bluuebunny/crossref_metadata_2025 huggingface dataset:
Combating anoikis resistance: bioactive compounds transforming prostate cancer therapy
Authors: Gulia Shweta , Chandra Prakash , Das Asmita
Published: May 2024

The study aims to discuss the challenges associated with treating prostate cancer (PCa), which is known for its complexity and drug resistance. It attempts to find differentially expressed genes (DEGs), such as those linked to anoikis resistance and circulating tumor cells, in PCa samples. This study involves analyzing the functional roles of these DEGs using gene enrichment analysis, and then screening of 102 bioactive compounds to identify a combination that can control the expression of the identified DEGs. In this study, 53 DEGs were identified from PCa samples including anoikis-resistant PCa cells and circulating tumor cells in PCa. Gene enrichment analysis with regards to functional enrichment of DEGs was performed. An inclusive screening process was carried out among 102 bioactive compounds to identify a combination capable of affecting and regulating the expression of selected DEGs. Eventually, gastrodin, nitidine chloride, chenodeoxycholic acid, and bilobalide were selected, as their combination demonstrated ability to modulate expression of 50 out of the 53 genes targeted. The subsequent analysis focused on investigating the biological pathways and processes influenced by this combination. The findings revealed a multifaceted and multidimensional approach to tumor regression. The combination of bioactive compounds exhibited effects on various genes including those related to production of inflammatory cytokines, cell proliferation, autophagy, apoptosis, angiogenesis, and metastasis. The current study has made a valuable contribution to the development of a combination of bioactive natural compounds that can significantly impede the development of treatment resistance in prostate tumor while countering the tumors’ evasion of the immune system. The implications of this study are highly significant as it suggests the creation of an enhanced immunotherapeutic, natural therapeutic concoction with combinatorial potential.
Surgical treatment of colorectal endometriosis: an updated review
Authors: Schneyer Rebecca J. , Hamilton Kacey M. , Meyer Raanan , Nasseri Yosef Y. , Siedhoff Matthew T.
Published: May 2024

Purpose of review

This review aims to summarize recent literature on the surgical treatment of colorectal endometriosis.

Recent findings

The last decade has seen a surge in the number of studies on bowel endometriosis, with a focus on preoperative evaluation, perioperative management, surgical approach, and surgical outcomes. Many of these studies have originated from large-volume referral centers with varying surgical approaches and philosophies. Colorectal surgery for endometriosis seems to have a positive impact on patient symptoms, quality of life, and fertility. However, these benefits must be weighed against a significant risk of postoperative complications and the potential for long-term bowel or bladder dysfunction, especially for more radical procedures involving the lower rectum. Importantly, most studies regarding surgical technique and outcomes have been limited by their observational design.

The surgical management of bowel endometriosis is complex and should be approached by a multidisciplinary team. Methodical preoperative evaluation, including appropriate imaging, is vital for surgical planning and patient counseling. The decision to perform a more conservative or radical excision is nuanced and remains an area of controversy. High quality studies in the form of multicenter randomized controlled trials are needed before clear recommendations can be made.
Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium
Authors: Paramanandam Vincent S. , Lensen Sarah , Gabes Michaela , Kann Gesina , Donhauser Theresa , Waters Niamh F. , Li Anna D. , Peate Michelle , Susanto Nipuni S. , Caughey Lucy E. , Rangoonwal Fatema , Liu Jingbo , Condron Patrick , Obalowu Ismaila Aberi , Archer David F. , Bell Robin J. , Christmas Monica , Davies Melanie , Davis Susan R. , Giblin Karen , Iliodromiti Stamatina , Jaisamrarn Unnop , Khandelwal Sunila , Kiesel Ludwig , Aggarwal Neelam , Mitchell Caroline M. , Mishra Gita D. , Nappi Rossella E. , Panay Nick , Roberts Helen , Rozenberg Serge , Shifren Jan , Simon James A. , Stute Petra , Vincent Amanda J. , Wolfman Wendy , Hickey Martha
Published: May 2024

Objective

The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects.

Methods

We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome.

Results

A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of “pain with sexual activity” and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure “distress, bother or interference” from genitourinary symptoms. Six definitions of “side effects” were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice.

Conclusions

Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes.
Insights into ALD and AUD diagnosis and prognosis: Exploring AI and multimodal data streams
Authors: Narayanan Praveena , Wu Tiffany , Shah Vijay H. , Curtis Brenda L.
Published: May 2024

The rapid evolution of artificial intelligence and the widespread embrace of digital technologies have ushered in a new era of clinical research and practice in hepatology. Although its potential is far from realization, these significant strides have generated new opportunities to address existing gaps in the delivery of care for patients with liver disease. In this review, we discuss how artificial intelligence and opportunities for multimodal data integration can improve the diagnosis, prognosis, and management of alcohol-associated liver disease. An emphasis is made on how these approaches will also benefit the detection and management of alcohol use disorder. Our discussion encompasses challenges and limitations, concluding with a glimpse into the promising future of these advancements.
Best Practices in Documenting and Coding High-Value Care in Workers’ Compensation Encounters—ACOEM Guidance Statement
Authors: Cloeren Marianne , Chen Brian , Caretto David
Published: May 2024

