bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of [18F]FDG-PET/CT in ARI0002h treatment, a CAR-T against BCMA for relapsed/refractory multiple myeloma
Authors: Zugasti Inés , Tormo-Ratera Marta , Oliver-Caldés Aina , Soler-Perromat Juan Carlos , González-Calle Verónica , Moreno David F. , Cabañas Valentín , López-Muñoz Nieves , Bartolomé-Solanas Álvaro , Español-Rego Marta , Reguera-Ortega Juan Luis , Rosiñol Laura , López-Corral Lucía , Tovar Natalia , Rodríguez-Lobato Luis Gerardo , Alvarez Perez Rosa Maria , Varea Sara , Olesti Eulàlia , Gomez-Grande Adolfo , Frutos Laura , Tamayo Pilar , Juan Manel , Moraleda José M. , Urbano-Ispizua Álvaro , González-Navarro E. Azucena , Martínez-López Joaquín , Mateos Maria-Victoria , Tomás Xavier , Setoain Xavier , Fernández de Larrea Carlos
Published: November 2024

Multiple myeloma (MM) remains incurable, with poor outcomes in heavily pretreated patients. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment; however, outcomes after such therapy in patients with soft-tissue plasmacytomas and other bone lesions remain poorly understood. This study included 63 patients with relapsed/refractory MM treated either in the CARTBCMA-HCB-01 clinical trial (ARI0002h; academic B-cell maturation antigen [BCMA]–targeted CAR T-cell therapy) or in compassionate use. The aim was to evaluate the impact of soft-tissue involvement (extramedullary [EMD] and paraskeletal [PS] plasmacytomas) in response, survival and safety. Baseline [18F]fluorodeoxyglucose (FDG)–positron emission tomography (PET)/computed tomography (CT) from 5 participating centers were reviewed centrally. Of 63 patients, 52.4% presented plasmacytomas at the time of inclusion (21 PS, exclusively; and 12 EMD). Per responses, there were no significant differences between patients with and without plasmacytomas. A correlation was present between International Myeloma Working Group responses and those obtained by [18F]FDG-PET/CT at day 100 (Bologna criteria). No differences were observed in progression-free survival (PFS) or overall survival (OS) between patients with or without plasmacytomas. However, both PFS and OS were significantly shorter in patients with EMD. Interestingly, [18F]FDG-PET/CT response assessed on day 100, in accordance with the Bologna criteria, was predictive of survival outcomes. A metabolic tumor volume of ≥25 cm3 at baseline [18F]FDG-PET/CT was associated with earlier disease progression and shorter OS. These results highlight the importance of EMD evaluation by [18F]FDG-PET/CT before and after CAR T-cell infusion. This trial was registered at www.ClinicalTrials.gov as #NCT04309981; and EudraCT, 2019-001472-11.
Purified α-Amylase from Bacillus cereus exhibits antibiofilm and antiquorum sensing activities against uropathogenic Escherichia coli, Downregulating fimH, and papC virulence genes: implications for urinary tract infections
Authors: Abo-Kamar Amal M. , Mustafa Abd-El-Rahman A. , Al-Madboly Lamiaa A.
Published: November 2024

Background and aim

Pathogenic Escherichia coli is a known harmful microorganism that takes advantage of favorable conditions to cause various infections in healthcare settings, such as bloodstream infections related to catheters, as well as infections in the urinary and respiratory tracts. E. coli utilizes biofilm development as a means to enhance its virulence and pathogenicity. This work aims to investigate the antibiofilm activity of α-amylase enzyme against uropathogenic E. coli (UPEC) and its effect on biofilm-regulatory genes.

Methodology

In this study, we evaluated the antibiofilm activity of α-amylase enzyme by spectrophotometric microtiter plate analysis and confocal laser scanning microscopy. Also, the antibacterial activity of the test enzyme was evaluated by measuring the MIC and MBC levels against UPEC. The quorum-quenching activity of α-amylase enzyme was assessed using a qRT-PCR to evaluate the impact on biofilm-regulatory genes.

Results

Based on our results, purified α-amylase showed MIC and MBC levels ranged between 128 and 512 µg /ml against UPEC isolates using broth microdilution assay. Crystal violet assay revealed MBIC of 128 µg/ml and MBEC of 256 µg/ml for the purified α-amylase. When the biofilm was analyzed by confocal laser scanning microscope, our results showed inhibition of biofilm thickness (56%) and live/dead cell percentages (43/55%). Furthermore, analysis of the effect on the expression of biofilm-encoding genes showed downregulation of both fimH and papC genes by 57 and 25%, respectively, upon treatment of UPEC with ½ of the MIC (64 µg/ml).

