally twice a week, Group B included 38 patients treated with a combination of letrozole 2.5 mg tablet orally twice a week plus CoQ10 400 mg per day. Both groups completed treatment for three months. Semen samples, serum follicle-stimulating hormone (FSH), estradiol (E 2), and testosterone (T) were analyzed at day one, and at the end of month one, two and three. Results: Both groups showed that sperm concentration, normal morphology, total sperm count and motility, serum testosterone and FSH levels, and T/E 2 ratio were significantly increased, while estradiol levels significantly decreased after three months of treatment. Seminal fluid volume changed significantly in group A only. In comparing between the two groups, all measured parameters, apart from sperm motility and FSH level, demonstrated a significant difference after three months of treatment, while sperm volume reached significant value after only two months of therapy. Conclusions: CoQ10 as adjuvant treatment to letrozole effectively improved most of the tested sperm parameters in Iraqi men with iOAT. Registration: ClinicalTrials.gov ( NCT05847257, May 6, 2023).

Study Protocol for Investigating the Impact of Economic Sanctions on Public Health and Healthcare Systems in Iran: A National and Sub-national Analysis from 2000 to 2020

: The economic sanctions imposed on Iran in recent decades have impacted the country's healthcare system and the health of its people. However, there has not been a thorough examination of the full scope and changes in these effects over time. Therefore, we designed a mixed-methods study, comprising a parallel quantitative analysis and qualitative study. The quantitative part assesses the effects of sanctions on public health and the healthcare system using 28 indicators, i.e., macroeconomic, healthcare resources, and health outcomes indicators at both national and sub-national levels from 2000 to 2020. The analyses will include descriptive analysis, change point regression analysis, and mediation analysis, performed using R software. The concurrent qualitative study aims to explore the pathways of the sanction effects by considering the perceptions of both patients and health policymakers. The perceptions and experiences of patients regarding living with and dealing with the long- and short-term health implications of sanctions, and the experiences of health policymakers regarding the effects of sanctions on the healthcare system will be analyzed. This study will provide comprehensive and evidence-informed recommendations for global health policymakers to support countries under economic sanctions to protect and promote the human right to health and well-being.

The need for and acceptability of a cancer training course for medical and nursing students in Tanzania: a convergent mixed methods study

BackgroundThe cancer burden in Africa is on the rise. A Cancer Training Course on screening, prevention, care, and community education is crucial for addressing a wide range of cancer health issues. When appropriately educated healthcare providers on cancer provide care, patient care improves, and healthcare costs decrease. However, in Tanzania, doctors and nurses receive little or no training in primary cancer care in their bachelor’s program.AimThis study assessed the need and acceptability of a cancer training course for nursing and medical doctor students at the Muhimbili University of Health and Allied Sciences (MUHAS) in Dar es Salaam, Tanzania.MethodsThis study was a cross-sectional parallel mixed method study during the 3-month follow-up within the larger study on sexual health training for health professionals. The study was a randomized controlled (RCT), single-blind, parallel trial of sexual health training versus a waitlist control among health students at MUHAS in Tanzania. Descriptive analysis was performed to analyze the participants’ demographic information, need, and acceptability of the cancer training courseto determine the frequencies and percentages of their distribution between disciplines. In addition, inductive thematic analysis was performed for the qualitative data. The RCT study was registered at Clinical Trial.gov (NCT03923582; 01/05/2021).ResultsData were collected from 408 students (272 medical doctors and 136 nursing students). The median age of the participants was 23 years. Most (86.0%) medical and 78.1% of nursing students reported receiving little to no cancer training. On the other hand, most (92.3%) medical and nursing (92.0%) students were interested in receiving cancer training. Furthermore, 94.1% of medical and 92.0% of nursing students needed a cancer training course in their undergraduate program. In addition, participants said a cancer training course would be important because it would help them improve the quality of cancer care and enhance the quality of life for patients by ensuring early diagnosis and treatment.ConclusionA cancer training course is both highly needed and acceptable to medical and nursing students. Implementation of this cancer training course will improve students’ knowledge and skills and eventually improve the quality of cancer care and patients’ quality of life by ensuring early diagnosis and management.