Workers’ compensation outpatient care requires attention to causation, functional assessment, work disability prevention, and return-to-work planning, elements not usually addressed in other types of outpatient encounters. Because these elements of care deviate from the usual pattern of ambulatory services, providers of workers’ compensation care have faced challenges in billing and auditing practices resulting in underpayment when providing high-value care based on evidence-based guidelines. Recent changes in Centers for Medicare & Medicaid Services rules on documentation requirements for coding outpatient evaluation and management encounters offer an opportunity for occupational health clinicians to be paid appropriately for care that follows occupational medicine practice guidelines. There remains a need to define the elements of documentation that should be expected in delivering high-value workers’ compensation care. This article provides guidance for documenting high-value workers’ compensation care.
A Qualitative Study Describing Experiences of Pregnancy Discrimination in the Workplace
Authors: Borrowman Jaclyn D. , Unke Mackenzie , Jones Melissa A. , Whitaker Kara M.
Published: May 2024

Objectives

Qualitatively assess experiences of occupational pregnancy discrimination.

Methods

A fully remote phenomenological qualitative study was completed leveraging semistructured interviews with a sample of pregnant employees in the United States. Inclusion criteria included being pregnant, working at least 35 hours per week, employed at least 1 year at current employer, and without diagnosed depression/anxiety.

Results

Participants (N = 20) were, on average, 30 years of age, worked 42.6 hours per week, self-identified as non-Hispanic black (50%), and earned least a bachelor’s degree (85%). Individuals successfully identified various forms of pregnancy discrimination, believing it occurred due to systemic issues or perceptions that women are weak. Most did not report experiences of discrimination fearing retaliation or being unaware of workplace protections.

Conclusion

Pregnancy discrimination in the workplaces comes in various forms and is an issue for some working pregnant individuals.
Potential Misinformation in the Official Disability Guidelines About the Diagnosis and Treatment of Rotator Cuff Tendinopathy
Authors: Dwyer Darby , Ramachandran Shyam S. , McCall Kyle , Ragsdale Masen , Ring David , Ramtin Sina
Published: May 2024

Objective

We selected statements in the Official Disability Guidelines that had the potential to reinforce misconceptions regarding symptoms from rotator cuff tendinopathy. These statements were revised and presented with the original statement to specialists.

Methods

Twelve statements regarding rotator cuff tendinopathy were identified as deviating from principles based on ethics, values, and the evidence regarding both pathophysiology and human illness behavior. One hundred fifteen upper extremity surgeons reviewed both original and revised versions of the statements and indicated their preference.

Results

We found that upper extremity surgeons preferred 3 revised statements, 4 Official Disability Guidelines statements, and 5 were rated as neutral between the 2 statements.

Conclusions

Statements revised for evidence, ethics, and healthy mindset were not preferred by specialists, which may indicate limited awareness about how negative thoughts and distressing symptoms impact human illness.
Stress and Coping in Emergency Nurses Following Trauma Patient Care: A Qualitative Grounded Theory Approach
Authors: Gillespie Gordon L. , Meyer Holly A. , Daugherty Margot , Puthoff Delinda , Fryman Lisa J. , Howard Patricia Kunz
Published: May 2024

BACKGROUND:

Experiencing symptoms of traumatic stress may be the cost of caring for trauma patients. Emergency nurses caring for trauma patients are at risk for traumatic stress reactions.

OBJECTIVE:

This study explored the stress and coping behaviors experienced by emergency nurses who provide trauma care.

METHODS:

Focus groups were held at three urban trauma centers in the Midwestern United States: a Level I pediatric trauma center, a Level I adult trauma center, and a Level III adult trauma center. Data were collected between December 2009 and March 2010. Data analysis was guided by the principles of grounded theory. Line-by-line coding and constant comparative analysis techniques were used to identify recurring constructs.

RESULTS:

A total of 48 emergency nurses participated. Recurring constructs emerged in the data analysis and coding, revealing four major themes: care of the trauma patient, professional practice, personal life, and support.

CONCLUSIONS:

Nurse job engagement, burnout, and professional and personal relationships are influenced by trauma patient care. The study’s resulting themes of care of the trauma patient, professional practice, personal life, and support resulted in the development of the “trauma nursing is a continual experience theory” that can be used as a framework to address these effects. Intentional support and timely interventions based on this new theory can help mitigate the effects of traumatic stress experienced by trauma nurses.
Prognostic value of systemic inflammation score in patients with esophageal cancer
Authors: Yoneda Akira , Ogata Ryosuke , Ryu Shintaro , Yoshino Kyohei , Fukui Saeko , Kugiyama Tota , Kitasato Amane , Sugiyama Nozomu , Takeshita Hiroaki , Minami Shigeki , Kuroki Tamotsu
Published: May 2024

Introduction:

The systemic inflammatory score (SIS), a new inflammatory marker based on a combination of the lymphocyte-to-monocyte ratio (LMR) and serum albumin concentration, has been reported to be a useful prognostic marker for several malignancies. The authors conducted this retrospective study on data from a cohort of esophageal cancer patients undergoing potentially curative resection to clarify the value of SIS as a prognostic marker for clinical outcome in this population.