Conclusions

The results demonstrate that our purified α-amylase from B. cereus exhibits promising antibiofilm activities against UPEC at both phenotypic as well as genotypic levels. These findings suggest that this enzyme may serve as a natural effective tool for removing bacterial biofilms, potentially offering new therapeutic avenues for treating infections caused by UPEC.
Promoting healthy practices among schools and children in rural bangladesh: a randomised controlled trial of skill-based health education
Authors: Omura Makiko , Venkatesh Mohini , Khandaker Ikhtiar , Rahman Md. Ataur
Published: November 2024

Background

Poor child health and hygiene practices are persistent issues in resource-constrained settings, particularly in low-income countries. This study assessed the impact of skill-based health education (SBHE) on school and child hygiene practices in rural Bangladesh.

Methods

A cluster-randomised-controlled intervention with cross-cutting/factorial design was conducted in 180 randomly selected primary schools, stratified by school type, in Jhenaidah District, Bangladesh. Weekly SBHE sessions were delivered to half of the schools by locally recruited para-teachers for one year. A cross-cutting soap provision treatment was given monthly to half of the SBHE-treatment schools and half of the SBHE-control schools. Treatment assignment was masked to all baseline and endline surveyors. Data were collected at both the school and child levels, with child-level data aggregated at the school level. Outcome measures were grouped into five thematic families. The primary outcome families wereschool hygiene practice & maintenance,school-aggregated child handwashingandschool-aggregated child dentalcare. Utilising the difference-in-differences estimator with seemingly unrelated regression, we estimated the average treatment effect for each family of multiple outcomes. The intervention spillover effect to neighbouring schools along with the time-period effect were also evaluated. The project’s cost-effectiveness was additionally assessed.

Results

Our findings revealed that SBHE had a positive impact on primary outcomes related to healthy practices and behavioural changes, resulting in a 0.32SD improvement in school hygiene practices and maintenance (p < 0.001), a 0.47SD increase in child handwashing (p < 0.001), and a 0.43SD enhancement in child dentalcare (p < 0.01). Despite its imperfect implementation, the provision of soap itself showed no significant effect. Furthermore, significant spillover effects of healthy practices were observed in neighbouring non-treatment schools. The cost-effectiveness analysis indicated that our SBHE program was cost-effective.

Conclusions

Our study provides compelling evidence of the positive impact of SBHE on school hygiene and child health practices in rural Bangladesh, with notable spillover effects. The cost-effectiveness analysis underscores the value of SBHE, affirming its potential as an effective intervention method in improving school health and hygiene practices in primary schools and beyond.
Clinical signs, morphological and phylogenetic characterization of Myxozoan spp. infecting Nile tilapia, Oreochromis niloticus and African catfish, Clarias gariepinus in Qalyubia Governorate, Egypt
Authors: Yassen Doaa A. , Abd El-Gawad Eman A. , Abd El-Razik Khaled A. , Mahrous Karima F. , Abbass Amany A.
Published: November 2024

Context

Myxosporean endoparasites (phylum cnidarian) are critical pathogens that affect both wild and cultured freshwater and marine water fishes globally causing huge economic losses and high mortalities.

Study objective

The present study investigated myxosporean infections in Nile tilapia and African catfish collected from the natural resources.

Methods

A total of four hundred Nile tilapia with an average weight (60 ± 5 g) and two hundred African catfish with an average weight (185 ± 30 g) were collected seasonally from Qalyubia Governorate, Egypt for parasitological and molecular diagnosis of isolated myxozoan species.

Results

Microscopic examination revealed Myxobolus heterosporous, Myxobolus brachysporus, Myxobolus tilapiae, and Myxobolus amieti in Nile tilapia and Henneguya suprabranchiae, and Myxobolus brachysporus in African catfish. Sequencing of 18S rDNA gene for isolated Myxozoan spp. from Nile tilapia revealed Myxobolus tilapiae deposited in GenBank under accession numbers (OR766325 and OR766326). In African catfish, the isolated Myxobolus brachysporus sequence was deposited under accession numbers (OR766327 and OR766328). Henneguya suprabranchiae was also identified in African catfish (accession. No. OR763724 and OR763433).

Conclusion

Overall, these results indicate a high prevalence of myxozoan infection in naturally inhabiting Nile tilapia and African catfish. Curiously, Henneguya suprabranchiae was detected in the digestive tract and kidneys of African catfish, which is considered a rare form.

Implication

This study highlighted the importance of parasitic surveys in natural resources that impact fish production.
Role of stretch-activated channels in light-generated action potentials mediated by an intramembrane molecular photoswitch
Authors: Florindi Chiara , Vurro Vito , Moretti Paola , Bertarelli Chiara , Zaza Antonio , Lanzani Guglielmo , Lodola Francesco
Published: November 2024

Background

The use of light to control the activity of living cells is a promising approach in cardiac research due to its unparalleled spatio-temporal selectivity and minimal invasiveness. Ziapin2, a newly synthesized azobenzene compound, has recently been reported as an efficient tool for light-driven modulation of excitation-contraction coupling (ECC) in human-induced pluripotent stem cells–derived cardiomyocytes. However, the exact biophysical mechanism of this process remains incompletely understood.

