bluuebunny/crossref_metadata_2025 huggingface dataset:
Literature review and case report of septic arthritis and purpura fulminans leading to a child limb amputation as chickenpox complications
Authors: Hijazi Bassel , Nairoukh Effat , Yahya Razan M. , Abunejma Fawzy M.
Published: August 2024

Introduction and significance:

Chickenpox, induced by the varicella-zoster virus (VZV), generally presents with an itchy rash and fluid-filled blisters. While complications such as pneumonia and sepsis are well-documented, occurrences of septic arthritis and purpura fulminans are exceedingly rare. Septic arthritis following varicella infection is infrequently reported and often attributed to Staphylococcus aureus. Purpura fulminans encompasses disorders characterized by rapidly progressing purpuric lesions, often fatal and associated with consumptive coagulopathy.

Case presentation:

The authors present the case of an 8-year-old boy diagnosed with chickenpox who concurrently developed severe left knee pain, erythema, and swelling indicative of septic arthritis, along with a single pustular lesion on his right foot that progressed to purpura fulminans. Laboratory investigations revealed elevated inflammatory markers. Knee ultrasound findings were consistent with septic arthritis, corroborated by synovial fluid analysis. Immediate initiation of empiric antibiotics was undertaken. Further investigation disclosed unusual coagulation parameters, positive autoantibodies, and reduced protein S levels. Treatment included anticoagulation, immunomodulation, and ultimately, amputation.

Clinical discussion:

This rare case underscores the complexity of varicella-related complications, representing the first documented instance of simultaneous septic arthritis and purpura fulminans in a pediatric patient. It highlights the necessity of a multidisciplinary approach for accurate diagnosis and management, emphasizing the importance of recognizing rare complications to improve patient outcomes.

Conclusion:

This case exemplifies the complexity of varicella-associated complications, showcasing a rare simultaneous occurrence of septic arthritis and purpura fulminans in a pediatric patient. It underscores the importance of a thorough understanding and collaborative management approaches for timely intervention and enhanced clinical outcomes.
Rhino-orbital-cerebral mucormycosis with Klebsiella and MRSA co-infection in a diabetic patient: a case report
Authors: Subedi Ram Chandra , Adhikari Ayush , Gurung Shekhar , Jha Pinky , Acharya Subi , Shiwakoti Tibbin Kumar , Bhatta Bhuwan , Kharbuja Naresh , Lamichhane Barada , Paudel Raju , Jha Saroj Kumar
Published: August 2024

Introduction and importance:

Rhino-orbital-cerebral mucormycosis is an opportunistic infection caused by fungus species Rhizopus and Mucor. Early recognition and aggressive management is crucial for favorable outcomes. A delay in diagnosis and treatment is fatal.

Case presentation:

A 32-year-old female presented with high-grade fever, right-sided facial deviation associated with facial swelling, and inability to move her left eye for 10 days. Biopsy from the left nasal cavity showed fibrinoid material, edema, and sheets of neutrophilic infiltrate while KOH preparation of nasal scrapping showed aseptate hyphae with obtuse-angled branching. Amphotericin B, oral posaconazole, and antibiotics were started with exploration and debridement of the affected tissue. The patient recovered well and was discharged.

Discussion:

Immunocompromised people are primarily affected by mucormycosis, a serious fungal illness. Inhaling fungal spores, especially those of the Rhizopus and Mucor species, is the usual cause. Rhinocerebral mucormycosis (ROCM), the most common type, increased during COVID-19 pandemic, frequently as a result of hyperglycemia brought on by steroids. Angioinvasion and tissue necrosis are pathogenesis-related processes that are made worse by diabetes and the overuse of glucocorticoids. Histopathology, culture, and imaging are used in the diagnosis. Surgery and antifungal drugs like Amphotericin B are used in treatment. Early intervention and interdisciplinary care, including hyperbaric oxygen therapy, are critical for survival. Results deteriorate with postponed therapy, underscoring the urgency of prompt action.

Conclusion:

Mucormycosis should be kept in mind while formulating differential diagnosis of infective pathology in immunocompromised patients. Early diagnosis and treatment are important in improving patient prognosis in rhino-orbital-cerebral mucormycosis.
Sigmoid colon cancer presenting as a large abdominal mass accompanied by abscess and rupture: a case report and literature review
Authors: Ding Haibo , Xu Baiying , Wang Yueming , Xu Bin , Qiu Wei , Zhang Wenzhong , Wang Yongbing , Li Gang
Published: August 2024

Introduction and Importance:

Colon cancer presenting as a large abdominal mass accompanied by abscess and rupture is rare and prone to be misdiagnosed and delayed. In addition, the treatment plan is not clear when combined with abdominal wall metastasis.