Methods:

This retrospective cohort study included 32 patients who underwent thoracoscopic esophagectomy after neoadjuvant chemotherapy for esophageal cancer between January 2016 and December 2019. Blood samples were collected within one week prior to the initiation of preoperative chemotherapy. Three inflammatory and nutritional markers; SIS, the neutrophil-to-lymphocyte ratio (NLR), and prognostic nutrition index (PNI) were examined in this study. Disease-free survival was assessed using the Kaplan–Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of SIS, NLR and PNI.

Results:

NLR and PNI were not associated with recurrence, while SIS scores of 1 and 2 were significantly associated with recurrence. In multivariate analysis, SIS scores of 1 or 2 were found to be independently associated with recurrence, each with a hazard ratio of 1.98. In addition, when examining immunologic and nutritional factors and survival rates, there was no significant difference in the survival rate for NLR and PNI; for SIS, however, the survival rate was significantly worse in patients with SIS scores of 1 or 2.

Conclusions:

The authors demonstrated that a novel and easily obtained prognostic score, termed SIS, based on pre-treatment serum albumin and LMR, can serve as an independent prognostic factor in postoperative esophageal cancer patients. It could be incorporated into conventional clinical and pathological algorithms to enhance the prognostic accuracy in this population.
Traumatic cavernosal artery pseudoaneurysm: a rare cause of erectile dysfunction following pelvic trauma: a case report and comprehensive literature review
Authors: katwal Shailendra , Ghimire Aastha , Paudel Pratiksha , Khatiwada Bidur
Published: May 2024

Introduction and importance:

Erectile dysfunction (ED) resulting from pelvic trauma, particularly cavernosal artery pseudoaneurysm, poses a complex clinical challenge. Traumatic injuries, including blunt force trauma, can lead to diverse vascular complications affecting erectile function. Recognizing and addressing these issues is pivotal for optimal patient management.

Case presentation:

A 40-year-old male presented with gradual-onset ED following a traumatic incident, involving a fall from a bike and subsequent hematoma on the penile shaft. Despite initial successful conservative management, the patient experienced recurrent symptoms. Comprehensive evaluation, including ultrasonography and computed tomography (CT) angiography, revealed a cavernosal artery pseudoaneurysm. The diagnostic journey involved Doppler ultrasound and penile arteriography, confirming the arteriogenic etiology.

Clinical discussion:

Pelvic trauma, a common cause of erectile dysfunction in men under 40, can lead to cavernosal arterial injuries and pseudoaneurysms. This condition often results from blunt perineal trauma or iatrogenic factors, requiring precise diagnostic tools like Doppler ultrasound and penile arteriography. Treatment options include coil embolization and Gelfoam application, emphasizing the importance of timely intervention.

Conclusion:

Successful angiography and coil embolization yielded significant improvement in symptoms for the presented case. This underscores the critical role of accurate diagnosis and tailored interventions in addressing cavernosal artery pseudoaneurysms resulting from pelvic trauma, thereby enhancing patient outcomes and quality of life.
Vascular Access Team Central Line Dressing Changes to Reduce Infection Risk
Authors: Draper Amelia , Nelson Susan , Taylor Beth , Arroyo Cassandra , Gasama Heather , Russell Robert
Published: May 2024

Due to low compliance by bedside nursing with a central line-associated bloodstream infection (CLABSI) prevention bundle and increased CLABSI rates, a mandatory re-education initiative at a 1200-bed university-affiliated hospital was undertaken. Despite this, 2 units, housing high-risk immunocompromised patients, continued to experience increased CLABSI rates. A quality improvement before-after project design in these units replaced bedside nursing staff with 2 nurses from the vascular access team (VAT) to perform central vascular access device (CVAD) dressing changes routinely every 7 days or earlier if needed. The VAT consistently followed the bundled components, including use of chlorhexidine gluconate (CHG)-impregnated dressings on all patients unless an allergy was identified. In this case, a non-CHG transparent semipermeable membrane dressing was used. There were 884 patients with 14 211 CVAD days in the preimplementation period and 1136 patients with 14 225 CVAD days during the postimplementation period. The VAT saw 602 (53.0%) of the 1136 patients, performing at least 1 dressing change in 98% of the patients (n = 589). The combined CLABSI rate for the 2 units decreased from 2.53 per 1000 CVAD days preintervention to 1.62 per 1000 CVAD days postintervention. The estimated incidence rate ratio (IRR) for the intervention was 0.639, a 36.1% reduction in monthly CLABSI rates during the postimplementation period.
Relative Cost and Infectious Days Averted Associated With Rapid Gonorrhea and Chlamydia Testing Among Men Who Have Sex With Men
Authors: Welford Elliott , Martin Thomas C.S. , Martin Natasha K. , Tilghman Winston , Little Susan J.
Published: May 2024

Background

Standard-of-care nucleic acid amplification tests (routine NAATs) for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) can take several days to result and therefore delay treatment. Rapid point-of-care GC/CT NAAT (rapid NAAT) could reduce the time to treatment and therefore onward transmission. This study evaluated the incremental cost per infectious day averted and overall cost of implementation associated with rapid compared with routine NAAT.

