bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma
Authors: Weber Jeffrey S. , Levinson Benjamin A. , Laino Andressa S. , Pavlick Anna C. , Woods David M.
Published: June 2022

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.
Mantle cell lymphoma presenting with severe upper gastrointestinal bleeding
Authors: Ali Khaled , Habib Mhd Baraa , Alloush Ferial , Yassin Mohamed A.
Published: June 2022

Introduction:

Although it usually involves extranodal sites such as the gastrointestinal tract in more than 80% of cases, mantle cell lymphoma is considered a rare cause of gastrointestinal bleeding, especially severe and life-threatening bleeding.

Patient concern:

A 60-year-old man with peptic ulcer disease, who presented with severe upper gastrointestinal (GI) bleeding and large gastric ulcer.

Diagnosis:

Primary gastric mantle cell lymphoma.

Interventions:

He was treated conservatively with blood transfusion and started on Traneximic acid for 3 days. Then, the patient underwent urgent hemostatic radiotherapy.

Outcomes:

The patient became stable and kept in the hospital for monitoring with a definite diagnosis of stage IV Mantle cell lymphoma is made.

Conclusion:

Mantle cell lymphoma should be kept in mind when assessing massive upper GI bleeding, as an unusual cause of bleeding gastric ulcer, given that bleeding is an uncommon presenting feature of GI lymphoma.
Effects of hydrodissection on anesthesia characteristics in ultrasound guided infraclavicular brachial plexus blockade
Authors: Er Samet , Baskan Semih , Akcay Murat , Akcay Feryal , Zengin Musa
Published: June 2022

Background:

The development of ultrasonography technology and its widespread application have increased peripheral nerve block applications, especially in limb surgeries, since it reduces complication rates and increases success rates in peripheral nerve block applications. However, even experienced physicians need to direct a large number of needles and injections for adequate local anesthetic spread, which can cause accidental vascular puncture and local anesthetic systemic toxicity. Such complications can be prevented by hydrodissection and a safer and successful anesthesia can be provided to patients in this study, it was aimed to investigate the effects of hydrodissection on anesthesia characteristics in the infraclavicular brachial plexus blockade.

Materials and methods:

Ninety patients were included in our study after approval by the Ethics Committee. These patients were randomly divided into 2 groups (Group I: Infraclavicular brachial plexus blockade with normal method and Group II: infraclavicular brachial plexus blockade with hydrodissection). After obtaining patient consent, monitoring and vascular access were provided. Group I patients were mixed with 30 mL of local anesthetic mixture (15 mL of distilled water and 15 mL of 0.5% bupivacaine), and Group II patients were treated with 15 mL of distilled water by hydrodissection and 15 mL of 0.5% bupivacaine anesthesia resident. Block characteristics were evaluated and recorded every 5 minutes for the first 30 minutes by a blinded observer. The sensory block score was 7, the total score was 14 or above, and the block was considered successful, and the patient was ready for surgery. Postoperative block removal times, analgesia, and complications were evaluated and recorded.

Results:

A significant difference was found between the sensory and motor block onset times and postoperative VAS scores between the normal and hydrodissection groups (P < .05). There were no significant differences in terms of block application times, postoperative block removal times, and complications between the groups.

Conclusion:

In this study, it has been shown that hydrodissection in peripheral nerve blocks does not lag in terms of block success and characteristics compared to normal methods, whereas anesthetists with less experience in peripheral nerve block experience obtain safer and more successful results in practice.
Caregiver Engagement Enhances Outcomes Among Randomized Control Trials of Transitional Care Interventions
Authors: Levoy Kristin , Rivera Eleanor , McHugh Molly , Hanlon Alexandra , Hirschman Karen B. , Naylor Mary D.
Published: June 2022

Background:

Fluctuations in health among chronically ill adults result in frequent health care transitions. Some interventions to improve patient outcomes after hospitalization include caregiver engagement as a core component, yet there is unclear evidence of the effects of this component on outcomes.

Objective:

The objective of this study was to synthesize evidence regarding the attention given to caregiver engagement in randomized control trials of transitional care interventions (TCIs), estimate the overall intervention effects, and assess caregiver engagement as a moderator of intervention effects.

Methods:

Three databases were systematically searched for randomized control trials of TCIs targeting adults living with physical or emotional chronic diseases. For the meta-analysis, overall effects were computed using the relative risk (RR) effect size and inverse variance weighting.

Results:

Fifty-four studies met criteria, representing 31,291 participants and 66 rehospitalizations effect sizes. Half (51%) the interventions lacked focus on caregiver engagement. The overall effect of TCIs on all-cause rehospitalizations was nonsignificant at 1 month (P=0.107, k=29), but significant at ≥2 months [RR=0.89; 95% confidence interval (CI): 0.82, 0.97; P=0.007, k=27]. Caregiver engagement moderated intervention effects (P=0.05), where interventions with caregiver engagement reduced rehospitalizations (RR=0.83; 95% CI: 0.75, 0.92; P=0.001), and those without, did not (RR=0.97; 95% CI: 0.87, 1.08; P=0.550). Interventions with and without caregiver engagement did not differ in the average number of components utilized, however, interventions with caregiver engagement more commonly employed baseline needs assessments (P=0.032), discharge planning (P=0.006), and service coordination (P=0.035).