Case Presentation:

A 79-year-old woman presented with a large abdominal mass accompanied by abscess and rupture. It was misdiagnosed as a soft tissue infection in a local hospital, and after a comprehensive examination, it was diagnosed as sigmoid colon cancer with abdominal wall metastasis and abscess formation. The patient underwent a one-stage surgery, including en bloc resection of the tumor and invaded abdominal wall, as well as autologous tissue abdominal wall reconstruction, with a good clinical prognosis.

Clinical Discussion:

For the diagnosis of large abdominal masses, abdominal CT, and pus culture are more valuable than ultrasound. For colon cancer with abdominal wall metastasis, one-stage surgery to completely remove the tumor and full-thickness of the abdominal wall, and the use of autologous tissue abdominal wall reconstruction technology to repair defects is feasible.

Conclusion:

This case highlights the importance of using colon cancer as one of the differential diagnoses for the diagnosis for large abdominal mass accompanied by abscess and rupture in elderly patients, as well as the possibility of one-stage surgical resection of the tumor and invasion of the abdominal wall and reconstruction of the abdominal wall with autologous tissue when there is abdominal wall metastasis.
Further Refinements in Otoplasty Surgery: A Modified Approach to Prevent Suture Extrusion in Cartilage-Suturing Otoplasty Using a Postauricular Dermofascial Flap
Authors: Bulstrode Neil W. , Ronde Elsa M. , Mazeed Ahmed S.
Published: August 2024

Background:

Suture extrusion has been reported to be the most common complication after cartilage-sparing otoplasty. Several studies have described various designs of postauricular flaps to cover the cartilage sutures and reduce the incidence of suture extrusion.

Methods:

A total of 100 consecutive patients with prominent ears were operated on between January of 2018 and February of 2023 using a deepithelialized postauricular dermofascial flap that is performed as an adjunct to the authors’ cartilage-sparing otoplasty technique, which is essentially a combined modified Mustardé and Furnas technique. The flap is used to cover the cartilage-holding sutures with an extra layer of vascularized tissue to avoid the scar being directly over these sutures.

Results:

The median age of patients was 12 years (interquartile range, 9 to 15). One out of the 100 patients (1%) developed a postauricular skin infection requiring surgical removal of sutures. Primary suture extrusion did not occur; in an earlier study of cartilage-sparing technique without the postauricular flap, 17 out of 200 patients had suture extrusion (P = 0.001). No hematoma occurred that necessitated return to the theater. Skin necrosis and wound dehiscence did not occur in any case. No patient developed cartilage deformities or relapse requiring surgical correction.

Conclusions:

Combining cartilage-sparing otoplasty using sutures and the described postauricular dermofascial flap is simple to perform and has significantly reduced the complication rate and improved the outcome compared with cartilage-sparing otoplasty alone. This flap is recommended for both primary and revisional otoplasty.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Breast-Conserving Therapy Preserves Sexual Well-Being More than Postmastectomy Breast Reconstruction: Trends, Factors, and Interventions
Authors: Stern Carrie S. , Kim Minji , Smith Montes Elizabeth , Boe Lillian A. , Zhang Kevin , Vingan Perri , Carter Jeanne , Mehrara Babak J. , Tadros Audree B. , Allen Robert J. , Nelson Jonas A.
Published: August 2024

Background:

Up to 85% of patients with breast cancer report sexual health concerns, but their concerns are not adequately addressed by providers. Sexual dysfunction among patients with breast cancer remains understudied. The authors aimed to investigate the impact of breast-conserving therapy (BCT) and postmastectomy breast reconstruction (PMBR) on the sexual health of patients with breast cancer and the frequency of sexual medicine consultation in postoperative care.

Methods:

The authors conducted a retrospective analysis of patients who underwent BCT or PMBR and completed the Sexual Well-Being section of the BREAST-Q BCT and Reconstruction modules from January of 2010 through October of 2022. They compared Sexual Well-Being scores between patients who received BCT or PMBR over time up to 5 years after surgery, delineated associated demographic and clinical factors with Sexual Well-Being scores, and evaluated the frequency of sexual medicine consultations.