Methods

To address this, we performed a detailed electrophysiological characterization in a more mature cardiac model, specifically adult mouse ventricular myocytes (AMVMs).

Results

Our in vitro results demonstrate that Ziapin2 can photomodulate cardiac ECC in mature AMVMs without affecting the main transporters and receptors located within the sarcolemma. We established a connection between Ziapin2-induced membrane thickness modulation and light-generated action potentials by showcasing the pivotal role of stretch-activated channels (SACs). Notably, our experimental findings, through pharmacological blockade, suggest that non-selective SACs might serve as the biological culprit responsible for the effect.

Conclusions

Taken together, these findings elucidate the intricacies of Ziapin2-mediated photostimulation mechanism and open new perspectives for its application in cardiac research.
Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism
Authors: Baytas Ozan , Davidson Shawn M. , Kauer Julie A. , Morrow Eric M.
Published: November 2024

Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2-null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2-null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2-null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.
Histamine H3 receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization during resting state: an exploratory cortex-wide imaging study in mice
Authors: Kaita Sentaro , Morishita Yoshikazu , Kobayashi Kenta , Nomura Hiroshi
Published: November 2024

The histaminergic system plays a key role in modulating learning and memory, wakefulness, and energy balance. Histamine H3 receptors constitutively inhibit the synthesis and release of histamine and other neurotransmitters. Therefore, H3 receptor inverse agonists/antagonists increase the synthesis and release of these neurotransmitters, enhancing cognitive functions, including memory consolidation and retrieval. Spontaneous neural activity across the cerebral cortex is essential for cognitive function, including memory consolidation. Abnormal spontaneous activity has, in fact, been associated with cognitive dysfunctions and psychiatric disorders. Given the cognitive improvement achieved with the use of H3 receptor inverse agonists/antagonists, we examined the effects of two inverse agonists/antagonists – thioperamide and pitolisant – on spontaneous cortical activity, using in vivo wide-field Ca2+ imaging. Changes in cortical activity, across multiple cortical regions and in inter-regional connectivity, from pre- to post-administration were evaluated using a linear support vector machine decoder. Thioperamide and pitolisant both modified the amplitude distribution of calcium events across multiple cortical regions, including a reduction in the frequency of low-amplitude calcium events in the somatosensory cortex. Graph theory analysis revealed increases in centrality measures in the somatosensory cortex with the use of both thioperamide and pitolisant, indicative of their importance in the organization of cortical networks. These findings indicate that H3 receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization of activity in the cerebral cortex during the resting state.
Modification of the COPSOQ adapted for the IT sector – a journey of validation and insight for futures research, prognosis global risks
Authors: Gren Maria
Published: November 2024

This study presents the validation process of the Copenhagen Psychosocial Questionnaire (COPSOQ) adapted for the IT sector, focusing on its reliability and validity within a German-speaking context (IT professionals in Austria). The COPSOQ is an established instrument for assessing psychosocial work environment factors. While previous research has highlighted its applicability across various cultural settings, this paper delves into its psychometric properties through exploratory factor analysis (EFA) using a sample of 200 IT professionals. The survey, conducted online, adapted the German COPSOQ including additional items relevant to the IT work environment, with some items being removed for greater efficiency and specificity. The analysis yielded seven factors, explaining 52.2% of the variance and reflecting key psychosocial dimensions: job identification, influencing factors, life satisfaction, self-determination, social support, life-dominant balance, and job concerns. The paper argues for the removal of certain items with loadings below .40 to enhance the questionnaire's economy and efficiency. Furthermore, it suggests that the refined COPSOQ could be a more effective tool for assessing work stress among IT workers, potentially leading to better-informed workplace interventions and improved prognosis for employee well-being. This research underscores the importance of adapting psychosocial assessment tools to specific industry contexts, providing a robust foundation for future studies on the work environment and its impact on quality of life and job satisfaction among IT professionals, and addressing global risks associated with workplace stress. Additionally, the paper ties these findings with broader global risks, such as technology-induced stress and the future of work, which are critical for developing resilient organizational frameworks.
Stress drives premature hive exiting behavior that leads to death in young honey bee (Apis mellifera) workers
Authors: Ellis Jordan Twombly , Rangel Juliana
Published: November 2024

Background

The Western honey bee, Apis mellifera, is an economically important pollinator, as well as a tractable species for studying the behavioral intricacies of eusociality. Honey bees are currently being challenged by multiple biotic and environmental stressors, many of which act concomitantly to affect colony health and productivity. For instance, developmental stress can lead workers to become precocious foragers and to leave the hive prematurely. Precocious foragers have decreased flight time and lower foraging efficiency, which can ultimately lower colony productivity and even lead to colony collapse.