Discussion:

Future TCIs must consistently incorporate the active participation of caregivers in design, delivery, and evaluation.
Contrasting the Social Cognitive and Metacognitive Capacities Among Patients With Schizophrenia and Autism Spectrum Disorders Enrolled in Psychiatric Rehabilitation
Authors: Dubreucq Julien , Martin Aude , Gabayet Franck , Plasse Julien , Wiesepape Courtney , Quilès Clélia , Verdoux Hélène , Franck Nicolas , Lysaker Paul H.
Published: June 2022

Unique deficits in synthetic metacognition have been found in schizophrenia when compared with other psychiatric conditions and community controls. Although persons with autism spectrum disorders (ASD) display similar deficits in social cognition relative to those with schizophrenia, to date no study has compared metacognitive function between these groups. We aimed to compare the metacognitive capacities of persons with schizophrenia and ASD and their associations with other outcomes (neurocognition, social cognition, depression, and quality of life). Fifty-six outpatients with schizophrenia or ASD (mean age, 32.50 [9.05]; 67.9% male) were recruited from two French Centers of Reference for Psychiatric Rehabilitation of the REHABase cohort. Evaluation included the Indiana Psychiatric Illness Interview, Metacognition Assessment Scale–Abbreviated, Movie for the Assessment of Social Cognition, and a large cognitive battery. Compared with those with schizophrenia, participants with ASD had higher self-reflectivity (p = 0.025; odds ratio, 1.38 [1.05–1.86]) in univariable analyses. Metacognitive deficits may be found in ASD with a profile that varies from what is found in schizophrenia. It is possible that methods for enhancing metacognitive abilities during psychiatric rehabilitation may be refined to assist adults with ASD to better manage their own recovery.
Assessing the Impact of Relationship Profile Test Scores, Self-Identified Ethnic Group, and Gender on Adult Attachment Style
Authors: Blanchard Mark P. , Jowers Callie E. , Huprich Steven K. , Porcerelli John , Haggerty Greg , Siefert Caleb
Published: June 2022

Research shows that the subscales of the Relationship Profile Test (RPT) are related to adult attachment. Gender differences have been implicated, but findings are inconsistent in terms of replication. A limited amount of research has been conducted on ethnic differences in the context of interpersonal dependency. This study aims to bridge the gap in the literature in terms of using the RPT to predict attachment styles and to assess gender and ethnic group differences in RPT scores. Four samples from various treatment settings were combined to yield a heterogeneous group of ethnically diverse men and women (N = 470) with a mean age of 31.96. No gender differences were observed; however, ethnic differences were noted, with the RPT scales predicting unique variance in secure and insecure attachment styles. This study evidences the incremental validity of the RPT scales when predicting adult attachment style with consideration of ethnic group differences, which can help inform the treatment and assessment process.
Fragility fracture management and FLS models in South Africa and Israel
Authors: Bernstein Brian P. , Duma Mlekeleli T.N. , Or Omer , Fisher-Negev Tamar , Weil Yoram
Published: June 2022

Osteoporosis is a common disease of the elderly. Many patients at high risk are neither identified nor treated. A Fracture Liaison Service is a coordinated model of care for secondary fracture prevention. Several national quality indicators have been published in each country to improve surgical treatment and osteoporosis medical treatment. Fracture Liaison Services in both countries have been created by local clinicians with different models depending on the medical geographic locations of patients and the local setup. The objective of this review is to describe the national guidelines and the current clinical treatment models for fragility fractures in South Africa and Israel. Successes and barriers to successful implementation have been identified and are summarized.
Osteoporosis management in the United States
Authors: Hoggard Timothy M. , Jeray Kyle J.
Published: June 2022

There are numerous organizational osteoporosis initiatives in the United States offering a variety of recommendations and guidelines. A common method of implementing these goals is centered around multidisciplinary provider teams with the broad task of diagnosis, treatment, and prevention of current and future osteoporosis related fractures. These teams have generally proved to be successful even though it remains debated, which specific provider specialty is ultimately responsible for osteoporosis care. The current United States healthcare infrastructure represents the significant obstacle in widespread adoption of successful treatment programs. The development of further quality standards and incorporation of fracture liaison services into reimbursement and funding models will allow for continued improvement in osteoporosis care.
Fragility Fracture Systems: International Perspectives - Asia & Australia
Authors: Tarrant Seth M. , Kim Ji Wan , Matsushita Takashi , Minehara Hiroaki , Noda Tomoyuki , Oh Jong-Keon , Park Ki Chul , Yamamoto Noriaki , Balogh Zsolt J.
Published: June 2022

Background:

The incidence and burden of fragility fractures have reached the level where comprehensive systematic care is warranted to optimize the care of these patients. Hip fractures are the most frequently lethal and independence level changing fragility fractures, responsible for 30-day mortality comparable to high-energy trauma patients with injury severity scores over 12. It is a reasonable expectation that countries have a hip fracture treating system of care in place for this high-risk population. This review explores the systems of care from the Asia-Pacific Perspective.