Results:

Of 15,857 patients, 8510 (53.7%) underwent BCT and 7347 (46.3%) underwent PMBR. Patients who underwent PMBR had significantly lower Sexual Well-Being scores than patients who underwent BCT from preoperatively to 5 years postoperatively. Regression analyses showed that patients who underwent PMBR scored 7.6 points lower at 1 year than patients who underwent BCT. Separated marital status, higher body mass index, cardiovascular disease, hyperlipidemia, psychiatric diagnosis, and neoadjuvant chemotherapy were associated with significantly lower Sexual Well-Being scores. A total of 299 patients (3.5%) who underwent BCT and 400 patients (5.4%) who underwent PMBR received sexual medicine consultations.

Conclusions:

Sexual health concerns must be considered in breast cancer care, particularly among patients who undergo PMBR. Although many patients experience sexual dysfunction, most do not receive a sexual medicine consultation, suggesting an opportunity for providers to improve the sexual health of patients with breast cancer.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Cost Comparison of Digital Nerve Repair Techniques
Authors: Hu Kevin , Williams Mica C. G. , Kammien Alexander J. , Canner Joseph , Mukherjee Thayer , Hill Elspeth , Colen David
Published: August 2024

Background:

Direct cost comparisons of nerve allograft with other techniques for repairing short digital nerve gaps are lacking. This study compares the costs of various techniques for digital nerve repair, anticipating significant cost increases for allograft implants.

Methods:

The State Ambulatory Surgery and Services Databases for Florida, New York, and Wisconsin from 2015 through 2020 were used. Patients with primary repair, short autograft, conduit, and allograft were compared along total, surgical supply, operating room, and anesthesia charges.

Results:

Among 5009 patients, there were 2967 primary nerve repairs (59.2%), 77 autografts (1.5%), 1647 conduits (32.9%), and 318 allografts (6.3%). A total of 2886 patients were male (57.6%), and the mean patient age was 40.4 ± 16.3 years. Over the study period, primary repairs decreased (from 63.9% in 2015 to 56.3% in 2020), whereas allografts increased significantly (from 8.8% in 2018 to 12.6% in 2020). Median total charges varied significantly across procedures, with the most expensive being allograft ($35,295), followed by conduit ($25,717), autograft ($24,749), and primary repair ($18,767). On multivariable regression, allografts were significantly more expensive than autografts in total charges of $11,224 (95% CI, $4196 to $18,252) and supply charges of $10,484 (95% CI, $6073 to $14,896), but not in operating room or anesthesia charges. Flexor tendon repair was associated with greater total, operating room, and anesthesia charges, but had similar supply charges.

Conclusions:

Nerve allografting is the most expensive digital nerve repair technique, most likely due to the cost of the implant. To minimize health care expenditure and ensure equitable patient access, surgeons should consider this cost along with clinical factors when choosing digital nerve repair techniques.
True and False Positive HIV Point of Care Test Results in a Prospective Multinational Study of At-Risk African Women: Implications for Large-Scale Repeat HIV Testing in HIV Prevention Programs
Authors: Morrison Susan , Batting Joanne , Wanga Valentine , Beesham Ivana , Deese Jennifer , Hofmeyr G. Justus , Kasaro Margaret P. , Louw Cheryl , Morrison Charles , Mugo Nelly R. , Palanee-Phillips Thesla , Pleaner Melanie , Reddy Krishnaveni , Scoville Caitlin W. , Smit Jenni , Stringer Jeffrey S.A. , Ahmed Khatija , Bukusi Elizabeth , Kotze Philip , Baeten Jared M. ,   for the ECHO Trial Team
Published: August 2024

Background:

Accurate HIV point of care testing is the cornerstone of prevention and treatment efforts globally, although false (both negative and positive) results are expected to occur.

Setting:

We assessed the spectrum of true and false positive HIV results in a large prospective study of HIV incidence in African women using 3 contraceptive methods tested longitudinally in Eswatini, Kenya, South Africa, and Zambia.

Methods:

HIV serologic testing was conducted quarterly using 2 parallel rapid HIV tests. When one or both tests were positive, additional confirmatory testing was conducted, including HIV enzyme immunoassay (EIA) and RNA.

Results:

A total of 7730 women contributed 48,234 visits: true positive results occurred at 412 visits (0.9%) and false positives at 96 visits (0.2%). Of 412 women with HIV seroconversion, 10 had discordant (ie, 1 negative and 1 positive) rapid tests and 13 had undetectable HIV RNA levels. Of 62 women with false positive rapid HIV results, most had discordant rapid testing, but 6 (9.7%) had dually positive rapid results, and 4 (6.5%) had false positive or indeterminate EIA results. The positive predictive value of dual positive rapid results was 98.3%.

