bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPV4‐mediated Ca2+ deregulation causes mitochondrial dysfunction via the AKT/α‐synuclein pathway in dopaminergic neurons
Authors: Sun Xiao , Kong Jun , Dong Shuangshan , Kato Hiroki , Sato Hiroshi , Hirofuji Yuta , Ito Yosuke , Wang Lu , Kato Takahiro A. , Torio Michiko , Sakai Yasunari , Ohga Shouichi , Fukumoto Satoshi , Masuda Keiji 
Published: October 2023

AbstractMutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca2+ permeable nonselective cation channel, cause TRPV4‐related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4‐mediated Ca2+ deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain‐of‐function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca2+ augmented AKT‐mediated α‐synuclein (α‐syn) induction, resulting in mitochondrial Ca2+ accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α‐syn knockdown, normalizes the mitochondrial Ca2+ levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca2+/AKT‐induced α‐syn in mitochondrial Ca2+ accumulation. Folic acid was effective in normalizing mitochondrial Ca2+ levels via the transcriptional repression of α‐syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4‐related disorders and related therapeutic strategies.
Human bone marrow mesenchymal stem cell‐derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR‐1246
Authors: Xia Yuxing , Cheng Tianfan , Zhang Chengfei , Zhou Min , Hu Zhekai , Kang Feiwu , Liao Chongshan 
Published: October 2023

AbstractT‐cell‐mediated immunity is crucial in the immunopathology of periodontitis. The restoration of the homeostasis between the T helper cell 17 (Th17) and regulatory T cell (Treg) subsets by extracellular vesicles (EVs) obtained from human bone marrow stem cells (hBMSCs) promotes new bone formation and suppresses inflammation. Uncovering the functions of hBMSC‐derived EVs in the immune microenvironment of periodontal tissue and their underlying regulatory mechanisms may shed new light on developing potential cell‐free immunotherapies for periodontal regeneration. Here, we reported that the Th17/Treg ratio elevated in peripheral blood from periodontitis patients. Furthermore, we found that hBMSC‐derived EVs could reduce the Th17/Treg ratio in CD4+ T cells from periodontitis patients in vitro and ameliorate conditions of experimental periodontitis in mice. Additionally, by investigating the differentially expressed miRNAs and target genes in EVs from hBMSCs stimulated with Porphyromonas gingivalis LPS using miRNA sequencing, we found that EV‐miR‐1246 is highly effective at downregulating the ratio of Th17/Treg in vitro. Mechanistically, EV‐miR‐1246 suppressed expression of its potential target angiotensin‐converting enzyme 2 (ACE2) and increased the p‐Yes‐associated protein (YAP)1/YAP1 ratio in CD4+ T cells. Our results indicated that hBMSC‐derived EVs improve periodontitis via miR‐1246, consequently downregulating Th17/Treg ratio, and represented a promising therapeutic target for precision treatment in periodontitis.
The Reset Neurotomy within a Nonidentifiable Zone of Injury after Trauma
Authors: Schnack Lauren L. , Rodriguez-Collazo Edgardo R. , Oexeman Stephanie A. , Costa Andrew J. 
Published: October 2023

Summary:
Recent reconstructive approaches to peripheral nerve surgery have been directed toward active approaches; one such approach is nerve grafting the injured nerve segment. Addressing a nerve injury proximal to the zone of injury has demonstrated reproducible results in preventing symptomatic neuroma formation. A 53-year-old woman with a history of an ankle fracture presented with neuritic symptoms that interfered with her activities of daily living. Her intractable pain was significantly but temporarily relieved with in-office nerve blocks to the superficial peroneal nerve and sural nerve. There were no identifiable zones of injury in the nerve conduction study. Orthopedic etiology was ruled out. Nerve allografts, each 3 cm in length, were utilized with conduits and placed at the location proximal to the zone of maximum tenderness. Once the neurotomy was performed, the nerve allografts and conduits were coapted to each nerve. The patient’s intractable neuritic pain was relieved even 15 months postoperatively. The visual analog scale went from eight of 10 preoperatively to two of 10 postoperatively. Additional nerve conduction studies were not needed, and the patient returned to daily activities once the skin incisions healed. The reset neurotomy is an option for the microsurgical surgeon to have for patients with a nonidentifiable zone of injury or no identifiable neuroma but presents with intractable nerve pain relieved by local anesthetic nerve blocks.
Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation
Authors: Vonada Anne , Wakefield Leslie , Martinez Michael , Harding Cary O. , Grompe Markus , Tiyaboonchai Amita 
Published: October 2023