Methods:

From the International Orthopaedic Trauma Association's member societies, nations from the Asia-Pacific Region were requested to contribute with an overview of their fragility fracture management systems. The content or the review was standardized by a template of headings, which each country endeavored to cover.

Results:

Australia, Japan, and South Korea contributed voluntarily from the 5 member countries of the region. Each country has made considerable efforts and achievements with diverse approaches to standardize and improve the care of fragility fractures, particularly hip fractures. Beyond the individual nations’ efforts there is also an existing Asia-Pacific Collaborative. The data collection and in some counties the existence of a registry is promising; funding and recognition of the problem among competing health care budget priorities are common.

Conclusions:

Our review covers some of the countries with strongest economy and highest health care standards. The lack of a universal robust system for hip fracture care is apparent. The data collection from registry initiations is expected to drive system development further in these countries and hopefully fast track the development in other countries within the most populous geographical region of the Earth.
Overview of fracture liaison services in the UK and Europe: standards, model of care, funding, and challenges
Authors: Chesser Timothy J.S. , Javaid Muhammad Kassim , Mohsin Zaineb , Pari Carlotta , Belluati Alberto , Contini Achille , Caiaffa Vincenzo , Chana-Rodríguez Francisco , Gómez-Vallejo Jesus , Sánchez-Pérez Coral , Dailiana Zoe H. , Stefanou Nikolaos , Tosounidis Theodoros , Laurent Michaël , Putzeys Guy , Poeze Martijn , Ponsen Kees Jan
Published: June 2022

Fragility fractures represent a growing global problem, including in the United Kingdom and European countries. Reports demonstrate the benefits of national guidance and organized fragility fracture programs through fracture liaison services to deliver care to patients who sustain these injuries. The challenge of assembling multidisciplinary teams, providing routine screening of appropriate patients, and monitoring therapies where there is a known compliance problem, remains an obstacle to the success of fragility fracture treatment programs to all. Efforts should continue to introduce and maintain fracture liaison services through coordinated national approaches and advanced systems.
EURO-MUSCULUS/USPRM Dynamic Ultrasound Protocols for (Adult) Hip
Authors: Mezian Kamal , Ricci Vincenzo , Güvener Orhan , Jačisko Jakub , Novotný Tomáš , Kara Murat , Chang Ke-Vin , Naňka Ondřej , Pirri Carmelo , Stecco Carla , Dughbaj Muhammad , Jain Nitin B. , Özçakar Levent
Published: June 2022

In this dynamic scanning protocol, ultrasound assessment of the adult hip is described using different maneuvers for various conditions. Real-time patient examination and ultrasound scanning videos are coupled for convenience as well as for better insight. The text covers the common conditions around the hip where especially dynamic ultrasound scanning provides valuable information in addition to static imaging. The protocol is prepared by an international consensus of several experts in the field of musculoskeletal ultrasound.
Accessibility of Level III trauma centers for underserved populations: A cross-sectional study
Authors: Jarman Molly P. , Dalton Michael K. , Askari Reza , Sonderman Kristin , Salim Ali , Inaba Kenji
Published: June 2022

BACKGROUND

By providing definitive care for many, and rapid assessment, resuscitation, stabilization, and transfer to Level I/II centers when needed, Level III trauma centers can augment capacity in high resource regions and extend the geographic reach to lower resource regions. We sought to (1) characterize populations served principally by Level III trauma centers, (2) estimate differences in time to care by trauma center level, and (3) update national estimates of trauma center access.

METHODS

In a cross-sectional study (United States, 2019), we estimated travel time from census block groups to the nearest Level I/II trauma center and nearest Level III trauma center. Block groups were categorized based on the level of care accessible within 60 minutes, then distributions of population characteristics and differences in time to care were estimated.

RESULTS

An estimated 22.8% of the US population (N = 76,119,228) lacked access to any level of trauma center care within 60 minutes, and 8.8% (N = 29,422,523) were principally served by Level III centers. Black and American Indian/Alaska Native (AIAN) populations were disproportionately represented among those principally served by Level III centers (39.1% and 12.2%, respectively). White and AIAN populations were disproportionately represented among those without access to any trauma center care (26.2% and 40.8%, respectively). Time to Level III care was shorter than Level I/II for 27.9% of the population, with a mean reduction in time to care of 28.9 minutes (SD = 31.4).

CONCLUSION

Level III trauma centers are a potential source of trauma care for underserved populations. While Black and AIAN disproportionately rely on Level III centers for care, most with access to Level III centers also have access to Level I/II centers. The proportion of the US population with timely access to trauma care has not improved since 2010.