Methods

Prospective sexually transmitted infection (STI) treatment data from men who have sex with men and transgender women in San Diego who received rapid NAAT between November 2018 and February 2021 were evaluated. Historical time from testing to treatment for routine NAAT was abstracted from the literature. Costs per test for rapid and routine NAAT were calculated using a micro-costing approach. The incremental cost per infectious day averted comparing rapid to routine NAAT and the costs of rapid GC/CT NAAT implementation in San Diego Public Health STI clinics were calculated.

Results

Overall, 2333 individuals underwent rapid NAAT with a median time from sample collection to treatment of 2 days compared with 7 to 14 days for routine NAAT equating to a reduction of 5 to 12 days. The cost of rapid and routine GC/CT NAAT was $57.86 and $18.38 per test, respectively, with a cost-effectiveness of between $2.43 and $5.82 per infectious day averted. The incremental cost of rapid NAAT improved when at least 2000 tests were performed annually.

Conclusions

Although rapid GC/CT NAAT is more expensive than routine testing, the reduction of infectious days between testing and treatment may reduce transmission and provide improved STI treatment services to patients.
Isolated Fallopian Tube Torsion in Children With Hydrosalpinx
Authors: Mariani Aurora , Hameury Frédéric , Dubois Rémi , Demède Delphine , Gelas Thomas , Mure Pierre Yves , Gorduza Daniela
Published: May 2024

Background

Isolated fallopian tube torsion (IFTT) is very rare gynecological emergency in pediatric population. Our objective is to assess treatment options and discuss outcome of a cohort of IFTT with a focus on the association between IFTT and hydrosalpinx (HSX).

Methods

A retrospective review was conducted. Pediatric patients with IFTT operated in the same center were included.

Results

Seventeen girls (aged: 11–16 years) were managed for acute abdominal pain between 2008 and 2018, with intraoperative diagnosis of IFTT. All patients underwent laparoscopic exploration, with laparoscopically fallopian tube detorsion in all patients. Based on the association of IFTT with HSX after fallopian tube detorsion, patients were divided into 2 groups: group 1 (IFTT without HSX; 12 girls) and group 2 (IFTT with HSX; 5 girls). During the same surgery, complementary surgical procedures were done. In group 1: salpingectomies (4), partial salpingectomies (2) and cystectomies (6) were done. In group 2: salpingectomy (1), salpingotomy (1), and cyst ablation (1). The treatment was called conservative when the tube was preserved.

Follow-up was uneventful in group 1. In group 2, for all patients with initial fallopian tube preservation, further surgical procedures were necessary (1–4 surgeries/patient), and, finally, another 3 patients required salpingectomy.

Conclusions

Conservative treatment with tube preservation of IFTT without HSX appeared to be beneficial compared to those with HSX, with no recurrence of torsion or symptoms during the follow-up. However, the same conservative treatment was not sufficiently effective for IFTT with HSX and required further procedures due to recurrence of torsion.

Level of Evidence

IV.
Training the Next Generation of Local Public Health Leaders: A Case Study of Community Health Organizers in Pennsylvania
Authors: Lentes Julie C. , Taylor Gehman Amanda J. , Lengerich Eugene J. , Osetek Jennifer , Veldheer Susan , Gumby Angela , Luquis Raffy R. , Beiler Jessica , Kraschnewski Jennifer L.
Published: May 2024

Few short-term training programs exist for persons with limited experience or training in public health to support public health initiatives. We describe a public health training designed by the Pennsylvania (PA) Training Center for Health Equity for the PA Community Health Organizer (CHO) program. The CHO program was created to address the immediate needs of underserved communities and promote lasting health equity during the pandemic. CHOs are professionals who promote community action and align efforts with local organizations to build sustainable public health infrastructure and apply evidence-based practices to program policy, planning, and development. The training content, delivered by Project Extension for Community Healthcare Outcomes (ECHO) in 12 monthly sessions, focused upon foundational public health concepts in a novel community case study approach. The ECHO All Teach, All Learn training model was successful in providing relevant public health information to this new workforce, and the pre-/post-training evaluation demonstrated a positive increase in knowledge across all domains.
Medial Epicanthoplasty with the Skin-Redraping Technique: Technical Refinements for Predictable Outcomes
Authors: Wong Chin-Ho , Hsieh Michael Ku Hung
Published: May 2024

