bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter phase 2 study of romidepsin plus lenalidomide for previously untreated peripheral T-cell lymphoma
Authors: Ruan Jia , Zain Jasmine , Palmer Brett , Jovanovic Borko , Mi Xinlei , Swaroop Alok , Winter Jane N. , Gordon Leo I. , Karmali Reem , Moreira Jonathan , Petrich Adam M. , Pro Barbara
Published: June 2023

Peripheral T-cell lymphomas (PTCLs) are associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a chemotherapy-free combination of romidepsin plus lenalidomide as initial treatment for patients with PTCL who were aged >60 years or noncandidates for chemotherapy. Treatment was initiated with romidepsin 10 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg taken orally from days 1 to 21 of 28-day cycle for up to 1 year. The primary objective was overall response rate (ORR). Secondary objectives included safety and survival. The study enrolled 29 patients with a median age of 75 years, including 16 (55%) angioimmunoblastic T-cell lymphoma (AITL), 10 (34%) PTCL– not otherwise specified, 2 ATLL, and 1 EATL. Grade 3 to 4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%), and anemia (28%). Grade 3 to 4 nonhematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), and infection (10%). At median follow-up of 15.7 months, 23 patients were evaluable and received a median treatment of 6 cycles. The ORR was 65.2% with complete response (CR) at 26.1%, including 78.6% ORR and 35.7% CR for AITL. Median duration of response was 10.7 months, with 27.1 months for patients achieving CR. The estimated 2-year progression-free survival was 31.5%, and 2-year overall survival was 49.5%. This study provides the first demonstration that the biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as #NCT02232516.
PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma
Authors: Brown-Burke Fiona , Hwang Inah , Sloan Shelby , Hinterschied Claire , Helmig-Mason JoBeth , Long Mackenzie , Chan Wing Keung , Prouty Alexander , Chung Ji-Hyun , Zhang Yang , Singh Satishkumar , Youssef Youssef , Bhagwat Neha , Chen Zhengming , Chen-Kiang Selina , Di Liberto Maurizio , Elemento Olivier , Sehgal Lalit , Alinari Lapo , Vaddi Kris , Scherle Peggy , Lapalombella Rosa , Paik Jihye , Baiocchi Robert A.
Published: June 2023

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that comprises up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is 5 years, and for most patients who progress on targeted agents, survival remains at a dismal 3 to 8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives antitumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of prosurvival AKT signaling, which led to the nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing identified multiple proapoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382, and the BCL-2 inhibitor, venetoclax. Single-agent and combination treatments were performed in 9 MCL lines. Loewe synergy scores showed significant levels of synergy in most MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with an increased survival advantage in 2 patient-derived xenograft models (P ≤ .0001, P ≤ .0001). Our results provide mechanistic rationale for the combination of PRMT5 inhibition and venetoclax to treat patients with MCL.
Event-related potential (ERP) markers of 22q11.2 deletion syndrome and associated psychosis
Authors: Francisco Ana A. , Foxe John J. , Molholm Sophie
Published: June 2023

22q11.2 deletion syndrome (22q11.2DS) is a multisystemic disorder characterized by a wide range of clinical features, ranging from life-threatening to less severe conditions. One-third of individuals with the deletion live with mild to moderate intellectual disability; approximately 60% meet criteria for at least one psychiatric condition.

22q11.2DS has become an important model for several medical, developmental, and psychiatric disorders. We have been particularly interested in understanding the risk for psychosis in this population: Approximately 30% of the individuals with the deletion go on to develop schizophrenia. The characterization of cognitive and neural differences between those individuals who develop schizophrenia and those who do not, despite being at genetic risk, holds important promise in what pertains to the clarification of paths to disease and to the development of tools for early identification and intervention.

Here, we review our previous event-related potential (ERP) findings as potential markers for 22q11.2DS and the associated risk for psychosis, while discussing others’ work. We focus on auditory processing (auditory-evoked potentials, auditory adaptation, and auditory sensory memory), visual processing (visual-evoked potentials and visual adaptation), and inhibition and error monitoring.

The findings discussed suggest basic mechanistic and disease process effects on neural processing in 22q11.2DS that are present in both early sensory and later cognitive processing, with possible implications for phenotype. In early sensory processes, both during auditory and visual processing, two mechanisms that impact neural responses in opposite ways seem to coexist—one related to the deletion, which increases brain responses; another linked to psychosis, decreasing neural activity. Later, higher-order cognitive processes may be equally relevant as markers for psychosis. More specifically, we argue that components related to error monitoring may hold particular promise in the study of risk for schizophrenia in the general population.
Outcomes following transcatheter repair in patients with functional mitral regurgitation not receiving guideline directed medical therapy in Israel
Authors: Leibowitz David , Haberman Dan , Goland Sorel , George Jacob , Beeri Ronen , Planer David , Wolf Rafael , Kutsher Becky , Hasin Tal , Shuvy Mony
Published: June 2023

Background

Transcatheter edge to edge repair (TEER) improves prognosis in patients with functional mitral regurgitation (FMR) receiving guideline directed medical therapy (GDMT). Many patients with FMR do not receive GDMT and the utility of TEER in this population remains unclear.