Background and Aims:
Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, the low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor-deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria by cell transplantation.

Approach and Results:
Hepatocytes from a wild-type donor animal were edited in vitro to create Cypor deficiency and then transplanted into phenylketonuric animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from < 1% to ~14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism.

Conclusions:
We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for phenylketonuria with long-term efficacy and a favorable safety profile.
Pigment epithelial detachment thickness and variability impacts visual outcomes in patients with neovascular age-related macular degeneration
Authors: Sarraf David , Khanani Arshad M. , Sadda SriniVas R. , Chang Andrew , Wong David T. , Kempf Anne-Sophie , Saffar Insaf , Tang Shuhan , Tadayoni Ramin 
Published: October 2023

ABSTRACT

Purpose:
To evaluate the impact of pigment epithelial detachment (PED) thickness (i.e. height) and thickness variability on best corrected visual acuity (BCVA) outcomes in patients with neovascular age-related macular degeneration (nAMD) in the Phase 3 HAWK and HARRIER trials.

Methods:
Optical coherence tomography images from the pooled brolucizumab 6mg and aflibercept 2mg arms were analysed for the maximum PED thickness across the macula at baseline through to Week 96. BCVA outcomes were compared in patients with different PED thickness and variability cut-off thresholds.

Results:
Greater PED thickness at baseline or at Week 12 was associated with lower mean BCVA gain from baseline to Week 96 (baseline PED ≥200 µm: +4.6 letters; <200 µm: +7.0 letters; Week 12 PED ≥100 µm: +5.6 letters; <100 µm: +6.6 letters). Eyes with the largest PED thickness variability from Week 12 through Week 96 gained fewer letters from baseline at Week 96 (≥33 µm: +3.3 letters; <9 µm: +6.2 letters). Furthermore, increased PED thickness at Week 48 was associated with higher prevalence of intraretinal and subretinal fluid.

Conclusions:
In this treatment-agnostic analysis, greater PED thickness and PED thickness variability were associated with poorer visual outcomes in patients with nAMD and greater neovascular activity.
A combination of clot formation abnormalities in thromboelastometry has a high prognostic value in patients with acute-on-chronic liver failure
Authors: Kampelos George , Alexopoulos Theodoros , Vasilieva Larisa , Mani Iliana , Hadziyannis Emilia , Giannouli Stavroula , Manioudaki Sofia , Nomikou Efrosyni , Alexopoulou Alexandra 
Published: October 2023

Background
Global coagulation tests offer a better tool to assess procoagulant and anticoagulant pathways, fibrinolysis and clot firmness and evaluate more accurately coagulation defects compared to conventional coagulation tests. Their prognostic role in acute-on-chronic liver disease (ACLF) or acute decompensation (AD) has not been well established.

Aims
To assess the properties and prognostic value of the coagulation profile measured by rotational thromboelastometry (ROTEM) in ACLF and AD.

Methods
84 consecutive patients (35 ACLF and 49 AD) were prospectively studied. Twenty healthy persons matched for age and gender were used as controls. ‘Hypocoagulable’ or ‘hypercoagulable’ profiles on admission were assessed based on nine ROTEM parameters and mortality was recorded at 30 and 90 days.

