bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic Approach for Identifying Unique Genomic Sequences for Fusarium oxysporum f. sp. lactucae Race 1 and Development of Molecular Diagnostic Tools
Authors: Li Ningxiao , Geiser David M. , Steenwyk Jacob L. , Tsuchida Cayla , Koike Steve , Slinski Stephanie , Martin Frank N.
Published: October 2024

Fusarium oxysporum f. sp. lactucae (FOLac) is a soil- and seedborne fungal pathogen that causes Fusarium wilt of lettuce, an important disease threatening global lettuce production. Based on pathogenicity on differential lettuce cultivars, four races (1 to 4) have been identified, with race 1 being the only race detected in the United States and the closely related, emerging race 4 known only in Europe. The development of race-specific diagnostic tools is hindered by insufficient genomic data to distinguish between the two races and FOLac from other F. oxysporum formae speciales and nonpathogenic isolates. Here, we describe a systematic approach for developing diagnostic markers for FOLac race 1 that utilized a comprehensive sequence database of F. oxysporum to identify 15 unique genomic sequences. Marker specificity was validated through an exhaustive screening process against genomic data from 797 F. oxysporum isolates representing 64 formae speciales and various plants and non-plant substrates. One of the unique sequences was used to develop a TaqMan quantitative PCR assay and a recombinase polymerase amplification assay, both exhibiting 100% sensitivity and specificity when tested against purified DNA from 171 F. oxysporum isolates and 69 lettuce samples. The relationship between quantitative PCR cycle threshold values and CFU/g values was also determined. This study not only introduces a new marker for FOLac race 1 diagnostics and soil quantitation but also underscores the value of an extensive genomic database and screening software pipeline for developing molecular diagnostics for F. oxysporum formae speciales and other fungal taxa.
Increased neutrophil extracellular traps caused by diet‐induced obesity delay fracture healing
Authors: Zhao Xuan , Wang Qijun , Wang Wei , Lu Shibao
Published: October 2024

Obesity, recognized as a risk factor for nonunion, detrimentally impacts bone health, with significant physical and economic repercussions for affected individuals. Nevertheless, the precise pathomechanisms by which obesity impairs fracture healing remain insufficiently understood. Multiple studies have identified neutrophil granulocytes as key players in the systemic immune response, being the predominant immune cells in early fracture hematomas. This study identified a previously unreported critical period for neutrophil infiltration into the callus. In vivo experiments demonstrated that diet‐induced obesity (DIO) mice showed earlier neutrophil infiltration, along with increased formation of neutrophil extracellular traps (NETs), compared to control mice during the endochondral phase of fracture repair. Furthermore, Padi4 knockout was found to reduce NET formation and mitigate the fracture healing delays caused by high‐fat diets. Mechanistically, in vitro analyses revealed that NETs, by activating NLRP3 inflammasomes, inhibited the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and concurrently promoted M1‐like macrophage polarization. These findings establish a connection between NET formation during the endochondral phase and delayed fracture healing, suggesting that targeting NETs could serve as a promising therapeutic approach for addressing obesity‐induced delays in fracture recovery.
A Concise Review of Marfan Syndrome with a Congenital Cardiac Surgery Focus
Authors: Vogel Andrew D. , Galan Gabriela M. , Rajab T. Konrad
Published: October 2024

Marfan syndrome is named after Antoine Marfan, who described a 5-year-old child with congenital elongation of the digits and other skeletal abnormalities in 1896. While Marfan syndrome is a systemic connective tissue disorder predominantly involving the skeletal, cardiovascular, and ocular systems, the cardiovascular system presents the most life-threatening complications. Most cardiovascular pathologies surround the left ventricular outflow tract and aorta, with aortic dissection requiring emergent surgical management to the progression of mitral regurgitation requiring elective surgery. Intensive care management, along with a tailored approach to the surgical management of a patient with Marfan syndrome, is critical to their survival. Current surgical operations for patients include aortic root surgery, valve-sparing root replacements, aortic root replacements with conduits, and mitral valve repairs. Further research is necessary to determine the molecular, endovascular, pharmaceutical, and surgical management of Marfan syndrome. This review attempts to concisely discuss the diagnosis, complications, and medical and intensive care management of Marfan syndrome while further divulging on the surgical management of those with this disease process.
The Living Lab at Home: Feasibility and Acceptability of Multimodal In-Home Data Collection Among Youth Across the Developmental Spectrum
Authors: Boerner Katelynn E. , Dudarev Veronica , Pearl-Dowler Leora , Wharton Marie-Noelle , Siden Harold , Holsti Liisa , Oberlander Tim F.
Published: October 2024

Objective:

Dynamic, real-time, in-home methods of data collection are increasingly common in child health research. However, these methods are rarely cocreated or used with families of youth with developmental disabilities. We aimed to determine the feasibility of codesigned methods for in-home data collection for youth across the developmental spectrum.