The tendency and affecting factors of nursing students' Xenophobia toward refugees from the perspective of ecological systems theory: A convergent parallel mixed method study

AimThis study aims to develop a comprehensive understanding of nursing students' xenophobic tendencies toward refugees and affecting factors from the perspective of Ecological Systems Theory. BackgroundNursing students' xenophobia toward refugees may negatively affect their care for patients. To effectively prevent xenophobia, it is essential to identify its underlying factors. DesignA convergent parallel mixed method. MethodsThis study was conducted with third and fourth-grade nursing students at a university in Turkey. In the quantitative phase, online surveys were used, employing convenience sampling, with 227 participants. In the qualitative phase, purposive sampling was used and data were collected through in-depth interviews with 17 participants on the Zoom platform. Data were obtained using the Participant Information Form, Xenophobia Scale and Semi-Structured Interview Form. ResultsNursing students who are male, in their third year, have low economic status, lack immigrant friends, lack immigrants in the family members, receive information about immigrants from social media and live in regions with a high concentration of immigrants have higher levels of xenophobia (p<0.05). In the qualitative phase, our study results showed that negative experiences with refugees, economic and social worries, perception of security threats, cultural conflicts and negative media messages toward refugees can lead to xenophobia. In addition, students stated that lessons about immigrants and caring for them in clinics can improve their ability to empathize with immigrants. ConclusionNursing curriculums should cover immigrant care and interaction to combat xenophobia, which can improve empathy skills and raise awareness.

Effects of Thermal Stimulation and Transcutaneous Electrical Nerve Stimulation on Sensory and Motor Function of Upper Extremity in Acute Stroke Survivors: A Randomized Controlled Pilot Study.

Objective Upper-limb coordination is crucial for daily activities, especially among stroke survivors who may encounter obstacles during upper-limb rehabilitation. This study aimed to investigate the effects of thermal stimulation (TS) and transcutaneous electrical nerve stimulation (TENS) on sensory and motor function during recovery in acute stroke patients. Design This is a parallel study with a randomized controlled design. The experiment was conducted in the E-Da Hospital Rehabilitation Department, Kaohsiung, Taiwan. Intervention Thirty participants were in-patients with acute stroke at the E-Da Hospital. Participants were randomly assigned tothree groups for a one-week intervention: exercise combined with TS, exercise combined with TENS, or conventional physical therapy with exercise alone. The Fugl-Meyer upper extremity scale, Brunnstrom stage, minimal current perception (MCP), and modified Ashworth scale were collected for the assessment. Results The outcomes demonstrated considerable improvement in MCP in all the groups after treatment. Specifically, the groups receiving TS and TENS showed significant improvements in the Brunnstrom stage, suggesting that both treatments improved distal motor recovery. Conclusion The results, following a one-week intervention period, suggested that both TS and TENS contributed to the improvement of motor and sensory function, with a significant impact on the Brunnstrom stage in the upper extremity, particularly in the distal region. The inclusion of TS or TENS in rehabilitation protocols improved distal motor function compared to baseline measures, suggesting these treatments as effective components in acute stroke rehabilitation.

The mechanism of Sangdantongluo granule in treating post-stroke spasticity based on multimodal fMRI combined with TMS: Study protocol

IntroductionPost-stroke spasticity (PSS) is among the prevalent complications of stroke, greatly affecting motor function recovery and reducing patients' quality of life without timely treatment. Sangdantongluo granule, a modern traditional Chinese patent medicine, has significant clinical efficacy in treating PSS. However, the mechanism of Sangdantongluo granule in treating PSS is still unknown. We designed this study to explore the mechanism of Sangdantongluo granule in treating PSS through multimodal functional magnetic resonance imaging (fMRI) combined with transcranial magnetic stimulation (TMS). Methods and analysisIn a single-center, randomized, double-blind, parallel placebo-controlled study, 60 PSS patients will be recruited in China and randomly assigned to either the experimental or control groups at a ratio of 1:1. For eight weeks, Sangdantongluo granule or placebo will be utilized for intervention. The main outcome is the Modified Ashworth Scale (MAS), the secondary outcome includes the Fugl-Meyer Assessment Scale-upper Extremity (FMA-UE), National Institute of Health Stroke Scale (NIHSS), and Modified Rankin Scale (mRS), the mechanism measure is the changes in cortical excitability and multimodal fMRI at baseline and after eight weeks. Ethics and disseminationThis study was approved by the Ethics Committee of the Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine (approval number: [202364]). Clinical trial registrationChinese Clinical Trial Registry, identifier: ChiCTR2300074793. Registered on 16 August 2023.