Results
Individual ROTEM parameters denoted significantly more hypocoagulability in patients compared to controls. ‘Hypocoagulable’ profile (defined as a composite of 4 or more ROTEM parameters outside the range) was associated with more severe liver disease assessed either as MELD or Child-Pugh scores (P < 0.001 for both) and higher 30-day mortality (Log-rank P = 0.012). ‘Hypocoagulable’ profile (HR 3.160, 95% CI 1.003–9.957, P = 0.049) and ACLF status (HR 23.786, 95% CI 3.115–181.614, P = 0.002) were independent predictors of 30-day mortality, in multivariate model. A higher early mortality rate was shown in ACLF patients with ‘hypocoagulable’ phenotype compared to those without (Log-rank P = 0.017). ‘Hypocoagulable’ profile was not associated with mortality in AD.

Conclusion
‘Hypocoagulable’ profile was associated with more advanced liver disease and higher short-term mortality in patients with ACLF.
Relevance of GLP-1 receptor agonists or SGLT-2 inhibitors on the recruitment for clinical studies in patients with NAFLD
Authors: Holzhey Michael , Petroff David , Wirkner Kerstin , Engel Christoph , Baber Ronny , Tönjes Anke , Zeynalova Samira , Yahiaoui-Doktor Maryam , Berg Thomas , Karlas Thomas , Wiegand Johannes 
Published: October 2023

Introduction
Guidelines increasingly recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) to prevent cardiovascular and cardiorenal endpoints. Both drugs also show beneficial effects in nonalcoholic fatty liver disease (NAFLD). Preexisting GLP-1 RA and SGLT2i therapies are frequently defined as exclusion criterion in clinical studies to avoid confounding effects. We therefore investigated how this might limit recruitment and design of NAFLD studies.

Methods
GLP-1 RA and SGLT2i prescriptions were analyzed in NAFLD patients with diabetes mellitus recruited at a tertiary referral center and from the population-based LIFE-Adult-Study. Individuals were stratified according to noninvasive parameters of liver fibrosis based on vibration-controlled transient elastography (VCTE).

Results
97 individuals were recruited at tertiary care and 473 from the LIFE-Adult-Study. VCTE was available in 97/97 and 147/473 cases.
GLP-1 RA or SGLT2i were used in 11.9% of the population-based cohort (LSM < 8 kPa), but in 32.0% with LSM ≥ 8 kPa. In the tertiary clinic, it was 30.9% overall, independent of LSM, and 36.8% in patients with medium and high risk for fibrotic NASH (FAST score > 0.35). At baseline, 3.1% of the patients in tertiary care were taking GLP-1 RA and 4.1% SGLT2i. Four years later, the numbers had increased to 15.5% and 21.6%.

Conclusion
GLP-1 RA and SGLT2i are frequently and increasingly prescribed. In candidates for liver biopsy for NASH studies (VCTE ≥ 8 kPa) the use of them exceeds 30%, which needs careful consideration when designing NASH trials.
Optimizing the pediatric transplant candidate
Authors: Squires James E. , Raghu Vikram K. , Mazariegos George V. 
Published: October 2023

Purpose of review
Advances in pediatric transplant parallel those in adult populations; however, there remain critical unique considerations and differences that require specialized knowledge and a specific skill set to optimize care afforded to the pediatric transplant candidate. We introduce general themes regarding optimization of the transplant candidate that are unique to children.

Recent findings
The pathologies leading to pediatric organ transplant candidacy differ from adults and a precise understanding of the physiologies and natural histories of such diseases is critical for optimized care. Regardless of etiology, comorbidities including malnutrition, sarcopenia, and developmental delay are seen and often require disease and organ specific approaches to management. Additionally, an understanding of the concepts of developmental immunology and their relevance to transplant is critical.