Methods:

Sixteen youth (14–18 years) with autism spectrum disorder, cerebral palsy, and/or chronic pain completed 14 days of data collection, wearing an accelerometer, answering Ecological Momentary Assessment (EMA) questionnaires, and collecting salivary cortisol samples. Participants completed a poststudy interview regarding their experiences. Data were analyzed for feasibility, quantity, and quality.

Results:

At least 1 EMA response was provided on 73% of days, with 54% of the total number of administered prompts answered before the next prompt arrived. In total, 77% of participants wore the accelerometer ≥10 hours for at least 7 days. Adherence to 8-day saliva sampling after accounting for protocol violations and dry samples was 28%. No significant adverse events were reported aside from mild emotional distress (25%). Families reported generally high satisfaction, willingness to participate again, and acceptability, with moderate burden and interference. Qualitative interviews described: (1) the research question's value to the family as a motivator of engagement; (2) in-home data collection is not a passive or neutral experience; (3) personalized approaches and context are important to families; and (4) a clear need for continued iteration and engagement.

Conclusion:

In-home multimodal data collection is potentially feasible for families across the developmental spectrum but requires iteration based on family feedback to increase adherence.
A Demographic Description of Children and Adolescents With Concomitant Autism and Anxiety Along With a Comparison of Receipt of Psychological Services
Authors: Salt Elizabeth , Wiggins Amanda T. , Toupin David N. , Parks Emma , Okoli Chizimuzo , Rayens Mary Kay
Published: October 2024

Objective:

(1) Evaluate differences in demographic distributions between those with autism alone and those with autism concomitant with anxiety and (2) assess demographic factors associated with receipt of psychological therapy in patients with autism.

Methods:

Using deidentified health care claims data, we extracted all encounters among children with the International Classification of Diseases-10-CM for Autism Spectrum Disorder (F84) and flagged those with concomitant anxiety (F41.9). Extracted data included age, sex, race, ethnicity, insurance status, and Rural-Urban Continuum Codes. Current procedural terminology codes for psychological services were extracted. Data were analyzed using Mann–Whitney U tests, χ2 tests of association, and logistic regression.

Results:

Demographic differences between children/adolescents with autism alone versus autism concomitant with anxiety were noted for age, sex, and race/ethnicity, with a greater prevalence of autism/anxiety identified in older-aged children and children identifying as female and non-Hispanic White residing in an urban area. While 21% of those included in this study had received psychotherapy, the percentages within the autism only and autism/anxiety groups were 12% and 50%, respectively (p < 0.001). Children/adolescents who were older age quartile, resided in an urban residence, and with a concomitant diagnosis of anxiety were more likely to receive psychological services, while non-Hispanic Other were less likely to, compared with the reference of non-Hispanic White.

Conclusion:

We identified demographic disparities in the diagnosis of autism versus autism with concomitant anxiety, including age, sex, race/ethnicity, and residence location. Age quartile, urban location, and concomitant anxiety were associated with increased likelihood of receipt of psychological services.
Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients
Authors: Momper Jeremiah D. , Venkataramanan Raman , Jantz Arin S. , Cibrik Diane M. , Birdwell Kelly , Nguyen Tk , Masters Brian M. , Patel Samir J.
Published: October 2024

Background:

For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac).

Methods:

A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile.

Results:

The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.

The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4–77.9) hours, whereas the t1/2z was 20.3 (17.6–22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8–23.0) hours and 12.2 (9.2–15.7) hours, respectively.

Conclusions:

Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.
Superior cervical ganglionectomy attenuates vascular remodeling in spontaneously hypertensive rats
Authors: Wang Jing-Xiao , Xu Xiao-Yu , Wang Yi-Ming , Chen Ai-Dong , Li Yue-Hua , Zhu Guo-Qing , Xiong Xiao-Qing
Published: October 2024

Background:

Sympathetic hyperactivity contributes to the pathogenesis of hypertension. However, it is unclear whether the excessive sympathetic activity is an independent and crucial factor for vascular remodeling in hypertension. This study focused on the effect of local sympathetic denervation with superior cervical ganglionectomy (SCGx) on vascular remodeling.

Methods:

Surgical bilateral SCGx was performed in 9-week-old male Wistar−Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Control rats received sham-operation without SCGx. All measurements were made 4 weeks after the surgery.

Results:

The effectiveness of SCGx was confirmed by the eye features of Horner syndrome, greatly reduced tyrosine hydroxylase (TH) contents in the superior cervical ganglion (SCG)-innervated arteries in the head. Although SCGx had no significant effects on blood pressure and heart rate in WKY and SHR, it attenuated vascular remodeling of facial artery and superficial temporal artery in SHR, two representative SCG-innervated extracranial arteries, without significant effects on non-SCG-innervated thoracic aorta and mesenteric artery. SCGx-treated SHR had more auricular blood flow and retina microvasculature than sham-operated SHR. However, SCGx had only a mild effect in attenuating the vascular remodeling of basilar artery and middle cerebral artery, two representative SCG-innervated intracranial arteries, in SHR. SCGx-treated SHR exhibited upregulation of α-smooth muscle actin, downregulation of proliferating cell nuclear antigen, and attenuation of oxidative stress and inflammation in facial artery and superficial temporal artery.