LEVEL OF EVIDENCE

Prognostic/Epidemiological; Level IV.
Time-keeping and decision-making in the cell cycle
Authors: Tyson John J. , Novák Béla
Published: June 2022

Cell growth, DNA replication, mitosis and division are the fundamental processes by which life is passed on from one generation of eukaryotic cells to the next. The eukaryotic cell cycle is intrinsically a periodic process but not so much a ‘clock’ as a ‘copy machine’, making new daughter cells as warranted. Cells growing under ideal conditions divide with clock-like regularity; however, if they are challenged with DNA-damaging agents or mitotic spindle disrupters, they will not progress to the next stage of the cycle until the damage is repaired. These ‘decisions’ (to exit and re-enter the cell cycle) are essential to maintain the integrity of the genome from generation to generation. A crucial challenge for molecular cell biologists in the 1990s was to unravel the genetic and biochemical mechanisms of cell cycle control in eukaryotes. Central to this effort were biochemical studies of the clock-like regulation of ‘mitosis promoting factor’ during synchronous mitotic cycles of fertilized frog eggs and genetic studies of the switch-like regulation of ‘cyclin-dependent kinases' in yeast cells. In this review, we uncover some secrets of cell cycle regulation by mathematical modelling of increasingly more complex molecular regulatory networks of cell cycle ‘clocks’ and ‘switches’.
Antifungal activity and potential mechanism of berberine hydrochloride against fluconazole-resistant Candida albicans
Authors: Huang Xiaoxue , Zheng Dongming , Yong Jiangyan , Li Yan
Published: June 2022

Introduction. The emergence of resistance to fluconazole in Candida albicans has made the clinical treatment of this microbe difficult. A potential strategy to address this problem involves diminishing fungal resistance to antimicrobial drugs.

Hypothesis. Berberine hydrochloride (BH), the primary active ingredient of the traditional Chinese medicine (TCM) Coptis, inhibits the growth of fluconazole-resistant C. albicans through its action on the high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway.

Aim. To examine the effect of BH on the HOG-MAPK pathway to assess the potential molecular mechanism by which BH inhibits fluconazole-resistant C. albicans.

Methodology. The minimum inhibitory concentration (MIC) of BH to fluconazole-resistant C. albicans was measured using the broth microdilution approach to determine the concentration of effective drug intervention. Changes in physiological functions regulated by the HOG-MAPK pathway in response to BH treatment were measured, as well as the expression of central signalling pathway genes and key downstream factors by qRT-PCR and Western blotting, respectively.

Results. BH inhibited fluconazole-resistant C. albicans and the sensitivity to fluconazole increased after BH treatment. At a concentration of 256 and 64 μg ml−1 BH may affect key downstream factors that regulate several physiological functions of C. albicans by upregulating the core genes expression of SLN1, SSK2, HOG1, and PBS2 in the HOG-MAPK pathway. Upregulation of GPD1, the key gene for glycerol synthesis, increased cell osmotic pressure. BH treatment increased the accumulation of reactive oxygen species by upregulating the expression of the key respiratory metabolism gene ATP11 and downregulating the expression of the superoxide dismutase gene SOD2. Furthermore, downregulation of mycelial-specific HWP1 hindered the morphological transformation of C. albicans and inhibition of the chitin synthase gene CHS3 and the β-(1,3) glucan synthase gene GSC1 impaired cytoderm integrity.

Conclusion. BH affects multiple target genes in diminishing the resistance of C. albicans strains to fluconazole. This effect may be related to the action of BH on the HOG-MAPK pathway.
The Feasibility of the Thai Sensory Profile Assessment Tool (TSPA) for Classifying the participants for Mind-Body intervention
Authors: Kanchanawong Thanaporn , Prasoetsang Thitichaya , Limvongvatana Faungfah , Ooraikul Ladarat , Kunapun Sukonta , Srikhamjak Tiam , Gomutbutra Patama
Published: June 2022

Background

The previous research found that multisensory interventions impact behavioral responses in healthy individuals and clinical populations, but few have been shown the impacts of Mind-Body intervention on cortisol levels in different sensory personalities. In Thailand, the earlier study found that the Thai Sensory Profile Assessment Tool (TSPA) had acceptable validity and reliability in classifying sensory personality called “sensory pattern”. The pattern is divided into sensory preference and sensory threshold, which is formulated from personal experience.

Objective

The main objective of this study is to examine the feasibility and interpretability of TSPA in classifying sensory patterns of participants attending Mind-Body Intervention consisting of Mindfulness-Based Flow Practice (MBFP) and Relax On-site program.

Materials and methods

There is a sub-study of a controlled cross-over trial study effect of a mindfulness intervention on anxiety and biomarkers in healthy nursing staff. For this study, we aim to categorize sensory patterns and find the feasibility of Mind-Body Intervention. Each participant was self-tested by TSPA before the intervention, either relaxation on-site or MBFP in the residential retreat program. The feasibility criteria include the time for finishing the test. The interpretability including participant’s comprehension and the classification phenotype provides insight into different effects of the intervention. The effect of MBFP and relaxation on-site was measured quantitatively by the change of morning cortisol before and after the intervention and qualitatively from satisfaction interviews after the intervention.

Results

The TSPA assessment takes an average time of 20 minutes. There is no complaint about the difficulty to understand participants. We classified participants by TSPA pattern into three groups by the sensory preference, including, 1) Balanced majority (14/20) have a moderate sensory preference and threshold, 2) low sensory preference for taste and smell (3/20), and 3) high sensory preference for sight smell and movement (3/20). At the same time, most participants show higher cortisol after relaxation on-site and decreased cortisol after MBFP.