Sex Influences the Extent of Physical Performance Adaptations in Response to Small-Sided Games and Running-Based High-Intensity Interval Training: A Parallel Study Design Involving Men and Women Soccer Players.

The aim of this study was two-fold: (i) to compare physical fitness adaptations following small-sided games (SSG) and running-based high-intensity interval training (HIIT), considering sex interactions; and (ii) to describe intra-individual variations of adaptations in both men and women developmental/trained soccer players over an 8-week randomized parallel study design involving 25 women and 27 men. Pre and post-intervention assessments included countermovement jump (CMJ), 10-meter linear sprint test, change-of-direction (COD) deficit, and final velocity at 30-15 Intermittent Fitness Test (VIFT). Significant interactions between time, groups and sex were found in 10-m sprint (F1,48 = 6.042; p = 0.018; ηp2 = 0.112). No significant interactions between time, groups and sex were found in CMJ (F F1,48 = 0.609; p = 0.439; ηp2 = 0.013), COD deficit (F F1,48 = 2.718; p = 0.106; ηp2 = 0.054) and VIFT (F F1,48 = 1.141; p = 0.291; ηp2 = 0.023). Significant interactions were found between time and sex in CMJ (F F1,48 = 29.342; p < 0.001; ηp2= 0.379), 10-m sprint (F F1,48 = 4.359; p = 0.042; ηp2 = 0.083), COD deficit (F F1,48 = 5.066; p = 0.029; ηp2= 0.095) and VIFT (F F1,48 = 11.248; p = 0.002; ηp2 = 0.190). In conclusion, this study suggests similar effects of HIIT in both sexes. However, for women, SSG may entail less efficacy and more inter-individual variability compared to men. Therefore, HIIT could potentially be a better solution for women, whereas both training approaches were equally effective in men.

A first-in-human, phase 1, dose escalation study of SGR-2921 as monotherapy in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

TPS6590 Background: Cell division cycle 7-related protein kinase (CDC7) is a cell cycle kinase that maintains DNA replication by phosphorylation and activation of the minichromosome maintenance protein 2 and 4 (MCMs), components of the replicative DNA helicase. Due to the CDC7's central role in maintaining replication fork integrity, chemical inhibition of CDC7 can ultimately lead to cancer cell death. SGR-2921 is an oral, small molecule inhibitor of CDC7. Preclinical studies demonstrate that SGR-2921 has potent anti-proliferative activity in AML cell lines representative of difficult to treat patient populations, agnostic of serious mutations (including those with p53 mutations), BTK resistance, and multiple prior lines of treatment. This anti-tumor activity has also been demonstrated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) AML models. Methods: This is a phase 1, FIH, open-label, single-agent, two-arm, dose escalation study (NCT#05961839) designed to evaluate safety and tolerability and identify the recommended phase 2 dose (RP2D) of SGR-2921 as monotherapy in subjects with relapsed or refractory (R/R) AML, high risk (HR) MDS, or very high risk (VHR) MDS. The study utilizes an accelerated titration design with single patient cohorts that transitions to a 3+3 design once a single Grade 2 event is observed. This is a multicenter global study (US, Spain and France). SGR-2921 will be administered orally, once daily, utilizing a 5-day on and 9-day off dosing schedule over a 28-day cycle. A maximum of 144 patients will be enrolled into dose escalation and exploratory cohorts. To evaluate the effect of CYP3A4 inhibition on SGR-2921 exposure, subjects will be enrolled into one of two staggered, parallel study treatment arms, according to concomitant administration with (Arm B) or without (Arm A) azole antifungals that are strong CYP3A4 inhibitors. A single dose PK run-in will be required for subjects enrolled into the first 3 cohorts of each treatment arm. Subjects will be treated at increasing doses of SGR-2921 until the maximum tolerated dose (MTD) is exceeded. A RP2D will be selected from one of the tolerable dose levels. Key study inclusion criteria include: Age ≥ 18 years of age; Life expectancy ≥ 8 weeks; Confirmed diagnosis of R/R AML or HR and VHR MDS; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Key study exclusion criteria include: Active malignancies not related to AML or MDS within two years prior to the first dose or requiring ongoing treatment; active CNS leukemia; QTcF ≥470 msec. The primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and to identify the RP2D. Secondary objectives include evaluating SGR-2921 pharmacokinetics and investigating preliminary antitumor activity. Clinical trial information: NCT05961839 .