Conclusions:

Sympathetic denervation by SCGx in SHR attenuated local vascular remodeling, suggesting that sympathetic overactivity is a crucial pathogenic factor of vascular remodeling in SHR.
Two-hit model for the development of aldosterone-producing adenoma: supporting from two new cases
Authors: Gao Yinjie , Wang Yu , Zhou Yue , Ding Jie , Chang Xiaoyan , Qiu Ling , Huo Li , Wen Jin , Zhang Yushi , Tong Anli
Published: October 2024

Recently, a two-hit model for the development of aldosterone-producing adenoma (APA) was proposed but until now, only two cases supporting the model have been reported. Here, we present two new cases of primary aldosteronism (PA), both of which had large functional adenomas with somatic mutations in aldosterone-driving genes. Furthermore, the first patient, who had a history of colorectal cancer, was found to have a germline and an additional somatic mutation in APC, and APC inactivation was confirmed by immunohistochemistry. The other patient had pathogenic somatic mutation inCTNNB1. These pro-proliferation mutations resulted in abnormal activation of the Wnt/β-catenin pathway. Two consecutive events apparent in these patients, namely, the first event leading to cell proliferation and the second driving hormonal hypersecretion, supported the two-hit model of APA development. The two-hit model usually occurs in the larger adenomas, and the driving factors of the first hit that promote cell proliferation still require further research and exploration.
The incremental predictive value of arterial stiffness over SCORE2 in the setting of primary cardiovascular prevention: a 6-year follow-up study
Authors: Ikonomidis Ignatios , Thymis John , Georgiopoulos Georgios , Pavlidis George , Katogiannis Konstantinos , Kostelli Gavriella , Vlastos Dimitrios , Plotas Panagiotis , Triantafyllidi Helen , Delialis Dimitrios , Mavraganis Georgios , Lambadiari Vaia , Stamatelopoulos Kimon
Published: October 2024

Aim:

Arterial stiffness hallmarks age-related cardiovascular diseases, precedes their onset and strongly links to accelerated disease progression. However, whether carotid-to-femoral pulse wave velocity (PWV), a proxy of arterial stiffness, predicts cardiovascular risk over and above SCORE2, a newly introduced risk score remains to be investigated.

Methods:

We measured PWV among 747 individuals without established atheromatosis. Study participants were followed up over a 6-year period for the incidence of cardiovascular events [[MACE)-cardiovascular mortality, stroke and myocardial infarction].

Results:

PWV emerged as an independent and additive predictor of first cardiovascular events when added in a model encompassing SCORE2 (hazard ratio = 1.10; 95% confidence interval (95% CI) = 1.07–1.14; P < 0.001, Brier score changed from 0.073 (0.060–0.086) to 0.067 (0.055–0.081); P < 0.001, c-statistic increased from 0.71 to 0.75; P = 0.017; likelihood ratio: 20.22; P < 0.001; the overall net reclassification improvement (NRI): 0.577; P < 0.001, AICc changed from 697.81 to 679.60; BIC changed from 702.42 to 688.82]. An increase in PWV predicted a greater risk of future MACEs additively to conventional risk factors (P < 0.05). We performed Kaplan-Meier survival analysis for the tertiles of PWV [first tertile < 8.04 m/s; the second tertile: (8.04–10 m/s); the third tertile: (10–17.10 m/s); (P < 0.05 for all comparisons between the tertiles). PWV tertiles also predicted MACE when added to SCORE2 [for the second tertile: hazard ratio: 5.87 (95% CI: 1.73–19.92); P = 0.004 and for the third tertile: hazard ratio: 9.69 (95% CI: 2.97–31.55); P < 0.001 with the respective change of c-statistic from 0.739 to 0.772; P = 0.012 and continuous NRI = 0.598].

Conclusion:

PWV confers additive prognostic value to the newly introduced SCORE2 for adverse outcome in primary prevention.
Standardized Approach to Pediatric Post-COVID Syndrome and Its Impact on Children and Adolescents: A Perspective From a Tertiary Center
Authors: Nzale Shadya , Perrin Anne , Soroken Cindy , Nehme Mayssam , Posfay-Barbe Klara M. , L’Huillier Arnaud G.
Published: October 2024

Background:

Pediatric post-COVID syndrome (pPCS) affects a notable number of children. This study aims to describe its clinical manifestations, biopsychosocial impact and management strategies.

Methods:

A prospective, single-center study was conducted to analyze data of pPCS patients presenting to our institution between May 2021 and November 2022. Functional impact was evaluated by assessing school absenteeism and by using the Adolescent Depression Rating Scale (ADRS), Pediatric Quality of Life Inventory (PedsQL) and Fatigue Severity Scale.