Conclusions

This pilot study showed that TSPA can be a feasible tool for assessing the sensory preference of the participants to match the health promotion modalities appropriately. We also got a preliminary insight that people with low smell sensory preference, low smell sensory threshold, high sensory preference insight, and movement with moderate threshold showed differences in MBFP. However, it needs a larger sample, and a simpler questionnaire related to the MBFP intervention program to prove these initial findings.
The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy
Authors: Khan Chaitali , Baker Nicholas E.
Published: June 2022

It is important to understand how p53 suppresses tumorigenesis. P53 activity contributes to many instances of cell competition in mammals. This has not been seen for Drosophila p53, where the transcription factor Xrp1 is an effector of cell competition. Xrp1 is induced in a p53-dependent manner by DNA damage, and we report that Xrp1 mediates multiple functions of p53 in the DNA damage response, contributing to p53-dependent gene transcription and DNA damage-induced apoptosis. Differences in either Xrp1 or p53 activity, occurring between wild type and mutant cells experiencing mild genotoxic stress, both resulted in cell competition. Unexpectedly, cell competition due to differential p53 activity did not require Xrp1 but instead was restrained by Xrp1. We show that Xrp1 has a p53-independent role in removing genomically-altered cells. Both Xrp1 and p53 limit the accumulation of abnormal cells that results from genotoxicity, and we propose that genomic alterations enhance cellular growth of p53 mutant cells and promote cell competition, potentially contributing to the tumorigenesis in p53 mutants.
Feedforward attentional selection in sensory cortex
Authors: Westerberg Jacob A. , Schall Jeffrey D. , Woodman Geoffrey F. , Maier Alexander
Published: June 2022

Salient objects stand out (pop-out) from their surroundings, grabbing our attention. Whether this phenomenon is a consequence of bottom-up sensory processing or predicated on top-down influence is debated. We show that the neural computation of attentional pop-out is embedded in the earliest cortical sensory response, seemingly void of feedback from higher-level areas. We measured synaptic and spiking activity across cortical columns in mid-level area V4 of monkeys searching for an attention-grabbing stimulus. Indexed by reaction times and behavioral accuracy, attention was captured at variable times. This moment of attentional capture occurred within the earliest feedforward response, both in terms of timing and spatial location. Moreover, the magnitude of the earliest sensory response predicted reaction times. Crucially, errant attentional selection and consequent behavior was associated with errant selection in sensory cortex. Together, these findings demonstrate a dominant role for feedforward activation of sensory cortex for dictating attentional priority and subsequent behavior.

In brief

Why do certain objects stand out from their surroundings and seemingly grab our attention? In this study, Westerberg et al. determine that attentional selection for salient objects in our environment is computed in sensory cortex as soon as sensory information arrives.

Highlights

Early sensory responses in V4 predict attentional selection and behavioral responses

Errant attentional selection in sensory cortex precedes errant behavior

Tonic modulation of sensory cortex can regulate attentional selection
Non-falciparum malaria infections are as prevalent as P. falciparum among Tanzanian schoolchildren
Authors: Sendor Rachel , Mitchell Cedar L. , Chacky Frank , Mohamed Ally , Mhamilawa Lwidiko E. , Molteni Fabrizio , Nyinondi Ssanyu , Kabula Bilali , Mkali Humphrey , Reaves Erik J. , Serbantez Naomi , Kitojo Chonge , Makene Twilumba , Kyaw Thwai , Muller Meredith , Mwanza Alexis , Eckert Erin L. , Parr Jonathan B. , Lin Jessica T. , Juliano Jonathan J. , Ngasala Billy
Published: June 2022

Efforts to achieve malaria elimination need to consider both falciparum and non-falciparum infections. The prevalence and geographic distribution of four Plasmodium species were determined by real-time PCR using dried blood spots collected during the 2017 School Malaria Parasitological Survey of eight regions of Tanzania. Among 3,456 schoolchildren, 22% had P. falciparum, 24% P. ovale spp., 4% P. malariae, and 0.3% P. vivax. Ninety-one percent of P. ovale infections had very low parasite densities, based on amplification at later cycle thresholds. Sixty-four percent of P. ovale infections were single-species, and 35% of these were detected in low malaria endemicity regions. P. malariae infections were predominantly co-infections with P. falciparum (73%). P. vivax was largely detected in northern and eastern regions. Overall, 43% of children with P. falciparum were co-infected with at least one non-falciparum species. A large, previously under-appreciated burden of P. ovale spp. infection exists among Tanzanian schoolchildren.

Article Summary

A previously unrecognized burden of non-falciparum malaria infections was detected among Tanzanian schoolchildren in a 2017 cross-sectional study, with P. ovale spp. prevalence comparable to P. falciparum, and low-level prevalences of P. malariae and P. vivax detected.
Development and Preliminary Validation of the Group Cognitive Therapy Scale to Measure Therapist Competence
Authors: Nakashima Misuzu , Matsunaga Miki , Otani Makoto , Kuga Hironori , Fujisawa Daisuke
Published: June 2022

Objective

The aim of this research was to create a scale to assess the competency of therapists who conduct group cognitive behavioral therapy (G-CBT), which can serve as a tool to aid the continued training of therapists.