Alterity and Tragicality in Shakespeare and Fitzgerald

Abstract This article attempts to trace the themes of alterity and tragicality in Shakespeare's Macbeth and Fitzgerald's The Great Gatsby. We offer a parallel study of the two works with an emphasis on the (anti)heroes’ struggles with time and the other human as metaphors of ‘alterity’. We present a thematic reading and argue that as Macbeth is preoccupied with his imaginatively fabricated future (time) and tries to execute anyone (the other) who jeopardises the totality of that ideal space, Gatsby is also preoccupied with his past (time) and tries to retrieve Daisy (the other). Tragedy, we discuss, is basically the ultimate result of these struggles. We suggest that Fitzgerald's work generally shares the similar theme of alterity with Shakespeare's Macbeth and somehow modernises the similar tragicality we witness in the latter.

A phase 2/3 study of fianlimab, cemiplimab, plus chemotherapy versus cemiplimab plus chemotherapy in first-line treatment of advanced non-small cell lung cancer.

TPS8660 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Anti–programmed cell death-1 (PD-1) therapies have improved outcomes in patients with NSCLC; however, most patients do not respond or only respond for a limited time. The combination of cemiplimab (anti–PD-1) and chemotherapy has been studied for the first-line treatment of advanced NSCLC (aNSCLC), regardless of programmed cell death-ligand 1 (PD-L1) status. While the standard of care continues to evolve for NSCLC, one approach to potentially improve outcomes is the combination of checkpoint inhibitors (IO) with chemotherapy. Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab are both high-affinity, fully human IgG4 monoclonal antibody IO therapies that have shown promising clinical activity when combined in patients with aNSCLC in a Phase 1 study (NCT03005782). This ongoing study will further investigate the combination of fianlimab + cemiplimab + chemotherapy. Methods: This is a randomized, multicenter, Phase 2/3 study of fianlimab + cemiplimab + platinum-doublet chemotherapy (chemo) versus cemiplimab + chemo in patients with unresectable stage IIIB/IIIC or stage IV NSCLC irrespective of PD-L1 expression levels (NCT05800015). This study will be conducted globally at approximately 210 sites. Patient eligibility criteria: ≥18 years old; squamous or non-squamous histology with stage IIIB, IIIC, or IV disease; valid PD-L1 result; ≥1 radiographically measurable lesion by computed tomography/magnetic resonance imaging; Eastern Cooperative Oncology Group performance status ≤1; adequate organ and bone marrow function. The Phase 2 portion will be used to determine the fianlimab dose selected for the Phase 3 portion: patients will be randomized 1:1:1 to receive fianlimab high dose + cemiplimab 350 mg + chemo (Arm A), fianlimab low dose + cemiplimab 350 mg + chemo (Arm B), or cemiplimab 350 mg + chemo + placebo (Arm C), Q3W IV. In Phase 3, patients will be randomized 1:1 into one of two treatment arms (either Arm A or Arm B, and Arm C) based on findings from Phase 2. The primary endpoint of Phase 2 is objective response rate (ORR) per blinded independent central review. The primary endpoint of Phase 3 is overall survival. The secondary endpoints include efficacy (ORR, disease control rate, time to tumor response, duration of response, progression-free survival, and overall survival), safety and tolerability, immunogenicity (anti-drug antibodies and neutralizing antibodies against fianlimab or cemiplimab in serum), patient-reported outcomes, and pharmacokinetics. This study and a parallel study of fianlimab + cemiplimab in patients with aNSCLC with tumors expressing PD-L1 ≥50% (NCT05785767) are currently open for enrollment. Clinical trial information: NCT05800015 .

Chemoselective Proteomics, Zinc Fingers, and a Zinc(II) Model for H2S Mediated Persulfidation

AbstractThe gasotransmitter hydrogen sulfide (H2S) is thought to be involved in the post‐translational modification of cysteine residues to produce reactive persulfides. A persulfide‐specific chemoselective proteomics approach with mammalian cells has identified a broad range of zinc finger (ZF) proteins as targets of persulfidation. Parallel studies with isolated ZFs show that persulfidation is mediated by ZnII, O2, and H2S, with intermediates involving oxygen‐ and sulfur‐based radicals detected by mass spectrometry and optical spectroscopies. A small molecule ZnII complex exhibits analogous reactivity with H2S and O2, giving a persulfidated product. These data show that ZnII is not just a biological structural element, but also plays a critical role in mediating H2S‐dependent persulfidation. ZF persulfidation appears to be a general post‐translational modification and a possible conduit for H2S signaling. This work has implications for our understanding of H2S‐mediated signaling and the regulation of ZFs in cellular physiology and development.