Results:

Among the 50 patients included [median age (interquartile range): 14.0 (12.9–15.8) years; females: 70%], the most common symptoms were extreme fatigue (84%), exertion intolerance (82%), orthostatism (66%), dyspnea (66%) and headache (66%); 25% had an abnormal Schellong test. Median (interquartile range) ADRS, PedsQL and Fatigue Severity Scale scores were 3.0 (1.0–5.0), 56% (49%–71%) and 45.0 (32.0–53.0), respectively. Sixty percent experienced partial (34%) or complete (26%) school absenteeism. The most common referrals to specialized consultations were child psychiatry (48%), pulmonology (46%), physiotherapy (36%) and an ear-nose-throat specialist (24%). Eighty percent had a typical form of pPCS, whereas 20% had a clinical presentation suggestive of a functional disorder triggered by COVID-19. The latter had more frequent thoracic pain (P = 0.012) and more referrals to pediatric neurology (P = 0.01), gastroenterology (P = 0.011), ophthalmology (P = 0.037) and child psychiatry (P = 0.035), but less to pulmonology (P = 0.014). School absenteeism and social withdrawal were also more common in this group, with more severe PedsQL and ADRS scores.

Conclusion:

pPCS is associated with a significant socio-educational burden that should be taken into account in medical, social and educational care.
Severe intraocular lens tilt after the Yamane technique
Authors: Kelkar Neil , Eid Kevin , Nakatsuka Austin S. , Johnson Catherine , Mamalis Nick , Werner Liliana
Published: October 2024

Purpose:

To evaluate CT Lucia 602 intraocular lenses implanted in cases lacking capsular support and explanted because of decentration/dislocation with subsequent pathological analysis. The main objectives were to (1) document the status of haptics and (2) verify the presence of the rotisserie effect.

Setting:

John A. Moran Eye Center, University of Utah, Salt Lake City, Utah.

Design:

Case series with clinicopathological correlation.

Methods:

13 explanted CT Lucia 602 lenses were included: 12 implanted by the Yamane technique and 1 that was iris-fixated. 4 lenses were explanted between October 2020 and February 2022. 9 lenses, explanted between November 2022 and February 2024, also exhibited severe optic tilt, leading to explantation. A chart review was performed to obtain clinical information from each case. Explanted lenses underwent gross and microscopic examination for haptic status and rotation, in the dry state (room temperature) and after hydration (body temperature).

Results:

Time between implantation and explantation was longer for lenses explanted before November 2022 (without severe tilt). Among the 26 haptics evaluated, 15 were deformed, 6 were broken, 2 were detached, and 3 were unremarkable. 4 haptics of Yamane lenses explanted between November 2022 and February 2024 showed free rotation within the optic insertion, after hydration at body temperature.

Conclusions:

Anecdotal reports of the rotisserie effect of CT Lucia 602 lenses implanted by the Yamane technique appeared mostly during the second half of 2022 and suggested that affected lenses were from specific batches, which seems to be consistent with the findings of this study.
Clinical outcomes of round spermatid injection vs intracytoplasmic sperm injection: The role of hormonal pretreatment for nonobstructive azoospermia
Authors: Cheng Nai-Ming , Huang William J. , Huang Chen-Yu , Chen Yi-Jen , Ho Chi-Hong
Published: October 2024

Background:

Round spermatid injection (ROSI) into oocytes offers men with nonobstructive azoospermia (NOA) the opportunity to have biological offspring in cases where mature spermatozoa are not detected. However, the clinical outcomes of ROSI remain poor. This study compared the outcomes of ROSI with intracytoplasmic sperm injection (ICSI) and investigated the effect of hormonal pretreatment.

Methods:

This retrospective cohort study enrolled infertile couples undergoing either ROSI or ICSI at the reproductive center in Taipei Veterans General Hospital. The administration of selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors in male patients were recorded. Relevant hormonal markers and biochemical parameters were determined. The outcomes of ROSI and ICSI were assessed based on fertilization rate, implantation rate, and live birth rate.

Results:

A total of 36 couples were recruited in the ROSI group, whereas 39 couples were recruited in the ICSI group for the analysis. Patients in each group demonstrated similar characteristics, except for a higher proportion of male patients in the ROSI group who were pretreated with anastrozole. The fertilization rate and implantation rate were similar between ROSI and ICSI groups after adjusting for confounding variables. The live birth rate was significantly lower in the ROSI group (8.3%) than in the ICSI group (30.8%) before and after adjusting for confounding variables.