Methods

Three stepped studies were conducted. Study 1: Through literature review and experts’ consensus process, essential skills for G-CBT were articulated and were categorized according to the criteria of the Cognitive Therapy Scale, a well-established rating scale to evaluate clinicians’ skills in individual cognitive behavioral therapy. The list of those skills was organized into a rating scale. Study 2: Behavioral anchors were added to each skill and were classified by the levels of difficulty (beginner, intermediate, and advanced levels), based on the rating by G-CBT experts. Study 3: Interrater reliability and validity of the rating scale were examined in a sample of forty-one videotaped G-CBT sessions of actual clinical sessions and educational role-plays.

Results

A twelve-item Group Cognitive Therapy Scale was developed. It consists of eleven items that have been adopted from the original Cognitive Therapy Scale, with the addition of a new item called “Intervention Using Relationships with Other Participants.” This scale showed excellent internal consistency (Cronbach’s alpha: 0.95), satisfactory inter-rater reliability (interclass correlation coefficients: 0.65 - 0.88), and high predictive validity.

Conclusion

A novel rating scale to evaluate therapists’ competency in G-CBT was developed and successfully validated.
A Cell-Based Assay for Detection of Anti-Fibrillarin Autoantibodies in Systemic Sclerosis
Authors: Keppeke Gerson Dierley , Satoh Minoru , Kayser Cristiane , Matos Pedro , Hasegawa Tomoko , Tanaka Shin , Santos Larissa Diogenes , Amaral Rogerio Quintiliano , Rodrigues Silvia Helena , Coelho Andrade Luis Eduardo
Published: June 2022

Objectives

Anti-fibrillarin antibodies are useful for establishing diagnosis and predicting distinct clinical features in systemic sclerosis (SSc). Anti-fibrillarin produces a characteristic clumpy nucleolar pattern in indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA) that is useful to guide further testing in antigen-specific immunoassays (ASI). Immunoprecipitation (IP) is the gold standard ASI for anti-fibrillarin determination. We established a new anti-fibrillarin Cell-Based Assay (CBA) and compared its diagnostic performance with IP and ASI commercial kits. The clinical features of SSc patients with and without anti-fibrillarin antibodies were analyzed.

Methods

A TransMembrane Signal (TMS) was added to the human fibrillarin gene in order to drive the transgenic fibrillarin to the cytoplasmic membrane. HEp-2 cells transfected with a vector containing the TMS-fibrillarin were used as substrate for IFA in the CBA. Sixty-two samples with high-titer nucleolar pattern in HEp-2 IFA (41 clumpy and 21 homogeneous/punctate) were tested for anti-fibrillarin in the CBA, IP, line-blot and ELISA. Clinical SSc phenotype was evaluated in 106 patients according to positive/negative anti-fibrillarin result in the CBA.

Results

TMS-fibrillarin was properly located to the cytoplasmic membrane and recognized by human autoantibodies. Thirty-eight of 41 clumpy nucleolar samples (92.7%) and none of 21 samples with other nucleolar patterns were positive for anti-fibrillarin in the CBA. There was 100% agreement between the positive/negative results in the CBA and IP. Among the 38 CBA-positive samples, only 15 (39.5%) and 11 (29%) were considered positive for anti-fibrillarin in the line-blot and ELISA, respectively. Anti-fibrillarin was associated with higher frequency of diffuse cutaneous SSc (dcSSc) phenotype (72.7% vs 36.8%; p=0.022), cardiac involvement (36.4% vs 6.5%; p=0.001) and scleroderma renal crisis (18.2% vs 3.3% p = 0.028).

Conclusion

With an innovative strategy of targeting the transgenic autoantigen to the cell membrane, we developed a new straightforward assay for detection of anti-fibrillarin autoantibodies. This new CBA presented high sensitivity and specificity for the detection of anti-fibrillarin autoantibody, comparable to the gold standard IP. Moreover, anti-fibrillarin antibodies detected in the CBA identified patients with a higher frequency of dcSSc, cardiac and renal involvement.
Correlations Between EEG Spectral Power and Cerebral Perfusion in Adults Undergoing Extracorporeal Membrane Oxygenation
Authors: Khan Imad R. , Dar Irfaan A. , Johnson Thomas W. , Loose Emily , Xu Yama Y. , Santiago Esmeralda , Donohue Kelly L. , Marinescu Mark A. , Gosev Igor , Schifitto Giovanni , Choe Regine , Selioutski Olga
Published: June 2022

Objective

Patients with acute lung or heart failure can experience hypoxic ischemic brain injury resulting in neurovascular unit (NVU) dysfunction. The NVU couples brain activity and perfusion. Extracorporeal membrane oxygenation (ECMO) is used for refractory lung and/or heart failure and often necessitates sedation, obfuscating neurological assessments. We hypothesized that combining cerebral electrographic activity and perfusion monitoring can detect brain injury in adults undergoing ECMO.

Methods

Fast Fourier transformation was used to identify fast (α+β) and slow (δ) power bands from cEEG. Diffuse correlation spectroscopy (DCS) measured blood flow index (BFI), a surrogate of perfusion, daily in adults undergoing ECMO. Correlations between α+β/δ ratio (ABDR) and BFI were compared between patients who were grouped into brain-injured and uninjured groups by neurologic exam and neuroimaging findings.