Chemoselective Proteomics, Zinc Fingers, and a Zinc(II) Model for H2S Mediated Persulfidation.

The gasotransmitter hydrogen sulfide (H2S) is thought to be involved in the post-translational modification of cysteine residues to produce reactive persulfides. A persulfide-specific chemoselective proteomics approach with mammalian cells has identified a broad range of zinc finger (ZF) proteins as targets of persulfidation. Parallel studies with isolated ZFs show that persulfidation is mediated by ZnII, O2, and H2S, with intermediates involving oxygen- and sulfur-based radicals detected by mass spectrometry and optical spectroscopies. A small molecule ZnII complex exhibits analogous reactivity with H2S and O2, giving a persulfidated product. These data show that ZnII is not just a biological structural element, but also plays a critical role in mediating H2S-dependent persulfidation. ZF persulfidation appears to be a general post-translational modification and a possible conduit for H2S signaling. This work has implications for our understanding of H2S-mediated signaling and the regulation of ZFs in cellular physiology and development.

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.

In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2-/-) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2-/- fibers present deficits in force production and calcium sensitivity. Structurally, passive C2-/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2-/-, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

Cinnamaldehyde hydrazone derivatives as potential cathepsin B inhibitors: parallel in-vitro investigation in liver and cerebrospinal fluid

The emergence of cathepsins as a potential target for anticancer drugs has led to extensive research in the development of their inhibitors. In the present study, we designed, synthesized, and characterized several cinnamaldehyde schiff bases employing diverse hydrazines, as potential cathepsin B inhibitors. The parallel studies on cathepsin B isolated from liver and cerebrospinal fluid unveiled the significance of the synthesized compounds as cathepsin B inhibitors at nanomolar concentrations. The compound, 7 exhibited the highest inhibition of 83.48 % and 82.96 % with an IC50 value of 0.06 nM and 0.09 nM for liver and cerebrospinal fluid respectively. The inhibitory potential of synthesized compounds has been extremely effective in comparison to previous reports. With the help of molecular docking studies using iGEMDOCK software, we found that the active site -CH2SH group is involved in the case of α-N-benzoyl-D, l-arginine-b-naphthylamide (BANA), curcumin 2, 3, 6, and 7. For toxicity prediction, ADMET studies were conducted and the synthesized compounds emerged to be non-toxic. The results obtained from the in vitro studies were supported with in silico studies. The synthesized cinnamaldehyde schiff bases can be considered promising drug candidates in conditions with elevated cathepsin B levels.

Understanding patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease in Mulago and Kiruddu hospitals, Uganda, a qualitative study.

In 2016, Uganda added Hydroxyurea (HU) to the list of essential drugs to treat sickle cell disease SCD. However, Hydroxyurea utilization has been low for several countries in sub-Saharan Africa. This study examined patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease in Mulago and Kiruddu hospitals, in Uganda. To understand the patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease, we conducted a parallel convergent mixed methods study at outpatient departments of two national referral hospitals in Uganda from October 2022 to January 2023. The cross-sectional mixed-methods study employed both quantitative and qualitative methods. We collected survey data from a systematic sample of 259 participants and conducted individual interviews with a purposive sample of 40 participants (20 adolescents or their caregivers and 20 adult patients with SCD) and interviewed them individually on their knowledge, perceptions, barriers, and facilitators of HU utilization. Descriptive data were analyzed using Stata 16, whereas qualitative data were analyzed thematically using an inductive approach supported by NVivo 12 software. We triangulated data to determine the concordance of qualitative and quantitative data. The study enrolled 40 participants for qualitative interviews and 259 patients for quantitative, with an average age of 16, over half being female, 46% having secondary education, and 96% unmarried. The prevalence of HU use was 78%. The study identified three themes as follows: Patient barriers at the individual including Inadequate knowledge about HU, Persistent pain, Poor adherence to HU, Poor communication with health care workers, and Psychosocial and emotional challenges. At the facility level, long queues and poor quality of care, drug-related side effects that affect HU, and drug stock-outs were reported. Myths, rumors, and misconceptions about HU, and gender-related barriers were reported to affect HU utilization at a community level. Facilitators for the use of HU and recommendations for improvement. Facilitators included perceived benefits, long duration on HU, information sharing by healthcare workers, availability of complementary drugs, confirmation of diagnosis, and availability of medication at public health facilities or private pharmacies. Patients suggested continuous adherence support, encouragement from healthcare workers, sensitization about benefits and risks, a peer-to-peer approach, and financial support for adolescents and women to start businesses to resolve financial problems. Implementing the use of HU has been challenging in Uganda and needs improvement. Facilitators to hydroxyurea use have been highlighted, though Patient-identified barriers at individual, facility, and community levels that need to be resolved. The experiences and insights shared by our participants provide invaluable guidance for increasing the uptake of HU. Further studies are needed to establish validated instruments to assess patients' pain communication and adherence to the HU regimen.