Conclusion:

ROSI demonstrated fertilization and implantation rates comparable to those of ICSI for male patient with NOA undergoing testicular sperm extraction surgery. Anastrozole may improve the outcomes of ROSI into oocytes. Further studies evaluating the effect of anastrozole administration on ROSI outcomes are warranted.
Comparative outcomes of living donor liver transplantation in elderly recipients: A study on morbidity and survival in 1018 recipients
Authors: Saner Fuat H. , Raptis Dimitri A. , Alchibi Leen , Kareem Sami A. , Marquez Kris Ann H. , Elsheikh Yasser , Alnemary Yasir , Alabbad Saleh , Boehnert Markus U. , Malago Massimo , Broering Dieter C.
Published: October 2024

Given the increasing demand of patients requiring liver transplants who are 70 years or older and may have health conditions, this study aimed to assess the outcomes of recipients of living donor liver transplants (LDLTs) in this age group. We conducted an analysis using a prospective registry that included all recipients of LDLT from January 2011 to May 2023. Patients were divided into 2 age groups, 18–69 years and 70 years or older, and their short-term and long-term outcomes were compared. We considered complications as major if they were grade ≥3a (Dindo-Clavien). Among 1018 recipients of LDLT, 71 (7%) were aged 70 years or older. The rates of posttransplant complications of any severity were comparable between the younger and older age groups (46.7% vs. 46%, p = 0.983), as were the rates of major complications (25% vs. 25%, p = 0.995) and in-hospital mortality (6% vs. 7%, p = 0.800). The 1-, 3-, and 5-year graft survival rates were 94%, 86%, and 81% in the younger group and 92%, 87%, and 65% in the older group (p = 0.090). Similarly, the overall 1-, 3-, and 5-year recipient survival rates were 90%, 85%, and 86% in the younger group and 88%, 86%, and 65% in the older group (p = 0.100). This study suggests that carefully selected elderly patients can undergo LDLT and achieve comparable short-term outcomes to their younger counterparts.
Does patient-ventilator asynchrony really matter?
Authors: Docci Mattia , Rodrigues Antenor , Dubo Sebastian , Ko Matthew , Brochard Laurent
Published: October 2024

Purpose of review

Past observational studies have reported the association between patient-ventilator asynchronies and poor clinical outcomes, namely longer duration of mechanical ventilation and higher mortality. But causality has remained undetermined. During the era of lung and diaphragm protective ventilation, should we revolutionize our clinical practice to detect and treat dyssynchrony?

Recent findings

Clinicians’ ability to recognize asynchronies is typically low. Automatized softwares based on artificial intelligence have been trained to largely outperform human eyesight and are close to be implemented at the bedside. There is growing evidence that in susceptible patients, dyssynchrony may lead to ventilation-induced lung injury (or patient self-inflicted lung injury) and that clusters of such dyssynchronous events have the highest association with poor outcomes. Dyssynchrony may also be associated with harm indirectly when it reflects over-assistance or over-sedation. However, the occurrence of reverse triggering by means of low inspiratory efforts during passive ventilation may prevent diaphragm dysfunction and atrophy and be beneficial.

Most recent evidence on the topic suggests that synchrony between the patient and the mechanical ventilator is a critical element for protecting lung and diaphragm during the time of invasive mechanical ventilation or may reflect inadequate settings or sedation. Therefore, it is a complex situation, and clinical trials are still needed to test the effectiveness of keeping patient-ventilator interaction synchronous on clinical outcomes.
Future directions in transmasculine genital gender-affirming surgery: tissue substitutes and transplant
Authors: Xu Alex J. , Zeki Jessica Abou , Khouri Joseph S. , Mishra Kirtishri , Gupta Shubham
Published: October 2024

Purpose of review

The present study reviews contemporary literature focused on transplantation and tissue substitutes for the purposes of masculinizing genital gender affirming surgery. Additional background is provided for both topics to provide a more comprehensive understanding of the modern applications.

Recent findings

Genitourinary vascularized composite allotransplantation has become a reality in recent years with several cases reported worldwide in cisgender men with promising reports of urinary and sexual function. A natural extension might be to apply these techniques to gender affirming surgery (GAS). Technical barriers include anatomic differences between vasculature supporting penoscrotal and vulvovaginal anatomy as well as size discrepancies between the corporal bodies which complicate the required anastomoses. Whether the smaller caliber of biologic female pelvic vasculature can support erection of a neophallus is another obstacle. Ethically, resource allocation, elective immunosuppression, society response to organ donation and gender identity, as well as the psychosocial safety of the patient given charged public opinion must all be considered.

Tissue substitutes have long been used in urologic reconstruction but more recently applied to masculinizing gender affirmation surgery which has traditionally relied on autografting. The focus has been on restoring form and function to the donor site as well as facilitating treatment of urethral stricture and wound complications after phalloplasty. Furthermore, aesthetic applications have also been described, most recently for glans atrophy.

The field of masculinizing gender affirmation surgery represents an exciting frontier for surgeons and patients alike. Given the relative nascency of the specialty and its propensity to draw techniques from various surgical disciplines there exists a unique opportunity for rapid innovation to overcome challenging problems posed by these complex procedures as evidenced by discussions around applying penile transplantation and the use of novel tissue grafting techniques.
Polymyxin-B induced Bartter-like syndrome: an unusual adverse effect
Authors: Taik Sophia , Hashmi Razi , Mahtani Arun , Piccione Gianpaolo , Albakri Mohamed , Farid Meena , Fabian Daniel , Tindoy Merschelle , Sethi Yashendra , Padda Inderbir , Bin Emran Talha
Published: October 2024

Introduction and importance:

Bartter syndrome is a rare autosomal recessive disorder affecting renal tubular function leading to disturbances in electrolyte and volume homeostasis. It can also manifest as Bartter-like syndrome (BLS), a rare side effect of certain medications. Polymyxin-B, an antibiotic used to treat multidrug-resistant infections is infrequently associated with BLS. Hence, early diagnosis of this adverse effect is crucial to prevent severe electrolyte imbalances.