Summary
When looking to optimize pretransplant care, awareness of the pediatric-specific challenges by the transplant community in addition to organ- and age-specific management strategies enable the best outcomes for children awaiting solid organ transplantation.
Examining the Nurse Manager Practice Environment Effects on Burnout
Authors: Miller Rebecca , Zanville Noah , Hasse Adam 
Published: October 2023

OBJECTIVEThis study examined the relationships between the dimensions of the nurse manager (NM) practice environment (PE) and burnout.BACKGROUNDNMs are critical to the success of their unit(s). Understanding the degree to which their PE characteristics impact their level of burnout is important to NM retention.METHODA cross-sectional research design using a 71-item questionnaire was used to measure NM characteristics, hospital characteristics, NM PE, and burnout. There were 110 completed respondents across 22 hospitals in the United States.RESULTSModerate inverse relationships exist between the NM PE and 2 of the 3 (work and personal) dimensions of burnout. NM age and tenure also showed an inverse relationship with burnout.CONCLUSIONSThis study added evidence showing a statistically significant relationship between NM PE and the work and personal dimensions of burnout. These results also suggest the relationships NMs have with the patients on their unit(s) do not add to their level of burnout.
Patient-Reported Experiences Filling Expedited Partner Therapy Prescriptions for Chlamydia, Including Recommendations for Mitigating Encountered Obstacles, New York City, 2019 to 2020
Authors: Gary Danielle E. , Klingler Ellen J. , Slutsker Jennifer Sanderson 
Published: October 2023

Background
Expedited partner therapy (EPT) is commonly provided by prescription. Multiple barriers to prescription-EPT have been described, although information on patient experiences with this practice is limited.

Methods
We conducted telephone interviews from July 2019 to January 2020, with women aged 15 to 24 years who were reported to the New York City Department of Health with chlamydia and for whom a health care provider report indicated provision of prescription-EPT (patients). A standard questionnaire was used to explore patients' experiences with filling an EPT prescription for their most recent sex partner and included questions about factors that would make it easier to obtain EPT medication.

Results
A total of 425 young women were reported with chlamydia and indicated to have received prescription-EPT. We completed interviews with 245 of these patients (57.6%), of whom 204 affirmed receiving prescription-EPT (83.3%). Nearly all patients (193 of 204 [94.6%]) took actions to fill the EPT prescription (visited the pharmacy themselves (139 of 193 [72.0%]) or directed their partner to fill the prescription (54 of 193 [28.0%]). Among these patients, most reported obtaining medication (173 of 193 [89.6%]). A small number of patients reported ways to enhance EPT practices, including 22, 19, and 12 who reported factors related to payment, health care providers, and the pharmacy, respectively, that would make it easier to obtain medication. Patients highlighted the importance of reducing cost and increasing convenience.

Conclusions
Most interviewed patients successfully filled EPT prescriptions. However, some patients encountered barriers during the process. Approaches to streamline EPT practices, such as provision of medication-EPT at the point of care, are critical.
Smartphone App PACOM to Provide Advice Regarding Self-Triage for the Acute Primary Care Needs of Children
Authors: Navion Anouk , Segretin Pierre , Bailhache Marion 
Published: October 2023

Background
We developed a phone app, PACOM (Parents Application Conseils et Orientation Médicale), to provide medical advice to caregivers based on several algorithms and a series of binary questions related to children's symptoms. We compared the recommendations of the PACOM algorithms and clinicians for children visiting the emergency department (ED).

Methods
Between January and February 2022, we prospectively recruited French-speaking parents of children without any chronic disease who presented to the pediatric ED with any complaint except for mental health problems or trauma. Isolated head trauma was included. They completed questionnaires and the various PACOM algorithms. The first algorithm, called “Quick Look,” was developed to identify children with life-threatening emergencies. The standard reference was the advice of the ED clinicians who were blinded to the parental responses to the PACOM algorithm questions. The recommendations included “call urgent medical support,” “visit the ED,” “visit your general practitioner within 24 hours,” and “visit your general practitioner in the next days.”