The epicanthus is a common feature of Asian eyes. A prominent medial epicanthal fold gives the impression of blunted affect. Medial epicanthoplasty for its removal is commonly requested by Asian patients. This may be performed as an isolated procedure or, more commonly, in combination with upper blepharoplasty. Many conventional medial epicanthoplasty techniques are based on skin flap transposition and excisions, usually variations of the V-Y, W, or Z-plasties. Although these have been variably successful at correcting the epicanthal fold, scarring in the medial canthal and lower eyelid regions is common. This is particularly problematic in Asian patients, who have greater tendencies for hypertrophic scarring and scar hypopigmentation or hyperpigmentation. Recently, the skin redraping method, designed with incisions limited within the margins of the medial canthus and precise and targeted disruption of the underlying fibromuscular tissues, has emerged as the preferred surgical technique for many surgeons in Asia because of its effectiveness and superior aesthetic outcomes. This technique delivers the most inconspicuous incisions and is advantageous because it is effective in eliminating epicanthal folds of various severities. Precise execution of this technique is difficult, given the complex 3-dimensional anatomy of the epicanthus. The authors present a detailed explanation of surgical concepts of the skin redraping epicanthoplasty and provide a step-by-step guide to performing this procedure in a safe and effective manner.
Using Behavioral Insights to Strengthen Strategies for Change. Practical Applications for Quality Improvement in Healthcare
Authors: Johansen Rie Laurine Rosenthal , Tulloch Simon
Published: May 2024

Objectives

For over 30 years, quality improvement (QI) methods have been used as a means of increasing the quality and safety of healthcare services, but with mixed success. One explanation highlighted in the literature for this outcome is the overemphasis on technical elements of change, and a failure to fully appreciate the human side of change. Behavioral insights (BI) is an approach that utilizes knowledge and tools from a broad range of scientific disciplines, such as neuroscience and behavioral psychology, to support behavior change. The aim of this paper is to explore the possibility of supplementing QI methods with tools and understanding from BI.

Methods

We outline a practical case that involved applying aspects BI methods into a QI program aimed at reducing the use of intravenous antibiotics in patients accessing services at a busy university hospital in Copenhagen, Denmark. We exemplify how to use BI tools to guide the analysis of staff behaviors during standard clinical processes and develop targeted interventions aimed at increasing actions and behaviors more aligned to best clinical practice.

Results

Outcomes suggest that it is possible to combine the models and methods from BI and QI in a way that is helpful in focusing attention on the human side of change when developing strategies for change. Potential psychological barriers identified from the analysis included the following: ‘default inertia,’ ‘decision complexity,’ ‘risk aversion,’ and biases related to confidence, confirmation, and omission.

Conclusions

Future quality improvement projects could benefit from integrating models and tools from BI to guide and support behavior change.
Care interruptions and mortality among adults in Europe and North America
Authors: Trickey Adam , Zhang Lei , Rentsch Christopher T. , Pantazis Nikos , Izquierdo Rebeca , Antinori Andrea , Leierer Gisela , Burkholder Greer , Cavassini Matthias , Palacio-Vieira Jorge , Gill M. John , Teira Ramon , Stephan Christoph , Obel Niels , Vehreschild Jorg-Janne , Sterling Timothy R. , Van Der Valk Marc , Bonnet Fabrice , Crane Heidi M. , Silverberg Michael J. , Ingle Suzanne M. , Sterne Jonathan A.C. ,   the Antiretroviral Therapy Cohort Collaboration (ART-CC)
Published: May 2024

Objective:

Interruptions in care of people with HIV (PWH) on antiretroviral therapy (ART) are associated with adverse outcomes, but most studies have relied on composite outcomes. We investigated whether mortality risk following care interruptions differed from mortality risk after first starting ART.

Design:

Collaboration of 18 European and North American HIV observational cohort studies of adults with HIV starting ART between 2004 and 2019.

Methods:

Care interruptions were defined as gaps in contact of ≥365 days, with a subsequent return to care (distinct from loss to follow-up), or ≥270 days and ≥545 days in sensitivity analyses. Follow-up time was allocated to no/preinterruption or postinterruption follow-up groups. We used Cox regression to compare hazards of mortality between care interruption groups, adjusting for time-updated demographic and clinical characteristics and biomarkers upon ART initiation or re-initiation of care.

Results:

Of 89 197 PWH, 83.4% were male and median age at ART start was 39 years [interquartile range (IQR): 31–48)]. 8654 PWH (9.7%) had ≥1 care interruption; 10 913 episodes of follow-up following a care interruption were included. There were 6104 deaths in 536 334 person-years, a crude mortality rate of 11.4 [95% confidence interval (CI): 11.1–11.7] per 1000 person-years. The adjusted mortality hazard ratio (HR) for the postinterruption group was 1.72 (95% CI: 1.57–1.88) compared with the no/preinterruption group. Results were robust to sensitivity analyses assuming ≥270-day (HR 1.49, 95% CI: 1.40–1.60) and ≥545-day (HR 1.67, 95% CI: 1.48–1.88) interruptions.