Conclusions:

Although most rapid test results were accurate, false positive results were expected and occurred in this population of initially HIV seronegative individuals tested repeatedly and prospectively. When HIV infection occurred, not all cases had textbook laboratory results. Our findings highlight the importance of confirmatory testing, particularly for individuals undergoing repeat testing and in settings where the point prevalence is expected to be low.

Trial registration:

ClinicalTrials.gov number NCT02550067.
Follow-Up Outcomes of Children, Adolescents, and Young People on Darunavir-Based Third-Line Antiretroviral Therapy: Observational Cohort From 9 African Countries
Authors: Tukei Vincent J. , Machekano Rhoderick , Tchounga Boris K. , Khumalo Philisiwe Ntombenhle , Tumwebaze Rachel , Murandu Mildrate , Viana Shannon , Masaba Rose Otieno , Mokone-Mwape Majoalane , Chirwa Lameck , Mashizwa Simba , Rakhmanina Natella , Tiam Appolinaire ,   The New Horizon's Study Team
Published: August 2024

Background:

We assessed clinical outcomes among children, adolescents, and people younger than 25 years on darunavir-based antiretroviral therapy (ART) in 9 sub-Saharan African countries.

Setting:

Third-line ART centers in Cameroon, Eswatini, Kenya, Lesotho, Nigeria, Rwanda, Uganda, Zambia, and Zimbabwe.

Methods:

From January 2019 to December 2022, we collected data from a cohort of children, adolescents, and young people receiving third-line ART from 9 sub-Saharan African countries. Data on treatment continuity, viral suppression, death, and clinic transfers were extracted from medical records and summarized. Cox proportional hazards models were used to identify factors independently associated with retention in care.

Results:

Of 871 participants enrolled, the median age was 14.8 (range: 0.2–24.7) years and 488 (56.0%) were male; 809 (92.9%) [median duration of follow-up of 28.3 months (interquartile range: 17.5–45.2)] had final outcomes after initiating third-line ART. Of these, 711 (87.9%) were alive and in care at the end of study follow-up, 29 (3.6%) died, 30 (3.7%) were transferred to other facilities, and 39 (4.8%) were lost to follow-up. Retention in care was less likely among male patients compared with female patients [aHR: 0.85, 95% confidence interval: 0.72 to 1.0] and in 10–14-year-old children compared with younger children. Adolescents (15–19 years old) had higher mortality compared with children younger than 10 years (aSHR: 4.20, 95% confidence interval: 1.37 to 12.87). Viral suppression was seen in 345/433 (79.7%), 249/320 (77.8%), and 546/674 (81.0%) patients with results at 6 months, 12 months, and study end, respectively.

Conclusions:

A high proportion of children and young people receiving third-line ART in sub-Saharan Africa remain in care and attain viral suppression during follow-up.
Performance and Interpretation of Lung Scintigraphy
Authors: Le Pennec Romain , Schaefer Wolfgang , Tulchinsky Mark , Lamoureux François , Roach Paul , Rischpler Christoph , Zukotynski Katherine , O’Brien Christopher , Murphy Declan , Pascal Pierre , Le Gal Grégoire , Salaun Pierre-Yves , Le Roux Pierre-Yves
Published: August 2024

Purpose

Although ventilation/perfusion (V/Q) scintigraphy is a widely used imaging test, different options are possible for the acquisition and interpretation of the scan. The aim of this study was to assess current practices regarding the use and interpretation of lung scintigraphy in various clinical indications.

Patients and Methods

An online survey comprising 25 questions was sent to nuclear medicine departments in Australia, Canada, France, Germany, and United States between 2022 and 2023. A single response per department was consolidated.

Results

Four hundred nineteen responses were collected (Australia: 32, Canada: 58, France: 149, Germany: 92, and United States: 88). For acute pulmonary embolism (PE) diagnosis, 82.8% of centers reported using SPECT acquisitions (Australia: 93.3%, Canada: 91.8%, France: 99.2%, Germany: 96.2%, and United States: 32.1%). Among them, SPECT images were combined with a CT scan in 70.5% of centers. A total of 10.6% of centers reported not using ventilation for acute PE diagnosis. SPECT acquisition was used in 97.8% of centers using 99mTc carbon particles, 97.1% 81mKr gas, 58.7% 99mTc-DTPA, and 19.4% 133Xe gas, respectively. For V/Q SPECT interpretation, the EANM criteria were used in 65.0% of departments. A very wide variety of practices were observed in pregnant women and in COVID-19 patients. SPECT acquisition was widely used in the follow-up of PE and for the screening of chronic thromboembolic pulmonary hypertension (>90% of centers), with inconsistency regarding the interpretation of matched perfusion defects in this setting.