Methods

We retrospectively studied patients undergoing TEER. Clinical, echocardiographic and procedural variables were recorded. GDMT was defined as use of RAAS inhibitors and MRAs unless GFR was under 30 as well as beta blockers. The primary endpoint of the study was one year mortality.

Results

168 patients (mean age 71.3 ± 9.3; 66% males) with FMR who underwent TEER were included of whom 116 (69%) received GDMT at the time of TEER and 52 (31%) did not. There were no significant demographic or clinical differences between the groups. There were no significant differences in procedural success and complications between groups. One year mortality was identical in the two groups (15% vs. 15%; RR 1.06, CI 0.43–2.63, P = 0.90).

Conclusions

Our findings suggest that procedural success and one year mortality following TEER was not significantly different in HFREF patients with FMR with or without GDMT. Larger, prospective studies are necessary to define the benefit of TEER in this population.
Effects of an educational compact intervention in self-care – a mixed methods study with postgraduate trainees in primary care
Authors: Schwill Simon , Bugaj Till Johannes , Rentschler Annalena , Nikendei Christoph , Szecsenyi Joachim , Krug Katja
Published: June 2023

Background

Multiple studies indicate that residents in family medicine (FM) are exposed to considerable stress and are particularly affected by burnout syndrome. Aim of the study was to specify the effects of a so-called “compact intervention” (i.e., a short intervention) in self-care on FM residents.

Methods

The authors performed a concurrent and independent mixed-methods study with FM residents on the KWBW VerbundweiterbildungPLUS© program. FM residents could voluntarily take part in a two-day seminar including 270 min on self-care, which can be regarded as a compact intervention. Study participants completed a questionnaire before (T1) and ten to twelve weeks after the course (T2), with subsequent recruitment to interview. The main outcomes of the quantitative part were to evaluate (I) self-rated change of cognition and (II) change in behavior. The qualitative outcomes were all possible effects of the compact intervention on participants´ competencies as well as all sorts of induced behavioral changes.

Results

From a total of n = 307 residents, n = 287 FM residents (intervention group: n = 212; control group: n = 75) participated in the study. At T2, 111 post-intervention questionnaires were completed. 56% rated the intervention to be helpful for their well-being (n = 63/111). At T2, there was a significant increase in those willing to act in comparison to T1 (p = .01): 36% (n = 40/111) had changed their behavior and half of the study participants had passed on competencies to others (n = 56/111). From the intervention group, n = 17 participants additionally gave an interview. FM residents favored a trustful learning atmosphere, an interactive teaching concept and practical exercises. They described an encouraging stimulus to act and specified behavioral changes.

Conclusions

A compact intervention in self-care could increase well-being, foster competencies and induce behavioral changes, if implemented into a training program with sufficient group cohesiveness. Further studies are required to specify long-term-results.
Expectations on implementation of a health promotion practice using individually targeted lifestyle interventions in primary health care: a qualitative study
Authors: Strid Emma Nilsing , Wallin Lars , Nilsagård Ylva
Published: June 2023

Background

There is moderate to strong evidence of the effectiveness of health-promotion interventions, but implementation in routine primary health care (PHC) has been slow. In the Act in Time project implementation support is provided for a health promotion practice using individually targeted lifestyle interventions in a PHC setting. Identifying health care professionals’ (HCPs’) perceptions of barriers and facilitators helps adapt implementation activities and achieve a more successful implementation. This study aimed, at a pre-implementation stage, to describe the expectations of managers, appointed internal facilitators (IFs) and HCPs on implementing a healthy lifestyle-promoting practice in PHC.

Methods

In this qualitative study five focus group discussions with 27 HCPs and 16 individual interviews with managers and appointed IFs were conducted at five PHC centres in central Sweden. The PHC centres are participating in the Act in Time project, evaluating the process and outcomes of a multifaceted implementation strategy for a healthy lifestyle-promoting practice. A deductive qualitative content analysis based on the Consolidated Framework for Implementation Research (CFIR) was followed using inductive analysis.

Results

Twelve constructs from four of five CFIR domains were derived: Innovation characteristics, Outer setting, Inner setting, and Characteristics of individuals. These domains are related to the expectations of HCPs to implement a healthy lifestyle-promoting practice, which includes facilitating factors and barriers. The inductive analysis showed that the HCPs perceived a need for a health-promotion approach to PHC. It serves the needs of the patients and the expectations of the HCPs, but lifestyle interventions must be co-produced with the patient. The HCPs expected that changing routine practice into a healthy lifestyle-promoting practice would be challenging, requiring sustainability, improved structures, cooperation in inter-professional teams, and a common purpose. A collective understanding of the purpose of changing practice was vital to successful implementation.