Conclusions:

Mortality was higher among PWH reinitiating care following an interruption, compared with when PWH initially start ART, indicating the importance of uninterrupted care.
Impact of HIV preexposure prophylaxis prescriptions on HIV diagnoses in New York City
Authors: Xia Qiang , Edelstein Zoe R. , Katz Benjamin , Bertolino Daniel , Berry Amanda , Tsoi Benjamin W. , Torian Lucia V.
Published: May 2024

Background:

HIV preexposure prophylaxis (PrEP) has proven to be efficacious and effective in preventing HIV infections, but few studies have reported its impact in the real world.

Methods:

We conducted an ecological analysis and compared the trends in HIV PrEP prescriptions with the trends in age-adjusted HIV diagnosis rates in New York City (NYC). Joinpoint regression analyses were used to identify any temporal trends in HIV diagnosis rates in NYC.

Results:

The number of people filling at least one PrEP prescription in NYC increased from 2551 in 2014 to 35 742 in 2022. The overall age-adjusted HIV diagnosis rate steadily decreased from 48.1 per 100 000 in 2003 to 17.1 per 100 000 in 2022. After the rollout of PrEP, accelerated decreases were detected in some subpopulations including white men [2014–2019 annual percentage change (APC): −16.6%; 95% confidence interval (CI) −22.7 to −10.0], Asian/Pacific Islander men (2016–2022 APC: −9.8%), men aged 20–29 years (2017–2020 APC: −9.4%) and 40 –49 years (2014–2020 APC: −12.2%), Latino/Hispanic people aged 40–49 years (2015–2020 APC: −13.0%), white people aged 20–29 years (2012–2022 APC: −11.4%) and 40–49 years (2014–2018 APC: −27.8%), and Asian/Pacific Islander people aged 20–29 years (2017–2022 APC: −13.0%).

Conclusion:

With a high coverage, PrEP can have a long-term impact in reducing HIV infections in a population, but if preexisting social determinants that contribute to racial, ethnic, and gender inequities are not well addressed, the implementation of PrEP can exacerbate these inequalities.
Early Non-Surgical Treatment For Microtia Types 1 and 2
Authors: Hilewitz Daniel , Olshinka Asaf
Published: May 2024

Esthetic concerns and psychosocial distress often accompany auricular deformities and malformations in both children and their parents. Approximately 30% of newborns are affected by auricular anomalies, with 15% to 20% resulting in permanent defects. While surgical intervention is typically considered the gold standard for malformations, a non-surgical approach, such as splinting, molding, or other non-invasive techniques, can effectively address deformations if promptly administered by a specialist. Microtia, classified into 4 types, presents challenges ranging from fundamental structural anomalies in types 1 and 2 to severe defects in type 3 and complete absence of the external ear in type 4 (anotia). This study introduces a novel non-invasive treatment modality for microtia types 1 and 2. The cohort consisted of 5 newborns treated for microtia types 1 or 2 between 2022 and 2023. Utilizing the EarWell system, treatment was initiated before 3 weeks of age (mean age: 2 weeks), with an average treatment duration of 6.6 weeks, supplemented by molding treatment as needed. Minor adverse effects, such as simple dermatitis, were observed in 2 patients. All parents expressed high satisfaction with the esthetic outcomes, with 60% reporting extreme satisfaction. The prompt initiation of the treatment protocol for microtia types 1 and 2 led to outstanding and timely outcomes in infants, enhancing the quality of life for both parents and their children. Early intervention for subsequent treatment may improve the condition and, in certain cases, serve as a satisfactory alternative for parents hesitant about further surgical intervention for their children.
Cell-type-specific Labeling of Endogenous Proteins Using the Split GFP System inDrosophila
Authors: Inal Melissa Ana , Banzai Kota , Kamiyama Rie , Kamiyama Daichi
Published: May 2024

i.

Accurate identification of the locations of endogenous proteins is crucial for understanding their functions in tissues and cells. However, achieving precise cell-type-specific labeling of proteins has been challengingin vivo. A notable solution to this challenge is the self-complementing split green fluorescent protein (GFP1-10/11) system. In this paper, we present a detailed protocol for labeling endogenous proteins in a cell-type-specific manner using the GFP1-10/11system in fruit flies. This approach depends on the reconstitution of the GFP1-10and GFP11fragments, creating a fluorescence signal. We insert theGFP11fragment into a specific genomic locus while expressing its counterpart,GFP1-10, through an available Gal4 driver line. The unique aspect of this system is that neither GFP1-10nor GFP11alone emits fluorescence, enabling the precise detection of protein localization only in Gal4-positive cells expressing the GFP11tagged endogenous protein. We illustrate this technique using the adhesion molecule geneteneurin-m(Ten-m) as a model, highlighting the generation and validation of GFP11protein trap lines via Minos-mediated integration cassette (MiMIC) insertion. Furthermore, we demonstrate the cell-type-specific labeling of Ten-m proteins in the larval brains of fruit flies. This method significantly enhances our ability to image endogenous protein localization patterns in a cell-type-specific manner and is adaptable to various model organisms beyond fruit flies.
Quinolinic acid links kidney injury to brain toxicity
Authors: Saliba Afaf , Debnath Subrata , Tamayo Ian , Tumova Jana , Maddox Meyer , Singh Pragya , Fastenau Caitlyn , Maity Soumya , Lee Hak Joo , Zhang Guanshi , Hejazi Leila , O’Connor Jason C. , Fongang Bernard , Hopp Sarah C , Bieniek Kevin F. , Lechleiter James D. , Sharma Kumar
Published: May 2024

Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2)conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a novel connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells adjacent to the ventricle in the setting of kidney failure. These findings were associated with brain inflammation and cell death. A separate mouse model of acute kidney injury also had an increase in circulating toxic tryptophan metabolites along with altered brain inflammation. Patients with advanced CKD similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life in humans. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.
Neuronal interactions in forebrain organoids lead to protective antiviral responses
Authors: Negatu Seble G. , Vazquez Christine , Bannerman Carl , Amses Kevin R. , Ming Guo-li , Jurado Kellie A.
Published: May 2024

Neurotropic viruses are the most common cause of infectious encephalitis and largely target neurons for infection. Our understanding of intrinsic neuronal innate immune response capacity to mediate protective antiviral responses remains incomplete. Here, we evaluated the role of intercellular crosstalk in mediating intrinsic neuronal immunity and its contribution to limiting viral infection. We found that in the absence of viral antagonism, neurons transcriptionally induce robust interferon signaling and can effectively signal to neighboring uninfected bystander neurons. Yet, in two-dimensional cultures, this dynamic response did not restrict viral spread. Interestingly, this differed in the context of viral infection in three-dimensional forebrain organoids with complex neuronal interactions, where we observed protective capacity. We show antiviral crosstalk between infected neurons and bystander neural progenitors is mediated by type I interferon signaling. Using spatial transcriptomics, we then uncover distinct regions of bystander progenitor interactions that reveal critical underpinnings of protective antiviral responses, including expression of distinct antiviral genes. These findings underscore the importance of intercellular communication in protective antiviral immunity in the brain and implicate key contributions to protective antiviral signaling.
Using informative priors to account for identifiability issues in occupancy models with identification errors
Authors: Monchy Célian , Etienne Marie-Pierre , Gimenez Olivier
Published: May 2024

Non-invasive monitoring techniques like camera traps, autonomous recording units and environmental DNA are increasingly used to collect data for understanding species distribution. These methods have prompted the development of statistical models to suit specific sampling designs and get reliable ecological inferences.

Site occupancy models estimate species occurrence patterns, accounting for the possibility that the target species may be present but unobserved. Here, two key processes are crucial: detection, when a species leaves signs of its presence, and identification where these signs are accurately recognized. While both processes are prone to error in general, wrong identifications are often considered as negligible with in situ observations. When applied to passive bio-monitoring data, characterized by datasets requiring automated processing, this second source of error can no longer be ignored as misclassifications at both steps can lead to significant biases in ecological estimates. Several model extensions have been proposed to address these potential errors.

We propose an extended occupancy model that accounts for the identification process in addition to detection. Similar to other recent attempts to account for false positives, our model may suffer from identifiability issues, which usually require another source of data with perfect identification to resolve them. As an alternative when such data are unavailable, we propose leveraging existing knowledge of the identification process within a Bayesian framework by incorporating this knowledge through an informative prior. Through simulations, we compare different prior choices that encode varying levels of information, ranging from cases where no prior knowledge is available, to instances with accurate metrics on the performance of the identification, and scenarios based on generally accepted assumptions. We demonstrate that, compared to using a default prior, integrating information about the identification process as a prior reduces bias in parameter estimates. Overall, our approach mitigates identifiability issues, reduces estimation bias, and minimizes data requirements.

In conclusion, we provide a statistical method applicable to various monitoring designs, such as camera trap, bioacoustics, or eDNA surveys, alongside non-invasive sampling technologies, to produce ecological outcomes that inform conservation decisions.
Robust and accurate method for measuring tumor volume using optical 3D scanning for nonclinical in vivo efficacy study
Authors: Kobayashi Takuma , Katsumata Mayumi , Nakamura Yoshiki , Terado Yuri , Araki Hideo , Maeda Eiki
Published: May 2024

In a nonclinicalin vivoefficacy test for anticancer drugs, immunodeficient mice subcutaneously transplanted with human cancer cells were quantified and evaluated with regard to the manner in which the skin bulges where locally proliferated cancer cells regress after drug administration. A caliper is conventionally used to measure the tumor bulge. However, its volume is an estimated value and results in high variability. Alternatively, cancer cell lines that express genetically encoded marker genes have been used in recent years for optical and nondestructive measurements. However, estimations using calipers exhibit large errors, and biological tissues have low light transparency. This hinders quantitative optical measurements. In addition, variations in measurements owing to subjective and human operations are likely.