Materials and methods

In this study, we tested the hypothesis that stress during pupal development can cause young workers to exit the hive prematurely before they are physically able to fly. This premature exiting behavior results in death outside the hive soon thereafter. To determine how various stressors may lead bees to perform this behavior, we subjected workers during the last pupal stage to either cold stress (26 °C for 24 h), heat stress (39 °C for 24 h), or Varroa destructor mite parasitization, and compared the rate of premature hive exits between stressed bees and their respective control counterparts. Upon emergence, we individually tagged focal bees in all treatment groups and introduced them to a common observation hive. We then followed tagged bees over time and monitored their survivorship, as well as their likelihood of performing the premature hive exiting behavior. We also dissected the hypopharyngeal glands of all treatment and control bees sampled.

Results

We found that significantly more bees in all three treatment groups exited the hive prematurely compared to their control counterparts. Bees in all treatment groups also had significantly smaller hypopharyngeal glands than control bees.

Conclusions

Our results suggest that premature hive exiting behavior is driven by stress and is potentially a form of accelerated age polyethism that leads to premature death.
Distribution of Candida species isolated from people living with human immunodeficiency virus with oropharyngeal and oral candidiasis in Africa in the era of universal test and treat policy: a systematic review and meta-analysis
Authors: Musinguzi Benson , Obuku Ekwaro A. , Mwesigwa Alex , Migisha Richard , Kinengyere Alison Annet , Ndagire Regina , Baguma Andrew , Okek Erick Jacob , Olum Ronald , Itabangi Herbert , Mboowa Gerald , Sande Obondo James , Achan Beatrice
Published: November 2024

Background

The introduction of antiretroviral therapy (ART) and the implementation of the human immunodeficiency virus (HIV) universal test and treat (UTT) policy have led to a decline in the incidence of opportunistic infections. However, oropharyngeal and oral candidiasis remain prevalent and continue to pose challenges among people living with human immunodeficiency virus (PLHIV) in Africa, indicating the need for a better understanding of the distribution of Candida species responsible for these infections. This systematic review and meta-analysis aimed to determine the distribution of Candida species isolated from PLHIV with oropharyngeal and oral candidiasis in Africa in the era of UTT policy.

Methods

The review followed the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. A comprehensive search was conducted to identify eligible studies to be included in the meta-analysis and analysed using a random effects model in STATA version 17.

The risk of bias was assessed using the Joanna Briggs Institute quality assessment tool.

Results

Fourteen studies with 4281 participants were included in the review. Overall, 2095 Candida isolates were reported, 78.7% (1650/2095) of which were C. albicans, 19.6% (410/2095), non-albicans Candida (NAC), and 1.7% (35/2095) could not be identified to the Candida specific species level. The most prevalent NAC species were C. glabrata (26.3%), followed by C. tropicalis (24.9%), C. krusei (15.6%), C. parapsilosis (11%), and C. dubliniensis (6.3%). The pooled prevalence of oropharyngeal and oral candidiasis was 48% (95% CI 34–62%). The prevalence of oropharyngeal candidiasis was higher in the pre-UTT era, at 56% (95% CI 40–72%, p < 0.001), than in the post-UTT era, at 34% (95% CI 10–67%, p < 0.001). The risk of bias assessment revealed that 71.4% (10/14) of the included studies had a low risk of bias and that 28.6% (4/14) had a moderate risk of bias.

Conclusions

While C. albicans remain, the predominant species causing oropharyngeal and oral candidiasis among PLHIV in Africa, NAC species also contribute significantly to the infection burden. Despite ART and UTT policies, oropharyngeal candidiasis remains prevalent, emphasizing the need for targeted interventions.
Cell fusion dynamics: mechanisms of multinucleation in osteoclasts and macrophages
Authors: Sabe Hideaki , Yahara Yasuhito , Ishii Masaru
Published: November 2024

Cell–cell fusion is a vital biological process where the membranes of two or more cells merge to form a syncytium. This phenomenon is critical in various physiological and pathological contexts, including embryonic development, tissue repair, immune responses, and the progression of several diseases. Osteoclasts, which are cells from the monocyte/macrophage lineage responsible for bone resorption, have enhanced functionality due to cell fusion. Additionally, other multinucleated giant cells (MGCs) also arise from the fusion of monocytes and macrophages, typically during chronic inflammation and reactions to foreign materials such as prostheses or medical devices. Foreign body giant cells (FBGCs) and Langhans giant cells (LGCs) emerge only under pathological conditions and are involved in phagocytosis, antigen presentation, and the secretion of inflammatory mediators. This review provides a comprehensive overview of the mechanisms underlying the formation of multinucleated cells, with a particular emphasis on macrophages and osteoclasts. Elucidating the intracellular structures, signaling cascades, and fusion-mediating proteins involved in cell–cell fusion enhances our understanding of this fundamental biological process and helps identify potential therapeutic targets for disorders mediated by cell fusion.
A deep learning based automatic two-dimensional digital templating model for total knee arthroplasty
Authors: Park Jaeseok , Kim Sung Eun , Kim Back , Lee Sanggyu , Lee Jae-Jun , Ro Du Hyun
Published: November 2024

Background

Preoperative templating is an important step for total knee arthroplasty (TKA), facilitating hospital personnel in the anticipation and preparation of necessary surgical resources. Despite its importance, this process currently lacks automation. This study aimed to develop an artificial intelligence (AI) model to automate implant size prediction.