Conclusions

The HCPs valued implementing a healthy lifestyle-promoting practice in a PHC setting. However, changing routine methods was challenging, implying that the implementation strategy should address obstacles and facilitating factors identified by the HCPs.

Trial registration

This study is part of the Act in Time project, registered in ClinicalTrials.gov with the numberNCT04799860. Registered 03 March 2021.
The effect of calcium supplementation on calcium and bone metabolism during load carriage in women: protocol for a randomised controlled crossover trial
Authors: Coombs Charlotte V. , Wardle Sophie L. , Shroff Rukshana , Eisenhauer Anton , Tang Jonathan C. Y. , Fraser William D. , Greeves Julie P. , O’Leary Thomas J.
Published: June 2023

Background

Military field exercises are characterised by high volumes of exercise and prolonged periods of load carriage. Exercise can decrease circulating serum calcium and increase parathyroid hormone and bone resorption. These disturbances to calcium and bone metabolism can be attenuated with calcium supplementation immediately before exercise. This randomised crossover trial will investigate the effect of calcium supplementation on calcium and bone metabolism, and bone mineral balance, during load carriage exercise in women.

Methods

Thirty women (eumenorrheic or using the combined oral contraceptive pill, intrauterine system, or intrauterine device) will complete two experimental testing sessions either with, or without, a calcium supplement (1000 mg). Each experimental testing session will involve one 120 min session of load carriage exercise carrying 20 kg. Venous blood samples will be taken and analysed for biochemical markers of bone resorption and formation, calcium metabolism, and endocrine function. Urine will be collected pre- and post-load carriage to measure calcium isotopes for the calculation of bone calcium balance.

Discussion

The results from this study will help identify whether supplementing women with calcium during load carriage is protective of bone and calcium homeostasis.

Trial registration

NCT04823156 (clinicaltrials.gov).
Randomized, prospective, multicenter trial assessing the numen coil embolization system in the endovascular treatment of small intracranial aneurysms: outcomes from the CATCH Trial
Authors: Jin Yazhou , Guo Xinbin , Quan Tao , Zhao Rui , Li Tianxiao , Zhao Zhenwei , Yang Hua , Zhu Xingen , Liang Guobiao , Leng Bing , Wu Xin , Wang Yang , Guan Sheng
Published: June 2023

Background and purpose

The CATCH (Coil Application Trial in China) trial was designed to assess the safety and efficacy of the Numen Coil Embolization System in the treatment of intracranial aneurysms in comparison with the Axium coil (ev3/Medtronic). Although the endovascular treatment of small (< 5 mm) intracranial aneurysms has been reported with favorable long-term clinical and angiographic outcomes, randomized trials are still lacking. Data for aneurysms smaller than 5 mm were extracted from the CATCH trial.

Materials and methods

A randomized, prospective, multicenter trial was conducted at ten centers throughout China. Enrolled subjects with small intracranial aneurysms were randomly assigned to receive treatment with the Numen Coil or the Axium coil. The primary outcome was successful aneurysm occlusion at the 6-month follow-up. In contrast, the secondary outcomes included complete aneurysm occlusion, recurrence rate, clinical deterioration, and safety data at the 6-month and 12-month follow-ups.

Results

A total of 124 patients were enrolled in the study. Overall, 58 patients were assigned to the Numen group, and 66 were assigned to the Axium group. At the 6-month follow-up, the successful aneurysm occlusion rate was 93.1% (54/58) in the MicroPort NeuroTech group and 97.0% (64/66) in the Axium group, with a common odds ratio of 0.208 (95% confidence interval, 0.023–1.914; P = 0.184). Complications were comparable between the groups.

Conclusions

Compared with the Aixum coil, the Numen coil is safe and effective in treating small intracranial aneurysms.

Trial registration

(13/12/2016, NCT02990156)
Intraoperative serum lactate levels as a prognostic predictor of outcome for emergency abdominal surgery: a retrospective study
Authors: Sugita Shinji , Ishikawa Masashi , Sakuma Takahiro , Iizuka Masumi , Hanai Sayako , Sakamoto Atsuhiro
Published: June 2023

Background

The relationship between intraoperative lactate levels and prognosis after emergency gastrointestinal surgery remains unclear. The purpose of this study was to investigate the prognostic value of intraoperative lactate levels for predicting in-hospital mortality, and to examine intraoperative hemodynamic managements.