Conclusions

This survey shows the strong adoption of SPECT in the various clinical indications of lung scintigraphy, except in the United States, where planar imaging is still mostly used. The survey also shows variability in interpretation criteria both for PE diagnosis and screening for chronic thromboembolic pulmonary hypertension, highlighting the need for further standardizations of practices.
Artificial Intelligence
Authors: Kron Philipp , Farid Shahid , Ali Sharib , Lodge Peter
Published: August 2024

We have assessed the chatbot Generative Pretrained Transformer, a type of artificial intelligence software designed to simulate conversations with human users, in an experiment designed to test its relevance to scientific writing. chatbot Generative Pretrained Transformer could become a promising and powerful tool for tasks such as automated draft generation, which may be useful in academic activities to make writing work faster and easier. However, the use of this tool in scientific writing raises some ethical concerns and therefore there have been calls for it to be regulated. It may be difficult to recognize whether an abstract or paper is written by a chatbot or a human being because chatbots use advanced techniques, such as natural language processing and machine learning, to generate text that is similar to human writing. To detect the author is a complex task and requires thorough critical reading to reach a conclusion. The aim of this paper is, therefore, to explore the pros and cons of the use of chatbots in scientific writing.
Early major fracture care in polytrauma—priorities in the context of concomitant injuries: A Delphi consensus process and systematic review
Authors: Pfeifer Roman , Klingebiel Felix Karl-Ludwig , Balogh Zsolt J. , Beeres Frank J.P. , Coimbra Raul , Fang Christian , Giannoudis Peter V. , Hietbrink Falco , Hildebrand Frank , Kurihara Hayato , Lustenberger Thomas , Marzi Ingo , Oertel Markus F. , Peralta Ruben , Rajasekaran Shanmuganathan , Schemitsch Emil H. , Vallier Heather A. , Zelle Boris A. , Kalbas Yannik , Pape Hans-Christoph ,   for the IMPACT group—International MultidisciPlinAry Consensus Panel on PolyTrauma
Published: August 2024

BACKGROUND

The timing of major fracture care in polytrauma patients has a relevant impact on outcomes. Yet, standardized treatment strategies with respect to concomitant injuries are rare. This study aims to provide expert recommendations regarding the timing of major fracture care in the presence of concomitant injuries to the brain, thorax, abdomen, spine/spinal cord, and vasculature, as well as multiple fractures.

METHODS

This study used the Delphi method supported by a systematic review. The review was conducted in the Medline and EMBASE databases to identify relevant literature on the timing of fracture care for patients with the aforementioned injury patterns. Then, consensus statements were developed by 17 international multidisciplinary experts based on the available evidence. The statements underwent repeated adjustments in online- and in-person meetings and were finally voted on. An agreement of ≥75% was set as the threshold for consensus. The level of evidence of the identified publications was rated using the GRADE approach.

RESULTS

A total of 12,476 publications were identified, and 73 were included. The majority of publications recommended early surgery (47/73). The threshold for early surgery was set within 24 hours in 45 publications. The expert panel developed 20 consensus statements and consensus >90% was achieved for all, with 15 reaching 100%. These statements define conditions and exceptions for early definitive fracture care in the presence of traumatic brain injury (n = 5), abdominal trauma (n = 4), thoracic trauma (n = 3), multiple extremity fractures (n = 3), spinal (cord) injuries (n = 3), and vascular injuries (n = 2).

CONCLUSION

A total of 20 statements were developed on the timing of fracture fixation in patients with associated injuries. All statements agree that major fracture care should be initiated within 24 hours of admission and completed within that timeframe unless the clinical status or severe associated issues prevent the patient from going to the operating room.

LEVEL OF EVIDENCE

Systematic Review/Meta-Analysis; Level IV.
Gender Representation in the ECT Workforce in the United States From 2013 to 2021
Authors: Luccarelli James , Hart Kamber L. , McCoy Thomas H.
Published: August 2024

Objectives

Electroconvulsive therapy (ECT) is an effective treatment for a range of psychiatric disorders. Although much research has examined what patients receive ECT, there is less research describing those physicians who provide ECT services. This study examines the ECT workforce in the United States by analyzing publicly available Medicare billing records.