#2810 Exploring non-renal vasculature: therapeutic implications of proton pump inhibitor and anthelmintic treatment in PCK rat model

Abstract Background and Aims Cystic kidney diseases represent ciliopathies that can cause vascular damage through renal hypertension. Additionally, there is growing experimental evidence of endothelial cell abnormalities associated with ciliary protein deficiencies. PCK rats, a strain derived from Sprague-Dawley (SD) rats that develops both polycystic kidney disease (PKD) and liver disease, serve as a model for recessive PKD. The PCK rat model also presents abnormalities in non-renal vascular function. Another study from our group suggests a potential therapeutic benefit of repurposed therapy with a proton pump inhibitor (PPi) and an anthelmintic agent in attenuating the progression of PKD in a PCK rat model. Here, we investigated whether these drugs can also improve endothelial function. Method The compounds were administered to 3-week-old male and female PCK rats (n = 5-6) for a total of 10 weeks. Untreated PCK rats and age-matched SD rats (n = 5-6) served as controls. After perfusion fixation, the aorta was harvested and its thoracic rings were used to evaluate the contraction/relaxation responses ex vivo by organ bath experiments. Additional rings were preserved for histological and molecular biological analyses. Results Male PCK rats exhibited impaired endothelial function compared to healthy controls. Endothelium-dependent relaxation to acetylcholine was improved by 10% after treatment with PPi, while the anthelmintic administration had no protective effect. PKD also impaired endothelial function in female PCK rats compared to healthy SD controls. There was an improvement in endothelium-dependent relaxation to acetylcholine after treatment with PPi by 5.5%, while administration of the anthelmintic agent further impaired endothelial function. Conclusion 13-week-old PCK rats show endothelial dysfunction in non-renal vasculature. Treatment with a proton pump inhibitor improved endothelial function in male PCK rats to the level of healthy SD controls. By contrast, in a parallel study, the anthelmintic had a positive effect on renal function but a detrimental impact on endothelial function. These intricate relationships underscore the need for further exploration to understand the underlying mechanisms and broader implications of our findings, illustrating the challenges and potential avenues for the development of effective treatments for PKD.

#2394 Inhibition of ACSS2-mediated H3K9 crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence

Abstract Background and Aims Histone lysine crotonylation (Kcr), a novel posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. Method Human renal tissue, fixed in formaldehyde, and embedded in paraffin, was selected from the files of the Service of Pathology of West China Hospital, Sichuan University.ACSS2 knockout mice and tubular specific knock out of ACSS2 mice in C57BL/6N background and wild-type littermates (WT) were used to induce the FAN and UUO model or as control groups (n = 6 each). In the parallel study, C57BL/6N mice were randomly divided into three groups: control, FAN/UUO and FAN/UUO+ACSS2 inhibitor (n = 6 each). At day 7, mice were sacrificed and the serum creatinine, BUN and urinary albumin/creatinine ratio (ACR) were tested. Renal histological injury was measured by HE and Masson's trichrome staining. SA-β-gal staining was used to check cellular senescence. Renal tissues of the mice were analyzed by western blot and qPCR assay for the expression of ACSS2, H3K9cr, fibrosis and cellular senescence related proteins and genes. RNA-sequencing and ChIP-sequencing combined with in vitro cell experiments were used to figure out the underlying mechanism. Results In this study, we reported that histone Kcr of tubular epithelial cells was abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) was found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys revealed that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppressed H3K9cr-mediated IL-1β expression, which thereby alleviated IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Conclusion Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.