Methods

We conducted a retrospective observational study of emergency GI surgeries performed at our institution between 2011 and 2020. The study group comprised patients admitted to intensive care units postoperatively, and whose intraoperative and postoperative lactate levels were available. Intraoperative peak lactate levels (intra-LACs) were selected for analysis, and in-hospital mortality was set as the primary outcome. The prognostic value of intra-LAC was assessed using logistic regression and receiver operating characteristic (ROC) curve analysis.

Results

Of the 551 patients included in the study, 120 died postoperatively. Intra-LAC in the group who survived and the group that died was 1.80 [interquartile range [IQR], 1.19–3.01] mmol/L and 4.22 [IQR, 2.15–7.13] mmol/L (P < 0.001), respectively. Patients who died had larger volumes of red blood cell (RBC) transfusions and fluid administration, and were administered higher doses of vasoactive drugs. Logistic regression analysis showed that intra-LAC was an independent predictor of postoperative mortality (odds ratio [OR] 1.210, 95% CI 1.070 –1.360, P = 0.002). The volume of RBCs, fluids transfused, and the amount of vasoactive agents administered were not independent predictors. The area under the curve (AUC) of the ROC curve for intra-LAC for in-hospital mortality was 0.762 (95% confidence interval [CI], 0.711–0.812), with a cutoff value of 3.68 mmol/L by Youden index.

Conclusions

Intraoperative lactate levels, but not hemodynamic management, were independently associated with increased in-hospital mortality after emergency GI surgery.
Learning does not just happen: establishing learning principles for tools to translate resilience into practice, based on a participatory approach
Authors: Haraldseid-Driftland Cecilie , Lyng Hilda Bø , Guise Veslemøy , Waehle Hilde Valen , Schibevaag Lene , Ree Eline , Fagerdal Birte , Baxter Ruth , Ellis Louise A. , Braithwaite Jeffrey , Wiig Siri
Published: June 2023

Background

Theories of learning are of clear importance to resilience in healthcare since the ability to successfully adapt and improve patient care is closely linked to the ability to understand what happens and why. Learning from both positive and negative events is crucial. While several tools and approaches for learning from adverse events have been developed, tools for learning from successful events are scarce. Theoretical anchoring, understanding of learning mechanisms, and establishing foundational principles for learning in resilience are pivotal strategies when designing interventions to develop or strengthen resilient performance. The resilient healthcare literature has called for resilience interventions, and new tools to translate resilience into practice have emerged but without necessarily stipulating foundational learning principles. Unless learning principles are anchored in the literature and based on research evidence, successful innovation in the field is unlikely to occur. The aim of this paper is to explore: What are key learning principles for developing learning tools to help translate resilience into practice?

Methods

This paper reports on a two-phased mixed methods study which took place over a 3-year period. A range of data collection and development activities were conducted including a participatory approach which involved iterative workshops with multiple stakeholders in the Norwegian healthcare system.

Results

In total, eight learning principles were generated which can be used to help develop learning tools to translate resilience into practice. The principles are grounded in stakeholder needs and experiences and in the literature. The principles are divided into three groups: collaborative, practical, and content elements.

Conclusions

The establishment of eight learning principles that aim to help develop tools to translate resilience into practice. In turn, this may support the adoption of collaborative learning approaches and the establishment of reflexive spaces which acknowledge system complexity across contexts. They demonstrate easy usability and relevance to practice.
A systematic review of the psychosocial factors associated with pain in children with juvenile idiopathic arthritis
Authors: Brandelli Yvonne N. , Chambers Christine T. , Mackinnon Sean P. , Parker Jennifer A. , Huber Adam M. , Stinson Jennifer N. , Wildeboer Emily M. , Wilson Jennifer P. , Piccolo Olivia
Published: June 2023

Background

Pain is one of the most frequently reported experiences amongst children with Juvenile Idiopathic Arthritis (JIA); however, the management of JIA pain remains challenging. As pain is a multidimensional experience that is influenced by biological, psychological, and social factors, the key to effective pain management lies in understanding these complex relationships. The objective of this study is to systematically review the literature on psychosocial factors of children with JIA and their caregivers 1) associated with and 2) predictive of later JIA pain intensity, frequency, and sensitivity in children 0–17 years of age.

Methods

The Joanna Briggs Institute methodology for etiology and risk and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guided the conduct and reporting of this review. Terms related to pain and JIA were searched in English without date restrictions across various databases (PubMed, CINAHL, PsycINFO, Embase, Scopus, and the Cochrane Central Register of Controlled Trials) in September 2021. Two independent reviewers identified, extracted data from, and critically appraised the included studies. Conflicts were resolved via consensus.