From the chemistry, manufacturing, and control (CMC) perspective, precise measurement is required to evaluate drug efficacy and quality. Therefore, we aimed to eliminate errors caused by the use of estimated values, subjectivity, and human manipulation by precisely quantifying the volume of the tumor bulge using a 3D scanner.

This study demonstrated that optical 3D scanner measurements were accurate, had low variability, and was highly correlated with tumor weight. The tumor bulge was observed to vary to a flattened oval dome shape rather than a semicircle. This caused high variability in measurements of tumor volume. However, the proposed 3D scanner was more sensitive to volumetric regression than the caliper. Additionally, it exhibited drug efficacies with higher resolution than the caliper. Furthermore, the high linearity of the scanner provided more accurate measurements over a wider range of tumor sizes than luminescence imaging. The accurate and sensitive properties of such 3D scanners are also likely to make these exceptionally effective analytical tools for ensuring product equivalency when modifying raw materials or manufacturing processes in the development of cell therapy products.

As described above, robust and accurate drug efficacy measurements using nondestructive and noninvasive 3D scanners that require no training and are convenient to operate provide many analytical improvements and advantages. This is likely to play an important role in 1) the efficacy evaluation of cell therapy products that have large variations originating from the raw materials and large differences between manufacturing lots and 2) the quality evaluation, property analysis of the characteristics of variations in the shape of tumor bulges over time, and comparability testing of the products in the CMC section of pharmaceutical companies.
Exploring the Limits of EPR-driven Tumor Accumulation with Non-opsonizing Nanomaterials
Authors: Serzants Rinalds , Svalbe Baiba , Cesnokova Irina , Stelfa Gundega , Sizovs Antons
Published: May 2024

The Enhanced Permeability and Retention (EPR) effect is a foundational concept used to rationalize nanomedicine development for cancer treatment and diagnostics. The attainable efficacy of passive tumor targeting due to EPR remains ambiguous owing to pervasive opsonization of nanoparticles. To address this, we developed nanomaterials with complete resistance to opsonization, exceptionally long systemic circulation, and used them to study the limits of the EPR in triple-negative breast cancer. Tumors exerted no impact on pharmacokinetic profiles, which were indistinguishable between healthy and tumor-bearing mice. Tumors were the primary accumulation sites and our data revealed that the maximum average achievable tumor accumulation via EPR is proximate to 60 %ID/g, tumor- to-liver selectivity is 4-to-1, and the optimal DHto fully exploit EPR lies between 18 and 54 nm. The significant heterogeneity observed in tumor accumulation, however, indicates that nanomedicines cannot achieve consistent efficacy across different patients by relying solely on EPR.
Targeting protein tyrosine phosphatase non-receptor type 2 with a novel inhibitor for AML therapy
Authors: Kuang Wenbin , Jiang Jinxin , Wang Xiao , Wang Dawei , Ji Minghui , Zhu Yasheng , Yuan Kai , Ding Jiayu , Wang Wenmu , Song Mingge , Min Wenjian , Huang Fei , Wang Liping , Gu Wanjian , Hao Haiping , Xiao Yibei , Yang Peng
Published: May 2024

Acute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knock down of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and C-MYC, establishing C-MYC as a direct acting substrate of PTPN2. Then, we performed a small-molecule compound screening to identify K73, a selective inhibitor of PTPN2. At the same time, K73 showed a good safety profile and exhibited strong activity against AML in vivo. In conclusion, we have pinpointed a considerable therapeutic potential in targeting PTPN2 for AML treatment and discovered a novel class of selective PTPN2 inhibitors suitable for AML therapy.
Inferring the composition of the blood plasma proteome by a human proteome distribution atlas
Authors: Malmström Erik , Hauri Simon , Mohanty Tirthankar , Scott Aaron , Karlsson Christofer , Gueto-Tettay Carlos , Åhrman Emma , Nozohoor Shahab , Tingstedt Bobby , Regner Sara , Elfving Peter , Bjermer Leif , Forsvall Andreas , Doyle Alexander , Magnusson Mattias , Hedenfalk Ingrid , Kannisto Päivi , Brandt Christian , Nilsson Emma , Dahlin Lars B , Malm Johan , Linder Adam , Malmström Lars , Nimeus Emma , Malmström Johan
Published: May 2024

The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent different organs and cells contribute to the plasma proteome composition, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in human plasma in health and disease. First, we constructed an extensive human proteome atlas from 18 vascularized organs and the most abundant cell types in blood. Second, the atlas was interfaced with previous RNA/protein atlases to objectively define proteome wide protein-organ associations to enable both the inference of origin and the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease-specific quantitative changes of organ-enriched protein panels in three separate patient cohorts with infection, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.