Case presentation:

A 73-year-old female with coronary artery disease, chronic obstructive pulmonary disease, and hyperlipidemia, presented with fever, respiratory distress, and hypoxia on mechanical ventilation. Initial labs showed leukocytosis, anemia, and normal potassium. Despite receiving broad-spectrum antibiotics there was no improvement in her clinical condition. A sputum culture revealed pandrug-resistant Acinetobacter baumannii, sensitive only to Polymyxin-B. After six days of receiving polymyxin-B, the patient developed fever, hypotension, hypokalemia, hypomagnesemia, and polyuria. Urine studies indicated increased potassium excretion. A diagnosis of BLS was made. Polymyxin-B was discontinued, and the patient’s electrolytes normalized. She was discharged with daily potassium and magnesium supplements.

Clinical discussion:

BLS can result from polymyxin-B-induced tubular dysfunction characterized by hypokalemia and hypomagnesemia. Early recognition allowed for the timely discontinuation of polymyxin-B, which rapidly reversed her electrolyte disturbances.

Conclusion:

This case underscores the importance of recognizing polymyxin-B-induced BLS. Clinicians should be vigilant for electrolyte disturbances in patients receiving treatment with polymyxin-B, ensuring timely interventions to mitigate adverse outcomes.
Analysis of time to regulatory approval in an exception from informed consent trial in trauma patients
Authors: Stephens Shannon W. , Carroll-Ledbetter Christy R. , Duckert Sarah , Coffman Tanner W. , Nelson Margaret A. , Rodgers Joel , Griffin Russell L. , Grzyb Sarah , Suen Amy , Casey Jeremy , Sloan Steven R. , Goldstein Brahm , Richwood Jay , Delfs Julia , McClintock Adam J. , Gelinas Luke , Higley Amanda , Joseph Bellal , Holcomb John B. , Jansen Jan O.
Published: October 2024

BACKGROUND

The interactive media–based approach to community consultation and public disclosure (CC/PD), a key step when conducting exception from informed consent (EFIC) clinical trials, is intended to be completed in 4 months. This analysis characterizes the process, from initiation of CC/PD activities to institutional review board approval, to better understand the barriers and how these can be mitigated.

METHODS

This is a retrospective post hoc analysis of data collected as part of the CC/PD campaigns conducted for a large trial involving up to 90 trauma centers in the United States. Each site was provided with templated materials that had been reviewed and approved by a central institutional review board (cIRB). We collected the dates of milestones, including the study “kickoff call,” start of the social media campaign, dates of online community meetings, date of submission of site report to the cIRB, and cIRB approval date.

RESULTS

Sixty-two sites were cIRB approved at the time of this analysis. The median time from the kickoff call to the start of the social media campaign was 79 days, with an interquartile range of 33 to 126 days (range, 0–285 days). All social media campaigns ran for the prescribed period of at least 2 months. All sites conducted at least four online community meetings. The median number of days from the kickoff call to cIRB approval was 216 days (interquartile range, 168–281 days; range, 116–459 days). There was no significant difference between sites that had previous experience of EFIC trials.

CONCLUSION

Using the interactive media–based approach, CC/PD can be completed quickly; however, there are barriers that can incur substantial delays. Greater harmonization of local administrative processes would shorten the time to conduct CC/PD activities and facilitate the timely commencement and execution of EFIC trials.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Prevention and management of medical adhesive-related skin injuries in tumor patients with peripheral central venous catheters: a best practice implementation project
Authors: Tang Huang , Zhong Xuemei , Wu Caixia , Fan Yunfei , Li Qinghua , Chen Qingxia , Li Xiaojin , Ruan Jing , Xia Chunxia
Published: October 2024

Introduction:

Peripheral central venous catheters are common vascular access devices used in patients with tumors. To prevent catheter shedding and displacement, it is essential to use medical adhesives to secure the catheters. Repeated adhesion and removal of medical adhesives can weaken the barrier function of the skin, leading to medical adhesive-related skin injuries (MARSI), which can increase the patients’ pain and medical expenses.

Objectives:

The objective of this project was to utilize the best evidence to prevent and manage MARSI in tumor patients with peripheral central venous catheters.

Methods:

This evidence-based audit and feedback project was theoretically informed by the JBI Evidence Implementation Framework. The framework involves seven phases in which a project team was established; measurable criteria were selected; baseline data were collected; improvement strategies were implemented to address gaps in compliance; a follow-up audit was conducted to assess improvements in compliance; and sustainability measures were considered. The project also used the JBI Practical Application of Clinical Evidence System (PACES) for project management, including data collection and analysis. The JBI Getting Research into Practice (GRiP) approach was also used to support implementation and compliance.