Results

Ten patients (21-78 years old, five females, five brain-injured) underwent cEEG and DCS monitoring. Sixty-eight monitoring sessions (average 127 minutes/session) were analyzed. ABDR-BFI correlation was significantly higher in uninjured patients than brain-injured ones. Sedation did not significantly impact CBF-power band correlation.

Conclusions

Brain-injured patients exhibited significantly less correlation between brain activity and perfusion, possibly as a result of NVU dysfunction.

Significance

ABDR-BFI correlation can be measured continuously and noninvasively at the bedside and may represent a marker of NVU dysfunction.

Highlights

Quantitative EEG and diffuse correlative spectroscopy can be used to measure markers of brain injury noninvasively, continuously, and at the bedside.

Decreased ABDR-BFI correlation may be a marker of neurovascular decoupling in patients with hypoxic ischemic brain injury.

ABDR-BFI correlation may be independent of analgosedation, which is used heavily in patients undergoing ECMO.
Seroprevalence of SARS-CoV-2 and risk factors in Bantul Regency, Yogyakarta, Indonesia
Authors: Ahmad Riris Andono , Indriani Citra , Arisanti Risalia Reni , Nanda Ratih Oktri , Mahendradhata Yodi , Wibawa Tri
Published: June 2022

COVID-19 case counts in Indonesia inevitably underestimate the true cumulative incidence of infection due to limited barriers to testing accessibility and asymptomatic infections. Therefore, community-based serological data are essential for understanding the true prevalence of infections. This study aims to estimate the seroprevalence of SARS-CoV-2 infection and factors related to the seropositivity in Bantul Regency, Yogyakarta, Indonesia. A cross-sectional study involving 425 individuals in 40 clusters was conducted between March and April 2021. Participants were interviewed using an e-questionnaire developed in the Kobo toolbox to collect information on socio-demographic, COVID-19 suggestive symptoms, history of COVID-19 diagnosis and COVID-19 vaccination status. A venous blood sample was collected from each participant and tested for immunoglobulin G (Ig-G) SARS-CoV-2 antibody titers using the enzyme-linked immunosorbent assay (ELISA). Seroprevalence was 31.1% in the Bantul Regency: 34.2% in semi-urban and 29.9% in urban villages. However, there is no significant proportion difference between both areas. A significant difference was reported in the age group. Participants in the 55-64 age group demonstrated the highest seroprevalence (43.7%; p=0.00), with a higher risk compared to the other age group (aOR= 3.79; 95% CI, 1.46-9.85, p<0.05). Seroprevalence in the unvaccinated participants was 29.9%. Family clusters accounted for 10.6% of the total seropositive cases. No significant difference was observed between individual preventive actions and their mobility with seropositivity status. This study observed a discrepancy with COVID-19 confirmed cumulative incidence data reported in the same period (11 out of 1000 population), indicating silent transmission may have occurred within the community. Higher seroprevalence in semi-urban areas rather than urban areas suggests a gap in health services access. Surveillance improvement through testing, tracing, and treatment, particularly in areas with lower access to health services, are necessary, along with more robust implementations of health protocols.
Structural conversion of α-synuclein at the mitochondria induces neuronal toxicity
Authors: Choi Minee L. , Chappard Alexandre , Singh Bhanu P. , Maclachlan Catherine , Rodrigues Margarida , Fedotova Evgenia , Berezhnov Alexey V. , De Suman , Peddie Chris , Athauda Dilan , Virdi Gurvir S. , Zhang Weijia , Evans James R. , Wernick Anna , Zanjani Zeinab Shadman , Angelova Plamena R. , Esteras Noemi , Vinikurov Andrey , Morris Katie , Jeacock Kiani , Tosatto Laura , Little Daniel , Gissen Paul , Clarke David J. , Kunath Tilo , Collinson Lucy , Klenerman David , Abramov Andrey Y. , Horrocks Mathew H. , Gandhi Sonia
Published: June 2022

Aggregation of α-Synuclein (α-Syn) drives Parkinson’s disease, although the initial stages of self-assembly and structural conversion have not been captured inside neurons. We track the intracellular conformational states of α-Syn utilizing a single-molecule FRET biosensor, and show that α-Syn converts from its monomeric state to form two distinct oligomeric states in neurons in a concentration dependent, and sequence specific manner. 3D FRET-CLEM reveals the structural organization, and location of aggregation hotspots inside the cell. Notably multiple intracellular seeding events occur preferentially on membrane surfaces, especially mitochondrial membranes. The mitochondrial lipid, cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial ROS generation, which accelerates the oligomerization of A53T α-Syn, and ultimately causes permeabilization of mitochondrial membranes, and cell death. Patient iPSC derived neurons harboring A53T mutations exhibit accelerated oligomerization that is dependent on mitochondrial ROS, early mitochondrial permeabilization and neuronal death. Our study highlights a mechanism of de novo oligomerization at the mitochondria and its induction of neuronal toxicity.
Wilcoxon rank-sum test still outperforms dearseq after accounting for the normalization impact in semi-synthetic RNA-seq data simulation
Authors: Li Yumei , Ge Xinzhou , Peng Fanglue , Li Wei , Li Jingyi Jessica
Published: June 2022