Results

Of the 9,929 unique studies identified, 61 were included in this review and reported on 516 associations. Results were heterogeneous, likely due to methodological differences and moderate study quality. Results identified predominantly significant associations between pain and primary and secondary appraisals (e.g., more child pain beliefs, lower parent/child self-efficacy, lower child social functioning), parent/child internalizing symptoms, and lower child well-being and health-related quality of life. Prognostically, studies had 1-to-60-month follow-up periods. Fewer beliefs of harm, disability, and no control were associated with lower pain at follow-up, whereas internalizing symptoms and lower well-being were predictive of higher pain at follow-up (bidirectional relationships were also identified).

Conclusions

Despite the heterogeneous results, this review highlights important associations between psychosocial factors and JIA pain. Clinically, this information supports an interdisciplinary approach to pain management, informs the role of psychosocial supports, and provides information to better optimize JIA pain assessments and interventions. It also identifies a need for high quality studies with larger samples and more complex and longitudinal analyses to understand factors that impact the pain experience in children with JIA.

Trial registration

PROSPERO CRD42021266716.
A role for P-selectin and complement in the pathological sequelae of germinal matrix hemorrhage
Authors: Hatchell Devin , Alshareef Mohammed , Vasas Tyler , Guglietta Silvia , Borucki Davis , Guo Chunfang , Mallah Khalil , Eskandari Ramin , Tomlinson Stephen
Published: June 2023

Background

Germinal matrix hemorrhage is a devastating disease of pre-term infancy commonly resulting in post-hemorrhagic hydrocephalus, periventricular leukomalacia, and subsequent neurocognitive deficits. We demonstrate vascular expression of the adhesion molecule P-selectin after GMH and investigate a strategy to specifically target complement inhibition to sites of P-selectin expression to mitigate the pathological sequelae of GMH.

Methods

We prepared two fusion proteins consisting of different anti-P-selectin single chain antibodies (scFv’s) linked to the complement inhibitor Crry. One scFv targeting vehicle (2.12scFv) blocked the binding of P-selectin to its PSGL-1 ligand expressed on leukocytes, whereas the other targeting vehicle (2.3scFv) bound P-selectin without blocking ligand binding. Post-natal C57BL/6 J mice on day 4 (P4) were subjected to collagenase induced-intraventricular hemorrhage and treated with 2.3Psel-Crry, 2.12Psel-Crry, or vehicle.

Results

Compared to vehicle treatment, 2.3Psel-Crry treatment after induction of GMH resulted in reduced lesion size and mortality, reduced hydrocephalus development, and improved neurological deficit measurements in adolescence. In contrast, 2.12Psel-Crry treatment resulted in worse outcomes compared to vehicle. Improved outcomes with 2.3Psel-Crry were accompanied by decreased P-selectin expression, and decreased complement activation and microgliosis. Microglia from 2.3Psel-Crry treated mice displayed a ramified morphology, similar to naïve mice, whereas microglia in vehicle treated animals displayed a more ameboid morphology that is associated with a more activated status. Consistent with these morphological characteristics, there was increased microglial internalization of complement deposits in vehicle compared to 2.3Psel-Crry treated animals, reminiscent of aberrant C3-dependent microglial phagocytosis that occurs in other (adult) types of brain injury. In addition, following systemic injection, 2.3Psel-Crry specifically targeted to the post-GMH brain. Likely accounting for the unexpected finding that 2.12Psel-Crry worsens outcome following GMH was the finding that this construct interfered with coagulation in this hemorrhagic condition, and specifically with heterotypic platelet–leukocyte aggregation, which express P-selectin and PSGL-1, respectively.

Conclusions

GMH induces expression of P-selectin, the targeting of which with a complement inhibitor protects against pathogenic sequelae of GMH. A dual functioning construct with both P-selectin and complement blocking activity interferes with coagulation and worsens outcomes following GMH, but has potential for treatment of conditions that incorporate pathological thrombotic events, such as ischemic stroke.
Ultrasound-mediated blood–brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer’s disease
Authors: Mehta Rashi I. , Carpenter Jeffrey S. , Mehta Rupal I. , Haut Marc W. , Wang Peng , Ranjan Manish , Najib Umer , D’Haese Pierre-François , Rezai Ali R.
Published: June 2023

Background

Focused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer’s disease (AD).

Methods

At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI.

Results

Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24–48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant.

Conclusions

FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics.

Trial registration: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018
Acceptability of donated breast milk among pregnant women in selected hospitals in central Uganda: a cross-sectional study
Authors: Namuddu Mary Gorreth , Kiguli Juliet , Nakibuuka Victoria , Nantale Ritah , Mukunya David
Published: June 2023

Background

Donated breast milk is considered beneficial to vulnerable infants. Thus, Uganda launched its first human milk bank in November 2021 to provide breast milk to preterm, low birthweight and sick babies. However, there is a scarcity of information on the acceptability of donated breast milk in Uganda. The study sought to assess the acceptability of using donated breast milk and associated factors among pregnant women at a private and a public hospital in central Uganda.