Methods

A total of 13,281 (2938 anteroposterior, 10,343 lateral) knee radiographs obtained from the authors’ institute were utilized for model training, with 2302 (1034 anteroposterior, 1268 lateral) images set apart for validation and testing. The templating AI model integrates a pipeline composed of multiple steps for automated implant size estimation. To predict implant size, anterioposterior (AP) and lateral radiograph predictions were merged, selecting the smaller of the predicted sizes to prevent implant overhang. The model’s size predictions were validated with 81 real TKA data set apart from the training data, and its accuracy was compared to that of manual templating by an orthopedic specialist. Predictions matching the actual implanted sizes were labeled “exact” and those within one size, “accurate.” The influence of patient characteristics on the model’s prediction accuracy was also analyzed. The measurement time elapsed for implant sizing was recorded for both the AI model and the orthopedic specialist. Implant position predicted by the model was validated by comparing insert locations with postoperative images.

Results

Compared with data from 81 actual TKA procedures, the model provided exact predictions for 39.5% of femoral and 43.2% of tibial components. Allowing a one-size margin of error, 88.9% of predictions were deemed “accurate” for both components. Interobserver reliability (Cohen’s kappa) were 0.60 and 0.70 for femoral and tibial implants, respectively, both classified as “substantial.” The orthopedic specialist produced results accurate within one-size margin of error in 95.1% and 100% of cases for femoral and tibial components, respectively. Interobserver reliability between the orthopedic specialist and ground truth was 0.76 and 0.8 for femoral and tibial components, respectively. The measurement time per case was 48.7 s for the AI model, compared with 97.5 s for the orthopedic specialist. Compared with postoperative radiographs, predicted implant position had an error of less than 4 mm on average.

Conclusions

An AI-based templating tool for TKA was successfully developed, demonstrating satisfactory accuracy and efficiency. Its application could significantly reduce the clinical workload in TKA preparation.
Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial
Authors: Langerbeins Petra , Robrecht Sandra , Nieper Pascal , Cramer Paula , Fürstenau Moritz , Al-Sawaf Othman , Simon Florian , Fink Anna-Maria , Kreuzer Karl-Anton , Vehling-Kaiser Ursula , Tausch Eugen , Schneider Christof , Müller Lothar , Eckart Michael Josef , Schlag Rudolf , Freier Werner , Gaska Tobias , Balser Christina , Reiser Marcel , Stauch Martina , Zahn Mark-Oliver , Dörfel Steffen , Staib Peter , Behlendorf Timo , Hensel Manfred , Hebart Holger , Klaproth Holger , Block Andreas , Liersch Rüdiger , Hauch Ulrich , Heinrich Bernhard , Wendtner Clemens-Martin , Fischer Kirsten , Stilgenbauer Stephan , Eichhorst Barbara , Hallek Michael
Published: November 2024

PURPOSE

The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies.

METHODS

The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments.

RESULTS

Ibrutinib significantly delayed progression to symptomatic disease (
P
< .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases (
P
= .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group.

CONCLUSION

Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.
Unveiling Swelling and Erosion Dynamics: Early Development Screening of Mirabegron Extended Release Tablets
Authors: Sousa Ana S. , Serra J. , Estevens C. , Costa R. , Ribeiro António J.
Published: November 2024

Although the development of extended release (ER) matrices has been extensively investigated, understanding the most appropriate mechanism of drug release to achieve the desired release remains a cost- and time-consuming challenge in the early stages of formulation development. This study aimed to investigate the early stage of developing ER hydrophilic matrix tablets containing mirabegron as a model drug, focusing on the effects of polymer type, diluent type, and polymer amount on critical quality attributes (CQAs), namely, tablet swelling and erosion behavior. A full factorial design was employed to explore the interactions of control factors through multivariate regression analysis, emphasizing the application of quality by design (QbD) principles. The swelling and erosion performances of 72 formulations were evaluated. The swelling data were fitted to the Vergnaud model. Finally, in vitro drug release profiles were investigated for four of the formulations studied. The polymer type, diluent type, and polymer amount had distinct effects on the swelling and erosion behavior of the ER matrix tablets. Compared with those with isomalt (G720) or dextrate (DXT), formulations with polyethylene glycol 8000 (P8000) consistently exhibited greater swelling. Additionally, higher molecular weight was correlated with increased swelling within the same polymer type. Hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO)-based formulations showed higher swelling rates, while polyvinyl alcohol (PVA-80) displayed the highest erosion percentage. The findings highlight the significance of incorporating early-stage screening designs to maximize efficiency and optimize time and resource. This approach enables the development of a comprehensive understanding of drug release mechanisms from ER matrix tablets.