In this response to the correspondence by Hejblum et al. [1], we clarify the reasons why we ran the Wilcoxon rank-sum test on the semi-synthetic RNA-seq samples without normalization, and why we could only run dearseq with its built-in normalization, in our published study [2]. We also argue that no normalization should be performed on the semi-synthetic samples. Hence, for a fairer method comparison and using the updated dearseq package by Hejblum et al., we re-run the six differential expression methods (DESeq2, edgeR, limma-voom, dearseq, NOISeq, and the Wilcoxon rank-sum test) without normalizing the semi-synthetic samples, i.e., under the “No normalization” scheme in [1]. Our updated results show that the Wilcoxon rank-sum test is still the best method in terms of false discovery rate (FDR) control and power performance under all settings investigated.
The efficacy of EphA2 tyrosine phosphorylation increases with EphA2 oligomer size
Authors: Zapata-Mercado Elmer , Biener Gabriel , McKenzie Daniel , Wimley William C. , Pasquale Elena B. , Raicu Valerica , Hristova Kalina
Published: June 2022

The receptor tyrosine kinase (RTK) EphA2 is expressed in epithelial and endothelial cells and controls the assembly of cell-cell junctions. EphA2 has also been implicated in many diseases, including cancer. Unlike most RTKs, which signal predominantly as dimers, EphA2 readily forms higher order oligomers upon ligand binding. Here we investigated if a correlation exists between EphA2 signaling properties and the size of the EphA2 oligomers induced by multiple ligands, including the widely used ephrinA1-Fc ligand, the soluble monomeric m-ephrinA1, and novel engineered peptide ligands. We used Fluorescence Intensity Fluctuation (FIF) spectrometry to characterize the EphA2 oligomer populations induced by the different ligands. Interestingly, we found that different monomeric and dimeric ligands induce EphA2 oligomers with widely different size distributions. Comparison of FIF brightness distribution parameters and EphA2 signaling parameters reveals that the efficacy of EphA2 phosphorylation on tyrosine 588, which is indicative of receptor activation, correlates with EphA2 mean oligomer size. However, other characteristics, such as the efficacy of AKT inhibition and ligand bias coefficients, appear to be independent of EphA2 oligomer size. This work highlights the utility of FIF in RTK signaling research and demonstrates a quantitative correlation between the architecture of EphA2 signaling complexes and signaling features.
Long-read RNA Sequencing Improves the Annotation of the Equine Transcriptome
Authors: Peng S. , Dahlgren AR. , Hales EN. , Barber A.M. , Kalbfleisch T. , Petersen JL. , Bellone RR. , Mackowski M. , Cappelli K. , Capomaccio S. , Coleman SJ. , Distl O. , Giulotto E. , Waud B. , Hamilton N.A. , Leeb T. , Lindgren G. , Lyons LA. , McCue M. , MacLeod JN. , Metzger J. , Mickelson JR. , Murphy BA. , Orlando L. , Penedo C. , Raudsepp T. , Strand E. , Tozaki T. , Trachsel DS. , Velie BD. , Wade CM. , Cieslak J. , Finno CJ.
Published: June 2022

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A high-quality reference genome assembly, a biobank of diverse equine tissues from the Functional Annotation of the Animal Genome (FAANG) initiative, and incorporation of long-read sequencing technologies, have enabled efforts to build a comprehensive and tissue-specific equine transcriptome. The equine FAANG transcriptome reported here provides up to 45% improvement in transcriptome completeness across tissue types when compared to either RefSeq or Ensembl transcriptomes. This transcriptome also provides major improvements in the identification of alternatively spliced isoforms, novel noncoding genes, and 3’ transcription termination site (TTS) annotations. The equine FAANG transcriptome will empower future functional studies of important equine traits while providing future opportunities to identify allele-specific expression and differentially expressed genes across tissues.
The Maximum Entropy Principle For Compositional Data
Authors: Weistuch Corey , Zhu Jiening , Deasy Joseph O. , Tannenbaum Allen R.
Published: June 2022

In this work, we provide a general method for inferring the stochastic behavior of compositional systems. Our approach is guided by the principle of maximum entropy, a data-driven modeling technique. In particular, we show that our method can accurately capture stochastic, inter-species relationships with minimal model parameters. We provide two proofs of principle. First, we measure the relative abundances of different bacteria and infer how they interact. Second, we show that our method outperforms a common alternative for the extraction of gene-gene interactions in triple-negative breast cancer.

Author summary

Compositional systems, represented as proportions of some whole, are ubiquitous. They encompass the abundances of proteins in a cell, the distribution of organisms in nature, and the stoichiometry of the most basic chemical reactions. Thus, a central goal is to understand how such processes emerge from the behaviors of their components and their pairwise interactions. Such a study, however, is challenging for two key reasons. Firstly, such systems are complex and depend, often stochastically, on their constituent parts. Secondly, the data lie on a simplex which influences their correlations. We provide a general and data-driven modeling tool for compositional systems to resolve both of these issues. We achieve this through the principle of maximum entropy, which requires only minimal assumptions and limited experimental data in contrast to current alternatives. We show that our approach provides novel and biologically-intuitive insights and is promising as a comprehensive quantitative framework for compositional data.