Methods

This cross-sectional study enrolled pregnant women attending antenatal care at the selected hospitals between July and October 2020. All pregnant women recruited had already given birth to at least one child. Data were collected using a semi-structured questionnaire, and we recruited participants through systematic sampling. Used frequencies, percentages and means with standard deviations to summarize variables. Assessed the association between the acceptability of donated milk and selected factors by comparing their arithmetic means using a generalized linear model to allow for clustering at the health facility level. Used a normal distribution and an identity link and calculated the adjusted mean differences together with 95% CIs [generated using robust variance estimators to correct for model misspecification].

Results

A total of 244 pregnant women with a mean age of 30 (± 5.25) years were enrolled. Sixty-one-point 5% (150/244) of the women reported that they would accept donated breast milk. Higher education (adjusted mean difference, technical versus primary level: 1.33; 95% CI 0.64, 2.02), being Muslim (adjusted mean difference, Muslim versus Christian: 1.24; 95% CI 0.77, 1.70), having heard of donated breast milk banking (adjusted mean difference, ever versus never: 0.62; 95% CI 0.18, 1.06) and presence of a serious medical condition (adjusted mean difference, preference of donated milk versus other feeds in a serious medical condition: 3.96; 95% CI, 3.28, 4.64) were associated with acceptability of donated breast milk.

Conclusions

The acceptability of using donated breast milk for infant feeding was high among pregnant women. Public sensitization and education campaigns are indispensable for the acceptability of donated milk. These programs should be designed to include women with lower education levels.
GAU-PED study for early diagnosis of Gaucher disease in children with splenomegaly and cytopenia
Authors: Pession Andrea , Di Rocco Maja , Venturelli Francesco , Tappino Barbara , Morello William , Santoro Nicola , Giordano Paola , Filippini Beatrice , Rinieri Simona , Russo Giovanna , Girardi Katia , Ruggiero Antonio , Galea Eulalia , Antonucci Roberto , Tovaglieri Nicola , Porta Fulvio , Tartaglione Immacolata , Giona Fiorina , Fagioli Franca , Burlina Alberto ,   Pediatric Gaucher Study Group, Mura Rosamaria , Russo Bambina , Tornesello Assunta , Menna Giuseppe , Russo Delia , Caniglia Maurizio , Schettini Sergio , Onofrillo Daniela , Ladogana Saverio , Civino Adele
Published: June 2023

Background

Gaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD.

Materials and methods

DBS samples were collected and tested for β-glucocerebrosidase enzyme activity for 154 patients selected through the algorithm proposed by Di Rocco et al. Patients showing β-glucocerebrosidase activity below normal values were recalled to confirm the enzyme deficiency with the gold standard essay on cellular homogenate. Patients tested positive at the gold standard analysis were evaluated through GBA1 gene sequencing.

Results

14 out of 154 patients were diagnosed with GD, with a prevalence of 9.09% (5.06–14.78%, CI 95%). Hepatomegaly, thrombocytopenia, anemia, growth delay/deceleration, elevated serum ferritin, elevated Lyso-Gb1 and chitotriosidase were significantly associated with GD.

Conclusions

GD prevalence in a pediatric population at high-risk appeared to be higher compared to high-risk adults. Lyso-Gb1 was associated with GD diagnosis. The algorithm proposed by Di Rocco et al. can potentially improve the diagnostic accuracy of pediatric GD, allowing the prompt start of therapy, aiming to reduce irreversible complications.
Prevalence and risk factors for laminitis within the Norwegian pony breed Nordlandshest/Lyngshest
Authors: Lykkjen Sigrid , Stenbakk Linda Koldal , Holmøy Ingrid Hunter
Published: June 2023

Background

Laminitis is a systemic condition resulting in debilitating pain and structural changes within the feet, and hence has major welfare implications. Causes include endocrine and systemic inflammatory conditions. Ponies are frequently affected, and observations in the field suggest that occurrence of laminitis is also common in Norwegian breeds. The aim of this study was to estimate the prevalence and risk factors for laminitis within the Norwegian pony breed Nordlandshest/Lyngshest.