Results:

In the baseline audit, the compliance rate for the nine audit criteria was low. In the follow-up audit, the compliance rate significantly improved, with each audit criterion exceeding a minimum of 80%, and four audit criteria reaching 100%. Knowledge of MARSI among nurses and patients significantly improved (p < 0.05) and the incidence of MARSI among patients with peripheral central venous catheters decreased.

Conclusions:

This project successfully enhanced nurses’ compliance with MARSI prevention and management and increased the knowledge and skills of both nurses and patients about MARSI.

Spanish abstract:

http://links.lww.com/IJEBH/A285
Inhibition of PIM kinase in tumor associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy
Authors: Clements Amber N. , Casillas Andrea L. , Flores Caitlyn E. , Liou Hope , Toth Rachel K. , Chauhan Shailender S. , Sutterby Kai , Deshmukh Sachin Kumar , Wu Sharon , Xiu Joanne , Farrell Alex , Radovich Milan , Nabhan Chadi , Heath Elisabeth I. , McKay Rana R. , Subah Noor , Centuori Sara , Wheeler Travis J. , Cress Anne E. , Rogers Gregory C. , Wilson Justin E. , Recio-Boiles Alejandro , Warfel Noel A.
Published: October 2024

Immunotherapy has changed the treatment paradigm for many types of cancer, but immune checkpoint inhibitors (ICIs) have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as important regulators of inflammasome activation in tumor associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone responsive PCa patients revealed that tumors from patients with high PIM1/2/3 display an immunosuppressive TME characterized by high inflammation (IL-1β and TNFα) and a high density of repressive immune cells, most notably TAMs. Strikingly, macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of prostate cancer. Transcriptional analyses indicate that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Collectively, our data implicate macrophage PIM as a driver of inflammation that limits the potency of ICIs and provides preclinical evidence that PIM inhibitors are an effective strategy to improve the efficacy of immunotherapy in prostate cancer.
Body dissatisfaction shapes time perception and interoception interplay
Authors: Rusinova Anna , Volodina Maria , Terenteva Kristina , Kosonogov Vladimir
Published: October 2024

This study explores the relationship between emotions, physiological responses, interoception, and time perception. We also aimed to understand how body dissatisfaction influences this interplay. Participants (N = 40) watched videos designed to evoke positive, neutral, and negative emotions while their heart rate was monitored via electrocardiography.

Our findings indicate that video duration perception varied depending on emotional content. Negative and neutral videos were perceived as shorter, while positive videos were estimated more accurately. Negative emotions were linked to a decrease in heart rate, suggesting a “freeze response,” while positive and neutral content did not significantly affect heart rate.

A significant correlation between heart rate and time perception was observed in participants with a normal body image, indicating that heart rate might serve as an internal clock. However, this correlation was absent in those with body image dissatisfaction, implying a weakened link between physiological states and time perception. Additionally, a strong negative correlation between heart rate and interoceptive accuracy was found in participants with body image dissatisfaction.

The results suggest that body image dissatisfaction disrupts the integration of emotional and physiological signals, affecting how we perceive and understand our internal bodily sensations and emotions.
Interaction of Genetic Variants Activates Latent Metabolic Pathways in Yeast
Authors: Sasikumar Srijith , Parkins Shannara Taylor , Sudarsan Suresh , Sinha Himanshu
Published: October 2024

Genetic interactions are prevalent across species, from yeast to humans, and play a crucial role in shaping complex traits. However, the molecular mechanisms underlying these interactions remain largely unexplored. Here, we answer the question of whether interactions between genetic variants can activate novel unique pathways and if such pathways can be targeted to modulate phenotypic outcomes. The model organismSaccharomyces cerevisiaewas used to investigate the interaction between two key SNPs,MKT189GandTAO34477C, during sporulation, a complex dynamic metabolic process. By integrating temporal gene expression and proteomics data, we show that these SNPs, in combination, activate amino acid metabolism, particularly the arginine biosynthesis pathway, while downregulating ribosome biogenesis, an energy-intensive process in response to nutrient starvation. This metabolic trade-off reveals a key mechanism by which SNP interactions modulate cellular responses to environmental stress, thereby enhancing sporulation. Further, the essential role of the arginine biosynthetic pathway in maintaining mitochondrial activity when these SNPs interact has been validated experimentally with deletion mutants. Our findings illustrate a broader impact beyond yeast, especially on complex human metabolic diseases like cancer, where specific SNP combinations hyperactivate ribosomal pathways while suppressing metabolic pathways that usually control cell growth, leading to uncontrolled proliferation.
Genetic interaction betweenGL15andFDL1modulates juvenile cuticle deposition and leaf permeability in maize
Authors: Castorina Giulia , Domergue Frédéric , Consonni Gabriella
Published: October 2024