Methods

Data regarding the providers performing ECT were accessed from the Medicare Physician and Other Supplier Data for the years 2013 through 2021 based on those physicians who billed the ECT procedural code 90870.

Results

During the study period, 1402 physicians performed ECT in at least 1 calendar year on a minimum of 11 Medicare beneficiaries, representing 3.9% of the 36,116 psychiatrists who billed Medicare during this period. Female physicians made up 39% of psychiatrists overall who bill Medicare, but 23% of psychiatrists billing for ECT. Fifty percent of billed ECT treatments were performed by 12% of ECT doctors; among these high-volume ECT providers, 16% were female.

Conclusions

Only a small subset of psychiatrists who bill Medicare provide ECT services, and female physicians are under-represented in the ECT workforce and among high-volume ECT providers. Improving workforce equity and with it access to ECT requires further study of psychiatric training and practice environment that may impose barriers on female participation as ECT providers.
Human Metapneumovirus (hMPV): An associated etiology of Severe Acute Respiratory Infection in Children of Eastern Uttar Pradesh, India.
Authors: Deval Hirawati , Kumar Niraj , Srivastava Mitali , Potdar Varsha , Mehta Anita , Verma Ayushi , Singh Rajeev , Kavathekar Asif , Kant Rajni , Murhekar Manoj
Published: August 2024

Acute respiratory infections (ARIs) are a serious public health concern across the world, causing considerable morbidity and mortality. Every year, around 13 million children under the age of five die. Approximately 95% of them are from developing nations, and ARIs are responsible for one-third of all deaths. Human Metapneumovirus (hMPV) is one of the causative agents associated with respiratory tract infections. There is lack of information about hMPV from the eastern region of Uttar Pradesh. In our centre, Indian Council of Medical Research- Regional Medical Research Centre Gorakhpur (ICMR‐RMRC Gorakhpur) at Gorakhpur, Uttar Pradesh, India; we tested for respiratory pathogens in under-five patients presenting with ARI and severe acute respiratory illness (SARI) through semi nested PCR. A total of 100 nasal and throat specimens were collected from the OPD and IPD of Department of Paediatrics, BRD Medical College, Gorakhpur during from February 2022 to April 2022. Out of 100 enrolled pediatric patients, 4 (4%) were found to be positive. Among the patients who tested positive for hMPV, 25% (1/4) patient unfortunately died. The phylogenetic analysis of hMPV showed the close resemblance with the clade of Singapore and USA hMPV isolates. Our work underlines the importance of hMPV as the cause of acute respiratory infections in children and the need for routine testing for this virus in laboratories. Further comprehensive information regarding the incidence of hMPV in this area is needed.
A new model of endotracheal tube biofilm identifies combinations of matrix-degrading enzymes and antimicrobials able to eradicate biofilms of pathogens that cause ventilator-associated pneumonia
Authors: Walsh Dean , Parmenter Chris , Bakker Saskia E. , Lithgow Trevor , Traven Ana , Harrison Freya
Published: August 2024

Ventilator-associated pneumonia is defined as pneumonia that develops in a patient who has been on mechanical ventilation for more than 48 hours through an endotracheal tube. It is caused by biofilm formation on the indwelling tube, which introduces pathogenic microbes such as Pseudomonas aeruginosa, Klebsiella pneumoniae and Candida albicans into the patient’s lower airways. Currently, there is a lack of accurate in vitro models of ventilator-associated pneumonia development. This greatly limits our understanding of how the in-host environment alters pathogen physiology and the efficacy of ventilator-associated pneumonia prevention or treatment strategies. Here, we showcase a reproducible model that simulates the biofilm formation of these pathogens in a host-mimicking environment and demonstrate that the biofilm matrix produced differs from that observed in standard laboratory growth medium. In our model, pathogens are grown on endotracheal tube segments in the presence of a novel synthetic ventilated airway mucus medium that simulates the in-host environment. Matrix-degrading enzymes and cryo-scanning electron microscopy were employed to characterize the system in terms of biofilm matrix composition and structure, as compared to standard laboratory growth medium. As seen in patients, the biofilms of ventilator-associated pneumonia pathogens in our model either required very high concentrations of antimicrobials for eradication or could not be eradicated. However, combining matrix-degrading enzymes with antimicrobials greatly improved the biofilm eradication of all pathogens. Our in vitro endotracheal tube model informs on fundamental microbiology in the ventilator-associated pneumonia context and has broad applicability as a screening platform for antibiofilm measures including the use of matrix-degrading enzymes as antimicrobial adjuvants.
Mitigating the Opioid Epidemic: The Role of Cannabinoids in Chronic Pain Management—A Systematic Review and Meta-Analysis of Clinical Evidence and Mechanisms
Authors: Borges Julian Yin Vieira
Published: August 2024