Results

The study was a cross-sectional study based on questionnaires sent to members of the Norwegian Nordlandshest/Lyngshest breed association. Questionnaires were received for 504 animals, of which 464 records were eligible and included in analyses. The population comprised 71 stallions, 156 geldings, and 237 mares, with an age between 1 and 40 years (median and interquartile ranges: 12 (6–18) years). The estimated 3-year period prevalence of laminitis was 8.4% (95% confidence interval (CI95): 6.0–11.3%), whereas lifetime prevalence was 12.5% (CI95: 9.6–15.9%). Mares had a significantly higher period- and lifetime prevalence of laminitis than male horses, and horses 10 years and older had a significantly higher prevalence than younger horses. The lifetime prevalence of laminitis was 3.2% in horses 9 years and younger, whereas from 17.3–20.5% in older horses. Multivariable logistic regression analysis identified age, sex, and regional adiposity as significantly (P < 0.05) associated with the 3-year period outcome of laminitis: Horses older than 9 years had a three-fold increase in the likelihood of having laminitis compared to the younger horses (Odds Ratio (OR)10–14 years = 3.37 (CI95 = 1.19–9.50), OR15-19 years = 3.06 (CI95 = 1.04–9.05), and OR>20 years = 2.70 (CI95 = 0.90–8.02). Mares were more than twice as likely (OR = 2.44 (CI95 = 1.17–5.12) to have laminitis compared to male horses, and horses with regional adiposity had increased odds (OR = 2.35 (CI95 = 1.15–4.82) of laminitis compared to horses without regional adiposity.

Conclusions

Laminitis appears to be a considerable welfare issue in the Norwegian pony breed Nordlandshest/Lyngshest. The identified risk factors age, sex, and regional adiposity highlight the need for improved owner education and awareness of strategies to reduce laminitis risk.
Towards measuring effective coverage: critical bottlenecks in quality- and user-adjusted coverage for major depressive disorder in São Paulo metropolitan area, Brazil
Authors: Henriques Franca Mariane , Bharat Chrianna , Novello Ercole , Hwang Irving , Medina-Mora Maria Elena , Benjet Corina , Andrade Laura Helena , Vigo Daniel V. , Viana Maria Carmen
Published: June 2023

Background

Major depressive disorder (MDD) contributes to a significant proportion of disease burden, disability, economic losses, and impact on need of treatment and health care in Brazil, but systematic information about its treatment coverage is scarce. This paper aims to estimate the gap in treatment coverage for MDD and identify key bottlenecks in obtaining adequate treatment among adult residents in the São Paulo Metropolitan area, Brazil.

Methods

A representative face-to-face household survey was conducted among 2942 respondents aged 18+ years to assess 12-month MDD, characteristics of 12-month treatment received, and bottlenecks to deliver care through the World Mental Health Composite International Diagnostic Interview.

Results

Among those with MDD (n = 491), 164 (33.3% [SE, 1.9]) were seen in health services, with an overall 66.7% treatment gap, and only 25.2% [SE, 4.2] received effective treatment coverage, which represents 8.5% of those in need, with a 91.5% gap in adequate care (66.4% due to lack of utilization and 25.1% due to inadequate quality and adherence). Critical service bottlenecks identified were: use of psychotropic medication (12.2 percentage points drop), use of antidepressants (6.5), adequate medication control (6.8), receiving psychotherapy (19.8).

Conclusions

This is the first study demonstrating the huge treatment gaps for MDD in Brazil, considering not only overall coverage, but also identifying specific quality- and user-adjusted bottlenecks in delivering pharmacological and psychotherapeutic care. These results call for urgent combined actions focused in reducing effective treatment gaps within services utilization, as well as in reducing gaps in availability and accessibility of services, and acceptability of care for those in need.
Impact of COVID-19 on the lives of people with severe mental illness—front-line community psychiatry workers observation from a provincial survey of assertive community treatment teams in Ontario, Canada
Authors: Kassam Aly , Beder Michaela , Sediqzadah Saadia , Levy Matthew , Ritts Madeleine , Maher John , Kirwan Nicole , Law Samuel
Published: June 2023

Using an online survey distributed to members of the provincial organization that represents the 88 Assertive Community Treatment (ACT) and Flexible ACT teams in Ontario, Canada, this descriptive study relied on the unique vantage points and observations of the front-line community psychiatry workers who maintained contact with patients through outreach and telecommunication during the height of COVID-19. The patients who suffer from serious mental illness (SMI) were uniquely affected by COVID-19 due to the changes, reduction or shut down of many essential clinical and community support services. Thematic and quantitative analyses of the workers’ observations highlighted 6 main areas of note, including significant social isolation and loneliness, clinical course deterioration and life disruption, increased hospital and ER use, police and legal contacts, and substance abuse and related deaths. There were also encouraging signs of positive adaptations in terms of independence and resilience. Reflections of these impacts and potential ameliorating approaches are further discussed.
Cervical collar use following anterior cervical hybrid surgery: protocol for a prospective randomized, time-controlled trial
Authors: He Junbo , Liu Qingyu , Yang Zijiao , Liu Hao , Wu Tingkui , Ding Chen , Huang Kangkang , Wang Beiyu
Published: June 2023

Introduction

Cervical hybrid surgery (HS) combines anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) to establish an individualized surgical plan for patients with multiple cervical disc degenerative diseases. In order to maintain the stability of the spine after HS, an external cervical collar is often used. However, there is still controversy regarding the importance of a cervical collar following surgery. This study aims to determine whether the cervical collar is effective and how long it should be worn after surgery.