The plant cuticle is a hydrophobic layer that serves as the primary barrier between plant surfaces and the external environment, limiting water loss and protecting against various stresses. This study investigates the genetic interaction between the maizeZmFDL1andZmGL15genes and their role in modulating juvenile cuticle deposition and leaf permeability. The research was undertaken to understand how these genes influence cuticle composition and structure, which are crucial for plant protection against environmental stresses such as drought. We analysed the chemical composition of cutin and waxes, as well as cuticle-dependent leaf permeability. Our findings reveal that ZmFDL1 and ZmGL15 individually and synergically regulate the deposition of cuticular components, with significant impacts on leaf permeability. Thegl15-Smutant exhibited an adult-like cuticle with higher cutin and lower wax contents, leading to reduced leaf permeability and improved water retention under drought conditions. These results highlight the importance of cutin in forming an effective water barrier and suggest that modulating cuticle composition with enhanced cutin content could be a strategy for improving drought tolerance in crops. This study provides new insights into the genetic regulation of cuticle biosynthesis and its relevance for plant adaptation to water scarcity.

Highlight

ZmFDL1 and ZmGL15 interact to modulate cuticle composition and reduce leaf water loss.

ZmFDL1andZmGL15genes regulate juvenile cuticle deposition in maize.

Thegl15-Smutant shows an adult-like cuticle with higher cutin and lower wax contents.

Thegl15-Smutation is epistatic tofdl1-1, partially rescuing the defectivefdl1cuticle phenotype.

The cuticle composition ingl15-Smutants leads to reduced leaf permeability and improved water retention under drought conditions.

Cuticular layer with enhanced cutin content could improve drought tolerance in crops.
Scale invariance of mechanical properties in the developing mammalian retina
Authors: Shelton Elijah Robinson , Frischmann Michael , Brinkop Achim Theo , James Rebecca Marie , Serwane Friedhelm
Published: October 2024

Neuronal tissues, like the retina, form through physical forces which induce remodeling over a range of time and length scales. How these mechanical stresses accumulate and relax during retinogenesis is unknown due to the difficulty in applying stressin situfrom seconds to hours in living neuronal tissue. In non-neuronal tissue and 2D cell culture, previous studies have revealed that material properties exhibit scale-free behavior. Whether this translates to developing neuronal tissues has remained an open question.

Here we demonstrate the existence of scale-free rheology in 3D neuronal tissue. We probed time-dependent tissue mechanics in anin vitromodel of the developing retina using magnetic droplets in mouse stem cell-derived retina organoids. We recorded strain responses to an applied stress across four orders of magnitude in time, up to one hour. Dynamic creep compliance and tensile moduli followed a power law with an exponent consistent with a material just above the glass transition. Our findings demonstrate that neuronal tissue remodels in a scale-free manner, prompting the question of whether scale-invariant mechanical properties are a general motif of neurodevelopment.
The effective multiplicity of infection for HCMV depends on activity of the cellular 20S proteasome
Authors: Cataldo Katie M. , Roche Kathryn L. , Monti Christopher E. , Dash Ranjan K. , Murphy Eain A. , Terhune Scott S.
Published: October 2024

Human cytomegalovirus (HCMV) is a betaherpesvirus capable of infecting numerous cell types and persisting throughout an infected individual’s life. Disease usually occurs in individuals with compromised or underdeveloped immune systems. Several antivirals exist but have limitations relating to toxicity and resistance. HCMV replication involves upregulation of host proteasomal activities which play important roles in the temporal stages of replication. Here, we defined the impact on replication kinetics of the proteasome inhibitor, bortezomib. We demonstrate that bortezomib significantly reduces levels of viral genomes and infectious virions produced from a population of cells. Inhibition reduced expression of viral proteins that are influenced by genome synthesis. When added prior to 24 hpi, we observe decreases in PCNA and Cdk1 while increases in p21 whose regulations contribute to efficient replication. This response synergized with an antiviral, maribavir. Since some replication occurred, we tested the hypothesis that a subset of infected cells might break through inhibition. Initially, we simulated bortezomib activities using a mechanistic computational model of late-lytic replication. Upon reducing MOIin-silico, we observed near identical simulated results compared to experimental data. Next, we analyzed replication using live-cell imaging. This revealed treated cultures do contain a population of cells with fully developed late-stage cytoplasmic assembly compartments but at significantly lower numbers. We refer to this as the effective MOI. Overall, our studies support a hypothesis in which 20S proteasome inhibition disrupts HCMV replication by reducing the MOI to an effective MOI, defined by a fraction of infected cells capable of progressing to fulminant infection.

IMPORTANCE

HCMV infection and reactivation continues to contribute to morbidity and mortality around the world. Antiviral compounds are available but have limitations. Here, we have defined the impact of the proteasome inhibitor bortezomib on HCMV replication. Proteasomal activities play a critical role in temporal changes required for replication. We demonstrate that disrupting these activities inhibits viral replication while likely supporting increased antiviral activity of the anti-HCMV agent, maribavir. Using a combination of live cell imaging and computational tools, we discover that a subset of infected cells progresses to fulminant infection which we define as the effective MOI, and this subset would otherwise be missed when analyzing the average of the population.