Background and Objectives

As the medical community seeks alternative pain management strategies, cannabinoids have emerged as a potential option. This review discusses the role of cannabinoids in chronic pain management and their potential as an alternative treatment in pain medicine, focusing on efficacy, safety, and possible opioid reduction. The objectives are to evaluate the efficacy and safety of cannabinoids in chronic pain management, explore their potential to reduce opioid use, and identify the mechanisms by which cannabinoids exert their analgesic effects. Additionally, the review seeks to highlight the clinical implications and limitations of using cannabinoids as an alternative to opioids.

Methods

A comprehensive literature review and meta-analysis were conducted, focusing on studies from PubMed, MEDLINE, and Cochrane,focusing on various types of studies. Data were extracted and analyzed to assess the efficacy, safety, and potential opioid-sparing effects of cannabinoids. Mechanistic insights were also explored to understand how cannabinoids modulate pain.

Results

Cannabinoids have shown efficacy in managing chronic pain, with evidence indicating their ability to reduce pain and improve quality of life. Studies suggest that cannabinoids can provide significant analgesic effects, although there is variability in efficacy across trials. Findings also show that Cannabinoids modulate pain through the endocannabinoid system, which plays a crucial role in pain perception and inflammation.

Limitations

The variability in efficacy across studies suggests a need for standardized formulations and dosing regimens. Long-term effects of cannabinoid use are not fully understood, necessitating further research. More high-quality trials are needed to confirm findings and address potential biases.

Conclusion

Cannabinoids offer a promising alternative for chronic pain management, with the potential to mitigate the opioid epidemic. Integrating cannabinoids into clinical practice, guided by evidence-based protocols, can provide a safer and effective approach to chronic pain management.
Urinary Biomarkers for Lung Cancer Detection
Authors: Matov Alexandre
Published: August 2024

Introduction

The current healthcare system relies largely on a passive approach toward disease detection, which typically involves patients presenting a “chief complaint” linked to a particular set of symptoms for diagnosis. Since all degenerative diseases occur slowly and initiate as changes in the regulation of individual cells within our organs and tissues, it is inevitable that with the current approach to medical care we are bound to discover some illnesses at a point in time when the damage is irreversible and meaningful treatments are no longer available.

Methods

There exist organ-specific sets (or panels) of nucleic acids, such as microRNAs (miRs), which regulate and help to ensure the proper function of each of our organs and tissues. Thus, dynamic readout of their relative abundance can serve as a means to facilitate real-time health monitoring. With the advent and mass utilization of next-generation sequencing (NGS), such a proactive approach is currently feasible. Because of the computational complexity of customized analyses of “big data”, dedicated efforts to extract reliable information from longitudinal datasets is key to successful early detection of disease.

Results

Here, we present our preliminary results for the analysis of healthy donor samples and drug-naïve lung cancer patients’ samples, for which we identify urinary biomarkers demonstrating that small RNAs can pass through the filtration by the kidneys.

Conclusions

We provide a proof-of-principle that it is possible to perform non-invasive health monitoring by sequencing of urinary small RNAs and that traces of neoplastic transformation originating in organs that are not adjacent to the urinary tract, like the lungs, can also be detected in urine.
Methamphetamine-Contaminated Residences in the United States: Assessment of the Environmental Health Significance of Third-Hand Exposure
Authors: Dennison James E.
Published: August 2024

Objectives

Methamphetamine (meth) use in the United States has been a significant problem for many years. Beyond impacts to the users, two additional consequences of the meth problem are on-going exposure to non-users in contaminated homes and the significant cost of remediation. This study reports the first U.S. national and state-level estimates of the number of contaminated properties, the number of exposed non-users, and the costs associated with remediation.