Graphical abstract
User-Friendliness Evaluation of Handling pMDI with Various Add-on Devices in Asthmatic Patients
Authors: Abdelfattah Ahmed M. , Sarhan Rania M. , Madney Yasmin M. , Mady Ahmed F. , Abdelrahim Mohamed E. A. , Harb Hadeer S.
Published: November 2024

The objective of this study was to assess the use of pMDI alone and pMDI with different spacers in asthmatic patients and to identify any associations between errors in handling the device for the first time and the sessions needed to reach the correct handling method, considering patient demographics and clinical characteristics. A total of 150 Asthmatic patients were crossed over to handle pMDI alone and with add-on inhalable devices (Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8) randomly, without receiving verbal or demonstrative instruction (baseline assessment). The assessment of the inhaler technique was performed using checklists that had been set beforehand. Subsequently, the proper utilization of the inhaler was exhibited, and the patient's inhaler usage was reassessed. The demonstration was repeated until an optimal technique was attained. The number of counselling attempts required to achieve successful management, together with patient demographics and clinical factors, were documented. The mean percentage of total errors at baseline shows that pMDI alone is significantly higher than pMDI attached to add-on devices (53.90 ± 9.71, 32.54 ± 13.93, 24.53 ± 14.93, 21.6 ± 14.48, 25.14 ± 10.99, 27.47 ± 10.28) for pMDI alone, Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8 respectively at p < 0.01. Able and Tips Haler spacers are significantly lower than other spacers with pMDI and pMDI alone in terms of total sessions needed to attain the complete optimal handling technique at p < 0.01. Weak and very weak correlations were observed between the percentage of total errors at baseline and the total sessions with education years, Montreal Cognitive Assessment, and age as well as some demographics and clinical variables. Handling pMDI can be challenging however the introduction of spacers simplifies this procedure. Different spacers cannot be treated as a homogeneous group due to variations in handling techniques and ease of use. the Able spacer requires the fewest handling steps of any spacer and has the highest percentage of patients who can use it without assistance.

Graphical Abstract
Double encephalocele in a four-year-old girl: A case report with literature review
Authors: Khizar Ahtesham , Zahid Hassaan , Khan Manal , Farooq Abdul Rahim , Natt Muhammad Aqeel
Published: November 2024

Encephalocele is a congenital neural tube defect (NTD). The pathophysiology of the NTDs is exceedingly complex. Numerous explanations have been proposed to explain it. Double encephaloceles are highly unusual. There have only been fifteen previously reported cases of double encephalocele in the medical literature, with this index case being the oldest and first from Pakistan. A four-year-old girl presented with two occipital scalp swellings from infancy. The occipital swelling measured about 7x5x3 cm, while the suboccipital swelling measured about 7x9x5 cm. The skin over both the swellings was intact. Following a thorough history, physical examination, and radiological investigations, surgical excision and repair was performed. Postoperative recovery was uneventful. She did not develop hydrocephalus until the three month follow-up.Double encephalocele is a rare entity. The multisite closure theory appears to be the most plausible explanation for the development of multiple NTDs. The management of double encephalocele requires a case based approach.
Abbreviations:NTD: Neural tube defect, CT: Computed tomography,MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid.
doi: https://doi.org/10.12669/pjms.40.12(PINS).10964
How to cite this: Khizar A, Zahid H, Khan M, Farooq AR, Natt MA. Double encephalocele in a four-year-old girl: A case report with literature review. Pak J Med Sci. 2024;40(12):S80-S86. doi: https://doi.org/10.12669/pjms.40.12(PINS).10964
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Incidence of postoperative cerebrospinal fluid leaks in endoscopic endonasal transsphenoidal surgery for pituitary adenomas without sellar floor reconstruction: A retrospective observational study from a low-middle-income country
Authors: Kiran Sumira , Ikram Shuja , Khizar Ahtesham , Iftikhar Muhammad Kaleem , Qadri Haseeb Mehmood , Umer Muhammad Waqas , Anwar Khawar , Bashir Asif
Published: November 2024