Results
The study included 269 parents. The response rate was 75%. The median age of the children was 3 years with interquartile range: 1 to 7 years. In total, 268 children completed the “Quick Look,” 141 “fever,” 83 “abdominal pain,” 72 “cough,” 70 “vomiting,” 130 questionnaires relative to other proposed symptoms, and 70 “other symptom” questionnaires. The PACOM recommendations were “call urgent medical assistant” for 98 children, “ED visit” for 131, “visit general practitioner within 24 hours” for 13, and “visit general practitioner during the next days” for 24. The sensitivity and specificity of the PACOM recommendation to “call urgent medical support or visit the ED” were 98.1% (95% confidence interval, 95.5–100.00) and 22.1% (95% confidence interval, 15.3–28.8), respectively.

Conclusions
The PACOM algorithms has high sensitivity but low specificity for reducing ED visits and calls for urgent medical support.
Child and Caregiver Beliefs of Importance of Physical Function and Quality of Life in Juvenile Idiopathic Arthritis: A Survey Study
Authors: Woolnough Leandra U. , Lentini Logan , Bhavsar Prachi H. , Thomas Maren F. , Casella Zachery M. , Vincent Heather K. 
Published: October 2023

Purpose:
To evaluate patient-caregiver beliefs of relative importance across 4 domains while living with juvenile idiopathic arthritis (JIA).

Methods:
This was a cross-sectional, anonymous survey study conducted in an academic medical center. Participants with JIA and caregivers (N = 151) completed a Likert-style survey to rate items by importance of knowledge about 4 domains: medications, physical activity, routine measures, and quality of life.

Results:
Knowledge of medication issues ranked higher than the remaining 3 domains (4.2 ± 0.7 points vs 4.0 ± 0.7, 4.1 ± 0.8, and 4.0 ± 0.9 points, respectively; P = .026; P = .026). Compared with caregivers, participants rated importance lower for all 4 domains.

Conclusions:
Gait and physical activity and well-being are not uniformly measured as part of routine clinical care and disease tracking in JIA. Both participants and caregivers ranked knowledge of physical activity similarly to routine office measures and quality of life. Inclusion of these measures in routine care could improve people centeredness and inform treatment plans.
Identifying Children in Foster Care and Improving Foster Care Documentation in Primary Care
Authors: Broussard Camille A. , Kim Julia M. , Hunter Brittany , Mobley LaToya , Trent Maria , Seltzer Rebecca 
Published: October 2023

Background:
Children and youth in foster care (CYFC) are a population with special healthcare needs, and the American Academy of Pediatrics has healthcare standards to care for this population, but implementation challenges include identifying clinic patients in foster care (FC). Documentation of FC status in the Electronic Health Record (EHR) can support the identification of CYFC to tailor care delivery. Therefore, we aimed to improve the percentage of CYFC with problem list (PL) documentation of FC status from 20% to 60% within 12 months.

Methods:
This study used a five-cycle plan-do-study-act quality improvement model in two co-located primary care teaching clinics. The primary outcome was the weekly percentage of patients with FC status on EHR PL. Ishikawa cause and effect analysis and resident survey identified barriers and informed interventions: education, patient list distribution, documentation training, email reminders, and clinic champion. We constructed statistical process control charts of the primary outcome to assess for improvement.

Results:
Mean weekly percentage of patients with FC status on PL improved from 19.8% to 60.2%. The most extensive improvements occurred after designating a clinic champion and providing email reminders with enhanced patient lists. The sustainability of PL documentation (mean = 71.7%) was demonstrated 3–4 years after the completion of plan-do-study-act cycle interventions.

Conclusions:
Educating providers, collaborating with child welfare to provide patient lists to providers, standardizing documentation, and designating clinic champions are promising methods of improving EHR documentation of FC status. Identifying and documenting FC status are important initial steps to optimizing care for this vulnerable population in primary care.