Methods

This is a randomized, single-center, prospective, parallel-controlled trial. Eligible participants will be selected according to the inclusion and exclusion criteria. The primary outcome is the neck disability index, which will be evaluated before surgery and at one week, 3 weeks, 6 weeks, 3 months, 6 months, and 12 months following surgery. The secondary outcomes consist of the Japanese Orthopedic Association Scores, MOS 36-item short-form health survey (SF-36), visual analog scale, Pittsburgh Sleep Quality Index (PSQI), Bazaz dysphagia scoring system, Falls Efficacy Scale, cervical collar satisfaction score, neck soft tissue assessment, and Braden Scale, as well as radiologic assessments for cervical lordosis, disc height of the operative levels, fusion rate, range of motion (ROM), and complications including anterior bone loss, prosthesis migration, and heterotopic ossification. The clinical and radiologic examinations were performed by investigators with no therapeutic relationship with the individual patient. All radiographs were examined by one independent radiologist.

Ethics and dissemination

The results of this study will be published in peer-reviewed journals and presented at conferences. Upon completion of this trial, our findings could provide an appropriate cervical collar-wearing guideline for patients receiving HS.

Trial registration

ChiCTR.org.cn ChiCTR2000033002. Registered on 2020–05-17.
Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents
Authors: Çapan İrfan , Hawash Mohammed , Jaradat Nidal , Sert Yusuf , Servi Refik , Koca İrfan
Published: June 2023

Background

The carbazole skeleton is an important structural motif occurring naturally or synthesized chemically and has antihistaminic, antioxidant, antitumor, antimicrobial, and anti-inflammatory activities.

Objectives

This study aimed to design and synthesize a novel series of carbazole derivatives and evaluate their antiproliferative and antioxidant activities.

Methods

The synthesized compounds were characterized utilizing HRMS,1H-, and13CAPT-NMR, and assessed for their anticancer, antifibrotic, and antioxidant effects utilizing reference biomedical procedures. In addition, the AutoDock Vina application was used to perform in-silico docking computations.

Results

A series of carbazole derivatives were synthesized and characterized in the current study. Compounds10and11were found to have a stronger antiproliferative effect than compounds2–5against HepG2, HeLa, and MCF7 cancer cell lines with IC50values of 7.68, 10.09, and 6.44 µM, respectively. Moreover, compound 9 showed potent antiproliferative activity against HeLa cancer cell lines with an IC50value of 7.59 µM. However, except for compound5, all of the synthesized compounds showed moderate antiproliferative activities against CaCo-2 with IC50values in the range of 43.7–187.23 µM. All of these values were compared with the positive control anticancer drug 5-Fluorouracil (5-FU). In addition, compound9showed the most potent anti-fibrotic compound, and the cellular viability of LX-2 was found 57.96% at 1 µM concentration in comparison with the positive control 5-FU. Moreover, 4 and 9 compounds showed potent antioxidant activities with IC50values of 1.05 ± 0.77 and 5.15 ± 1.01 µM, respectively.

Conclusion

Most of the synthesized carbazole derivatives showed promising antiproliferative, antioxidant, and antifibrotic biological effects, and further in-vivo investigations are needed to approve or disapprove these results.
The first facile optical density-dependent approach for the analysis of doxorubicin, an oncogenic agent accompanied with the co-prescribed drug; paclitaxel
Authors: Hamad Ahmed Abdulhafez
Published: June 2023

Doxorubicin (DRB) is an anthracycline oncogenic drug extracted from cultures of Streptomyces peucetius var. caesius. It is frequently recommended as an anti-neoplastic agent for the treatment of diverse malignancies. It exerts its antineoplastic effect either via inhibiting the enzyme topoisomerase II and/or via intercalation to DNA or reactive oxygen species generation. In the present article, the direct, simple, one-pot, somewhat eco-safe, and non-extractive spectrophotometric system was executed to track doxorubicin, a chemotherapeutic remedy, in the presence of paclitaxel, a naturally occurring Taxan antineoplastic radical, through the greenness rated method. DRB’s optical density was studied in various mediums and solvents to develop the current approach. An acidic ethanolic solution was found to increase the optical density of the sample significantly. At 480 nm., the most remarkable optical density was obtained. Various experimental factors, including intrinsic media, solvent, pH, and stability time, were investigated and controlled. The current approach achieved linearity within the 0.6–40.0 µg mL-1 range, accompanied by a limit of both detection and quantification (LOD and LOQ) of 0.18 and 0.55 µg mL-1, correspondingly. The approach was validated under the ICH guidelines (Quality Guidelines). The system’s greenness and enhancement degree were estimated.