Objectives: To determine the incidence of postoperative cerebrospinal fluid (CSF) leaks after endoscopic endonasal transsphenoidal surgery (EETS) for pituitary adenomas without sellar floor reconstruction (SFR).
Methods: This retrospective observational study was conducted at Department of Neurosurgery, Punjab Institute of Neurosciences (PINS), Lahore, Pakistan from January, 2018 to December, 2022. It is a non-probability based consecutive case series. A total of 316 patients meeting the inclusion criteria were selected.
Results: Among the 316 patients, 102 (32.3%) were male, while 214 (67.7%) were female. Mean age was 40.98±7.8 SD (range 23 to 65 years). Regarding size of pituitary adenomas, 19 (6%) were microadenomas and 297 (94%) were macroadenomas. Overall postoperative CSF (poCSF) leak in our patients was 2.8%. Among cases with poCSF leak, 4 (3.9%) were male and five were female (2.3%) with the P-value of 0.477. Regarding size of pituitary adenomas, only one (5.3%) microadenoma had poCSF leak whereas 8 (2.7%) macroadenomas had poCSF leak with the P-value of 0.432.
Conclusion: Pituitary adenomas can be successfully treated with EETS without SFR in patients who do not experience intraoperative CSF leak.
List of Abbreviations: CSF: Cerebrospinal fluid, EETS: Endoscopic endonasal transsphenoidal surgery, ioCSF: Intraoperative CSF, poCSF: Postoperative CSF, SFR: Sellar Floor Reconstruction, T1WI: T1 weighted image, T1WI C+: T1 weighted image with contrast, T2WI: T2 weighted image.
doi: https://doi.org/10.12669/pjms.40.12(PINS).11109
How to cite this: Kiran S, Ikram S, Khizar A, Iftikhar MK, Qadri HM, Umer MW, et al. Incidence of postoperative cerebrospinal fluid leaks in endoscopic endonasal transsphenoidal surgery for pituitary adenomas without sellar floor reconstruction: A retrospective observational study from a low-middle-income country. Pak J Med Sci. 2024;40(12):S20-S24. doi: https://doi.org/10.12669/pjms.40.12(PINS).11109
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Effect of Bilateral Subthalamic Nucleus (STN) Deep Brain Stimulation (DBS) on drug reduction for Parkinson’s Disease: A retrospective observational study from Pakistan
Authors: Khan Zubair Mustafa , Ahmad Shahzeb , Qadri Haseeb Mehmood , Khizar Ahtesham , Bashir Asif
Published: November 2024

Objectives: To determine the effect of Bilateral Subthalamic Nucleus (STN) Deep Brain Stimulation (DBS) on drug reduction for Parkinson’s disease (PD) in a low-middle-income country.
Methods: This retrospective cohort study included 49 patients following interview based questionnaires who underwent bilateral STN DBS at the Department of Neurosurgery, Punjab Institute of Neurosciences, Lahore, Pakistan over five years (July 30, 2018 to June 29, 2023). Patients meeting the inclusion and exclusion criteria (49 patients) were selected and the effect of bilateral STN DBS on drug reduction was evaluated.
Results: Following bilateral STN for Parkinsons Disease Levodopa equivalent daily dose (LEDD) and Unified Parkinson’s Disease Rating Scale (UPDRS)-III results were statistically significant, with a P-value of 0.0001. Effect of DBS on UPDRS-IV was 0.2751, which is statistically insignificant. LEDD reduced by 55.03% (P<0.0001), UPRS-III improved by 80.49% (P<0.0001), and UPDRS-IV improved by 1% (P<0.0001). Time spent with dyskinesia reduced by 17.54% (P<0.0001), whereas time spent off period reduced 22.44% (P<0.0001).
Conclusion: When the disease is in its early stages and has not yet manifested advanced Parkinsons symptoms, bilateral STN DBS is an effective treatment option. It considerably reduces the need for levodopa and significantly improves the motor symptoms of rigidity, tremors, and bradykinesia.
List of abbreviations: STN: Subthalamic nucleus, DBS: Deep brain stimulation, PD: Parkinson’s disease, MSA: Multiple system atrophy, PSP: Progressive supranuclear palsy, CBD: Corticobasal degeneration, UPDRS: Unified Parkinson’s Disease Rating Scale, MMSE: Mini mental state examination, MoCA: Montreal cognitive assessment, LEDD: Levodopa equivalent daily dose, PWP: People with Parkinson’s, SEM: Standard error of mean, CI: Confidence interval, LMICs: Low and Middle Income Countries, LEDD: Levo dopa equivalent daily dose, UPDRS: Unified Parkinson’s Disease Rating Scale.
doi: https://doi.org/10.12669/pjms.40.12(PINS).11111
How to cite this: Khan ZM, Ahmad S, Qadri HM, Khizar A, Bashir A. Effect of Bilateral Subthalamic Nucleus (STN) Deep Brain Stimulation (DBS) on drug reduction for Parkinson’s Disease: A retrospective observational study from Pakistan. Pak J Med Sci. 2024;40(12):S25-S31.  doi: https://doi.org/10.12669/pjms.40.12(PINS).11111
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Punjab Institute of Neurosciences: Annual Report 2023
Authors: Bashir Asif , Qadri Haseeb Mehmood , Bashir Momin
Published: November 2024

doi: https://doi.org/10.12669/pjms.40.12(PINS).11420
How to cite this: Bashir A, Qadri HM, Bashir M. Punjab Institute of Neurosciences: Annual Report 2023. Pak J Med Sci. 2024;40(12):S4-S5.  doi: https://doi.org/10.12669/pjms.40.12(PINS).11420
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Acute effects of virtual reality exercise bike games on psychophysiological outcomes in college North-African adolescents with cerebral palsy: A randomized clinical trial
Authors: Soudani Makrem , Farhat Faical , Ghram Amine , Ben Saad Helmi , Chlif Mehdi
Published: November 2024

Background Cerebral palsy (CP) is a neurological disorder that can affect motor skills and psychophysiological well-being. Virtual Reality Exercise (VRE) improves cognitive and physical outcomes in patients with CP. Therefore, this study aimed to investigate the effects of VRE on attention, vigor, and decision-making abilities in adolescents with CP. Methods A randomized controlled trial was conducted. The intervention consisted of a single 40-minute session of VRE compared to TE conducted in a controlled laboratory environment. Results Fourteen participants (42.9 % female) were included in this analysis. The results indicated that VRE had a statistically significant positive effect on attention and vigor compared to TE. While participants in the VRE group exhibited enhanced attention levels and reported elevated levels of vigor subsequent to the exercise sessions, the memory results did not reach statistical significance. Conclusions The findings suggest that VRE is an effective intervention for improving attention and vigor in adolescents with CP. Registration Pan African Clinical Trial Registry (PACTR202308598603482; 31/08/2023). The trial was reported in accordance with the CONSORT reporting guidelines.
Can indoor plants reduce formaldehyde levels in the anatomy dissection hall? A study to evaluate the practicality of using plants in reducing formaldehyde levels
Authors: Joshi Adish G , Punja Dhiren , Punja Rohini
Published: November 2024

Background Formaldehyde a commonly used embalming fluid for the preservation of cadavers, produces numerous short and long-term side effects on the students and staff working with it. Indoor plants have been shown to reduce atmospheric formaldehyde levels. The purpose of the study was to compare the efficacy of indoor plants in reducing formaldehyde levels in ambient air to levels deemed safe by WHO standards Methods The study was conducted in the storage room of the Anatomical dissection hall. 7 potted plants of one variety were kept in the storage room for 14 days and the Formaldehyde reading was measured using a VOC (Volatile Organic Compound) monitor. Then the same was done with no plant. This cycle was repeated 2 more times, with two different plant species. The three spieces of plants used for this study were as follows: Dracaena trifasciata, Epipremnum aureum, Spathiphyllum. Results The results were analysed and compared and it was determined that the effect of having a plant present versus having no plant present on the Formaldehyde concentration in the air was inconclusive as Dracaena trifasciata failed to reject the null hypothesis altogether (p-value>0.05), while Epipremnum aureum and Spathiphyllum rejected the null hypothesis (p-value<0.05), however they both had a weak positive correlation with formaldehyde concentration. Conclusion The efficacy of indoor plants in reducing formaldehyde levels in ambient air needs to be further explored and validated since all the prior studies conducted were in controlled environment and should be done in a real time scenario for its practical and beneficial uses.
Interventions and implementation considerations for reducing pre-treatment loss to follow-up in adults with pulmonary tuberculosis: A scoping review
Authors: Mulaku Mercy , Owino Eddy Johnson , Ochodo Eleanor , Young Taryn
Published: November 2024

Background Tuberculosis (TB) is a leading cause of death worldwide with over 90% of reported cases occurring in low- and middle-income countries (LMICs). Pre-treatment loss to follow-up (PTLFU) is a key contributor to TB mortality and infection transmission. Objectives We performed a scoping review to map available evidence on interventions to reduce PTLFU in adults with pulmonary TB, identify gaps in existing knowledge, and develop a conceptual framework to guide intervention implementation. Methods We searched eight electronic databases up to February 6 2024, medRxiv for pre-prints, and reference lists of included studies. Two review authors independently selected studies and extracted data using a predesigned form. We analysed data descriptively, presented findings in a narrative summary and developed a conceptual framework based on the Practical, Robust Implementation, and Sustainability Model to map the factors for effective intervention implementation. Results We reviewed 1262 records and included 17 studies. Most studies were randomized controlled trials (8/17, 47%). Intervention barriers included stigma and inadequate resources; enablers included mobile phones and TB testing and results on the same day. We identified eight interventions that reduced PTLFU: treatment support groups; mobile notifications; community health workers; integrated HIV/TB services; Xpert MTB/RIF as the initial diagnostic test; computer-aided detection with chest radiography screening; active linkage to care; and multi-component strategies. Conclusion Given the variation of healthcare settings, TB programs should consider contextual factors such as user acceptability, political commitment, resources, and infrastructure before adopting an intervention. Future research should utilize qualitative study designs, be people-centred, and include social and economic factors affecting PTLFU.