Methods

The ability to estimate these endpoints relies on having random surveys of the frequency or incidence of residential contamination, but such surveys are difficult to perform and therefore scarce. The results of the only identified random survey were used in this study and appropriate geographical and temporal adjustments were made. The overall rate of contamination of Housing Units (HUs) was determined from estimates of the rates of HU contamination by meth smoking, rates of contamination from meth manufacturing, and rates of HU decontamination. Rates equations were integrated to estimate the number of contaminated HUs, the number of people living in contaminated HUs, and potential remediation costs.

Results

The random survey found 3.5% of HUs to be contaminated in 2018. Currently, over 5,000,000 (4%) of U.S. HUs are estimated to be contaminated above average health standards. Based on this, the current estimated cost for remediation of all contaminated HUs would be $15 billion per year and $250 billion for the backlog of all currently contaminated HUs. The estimated number of persons currently exposed to meth above average health standards is 13,000,000 people.

Conclusions

While the accuracy of these estimates is limited, they indicate that meth-contaminated housing is a significant environmental health and economic issue in the U.S. that has been previously under-recognized. Additional studies of health effects, fate and transport mechanisms, and remediation methods are needed.
Integrating genomic variants and developmental milestones to predict cognitive and adaptive outcomes in autistic children
Authors: Bourque Vincent-Raphaël , Schmilovich Zoe , Huguet Guillaume , England Jade , Okewole Adeniran , Poulain Cécile , Renne Thomas , Jean-Louis Martineau , Saci Zohra , Zhang Xinhe , Rolland Thomas , Labbé Aurélie , Vorstman Jacob , Rouleau Guy A. , Baron-Cohen Simon , Mottron Laurent , Bethlehem Richard A. I. , Warrier Varun , Jacquemont Sébastien
Published: August 2024

Although the first signs of autism are often observed as early as 18-36 months of age, there is a broad uncertainty regarding future development, and clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Here, we developed predictive models of ID in autistic children (n=5,633 from three cohorts), integrating different classes of genetic variants alongside developmental milestones. The integrated model yielded an AUC ROC=0.65, with this predictive performance cross-validated and generalised across cohorts. Positive predictive values reached up to 55%, accurately identifying 10% of ID cases. The ability to stratify the probabilities of ID using genetic variants was up to twofold greater in individuals with delayed milestones compared to those with typical development. These findings underscore the potential of models in neurodevelopmental medicine that integrate genomics and clinical observations to predict outcomes and target interventions.
Identifying interactions between TDP-43’s N-terminal and RNA binding domains
Authors: Scott David D. , Jena Lipsa , Perez-Miller Samantha , Kumirov Vlad , Khanna Rajesh , Khanna May
Published: August 2024

TAR DNA-binding Protein 43 (TDP-43) plays a crucial role in the pathophysiology and progression of Amyotrophic Lateral Sclerosis (ALS), affecting both familial and sporadic cases. TDP-43 is an intrinsically disordered multidomain protein that consists of an N-terminal domain (NTD1-102), two tandem RNA recognition motifs (RRM1102-177and RRM2191-260), and an intrinsically disordered glycine-rich C-terminal261-414domain. We previously identified a chemical probe which led to allosteric alterations between the RRM and NTD of TDP-43. We attributed these changes to potential interdomain interactions between the NTD and RRM segments. In this work, we compared the 2D [1H,15N] HSQC-NMR resonances of two constructs, TDP-43102-260(RRM domain alone) against TDP-431-260(NTD linked to RRM) and observed clustered shifts in the RNA binding sites of both RRM domains. To investigate why these shifts appeared in the RRM domains, in the absence of RNA, we hypothesized that the NTD domain could be stacking on the RRM domains. Thus, we modeled NTD-RRM interactions using protein-protein docking along withde novosequence-to-structure predictions of TDP-431-260that propose NTD stacking onto the RRM domains. Using Carr-Purcell-Meiboom-Gill (CPMG)-relaxation dispersion NMR spectroscopy, we demonstrated evidence of an interaction between NTD1-102and RRMs102-260. Finally, we investigated the impact of NTD on RNA binding using 2D15N-HSQC-NMR and microscale thermophoresis (MST) by titration of a short UG-rich RNA sequence and observed significant changes in RNA binding between TDP-43102-260and TDP-431-260, further suggesting the NTD plays a role in TDP-43 RNA interactions.
Dynorphin modulates motivation through a pallido-amygdala cholinergic circuit
Authors: Sun Qingtao , Liu Mingzhe , Guan Wuqiang , Xiao Xiong , Dong Chunyang , Bruchas Michael R. , Zweifel Larry S. , Li Yulong , Tian Lin , Li Bo
Published: August 2024

The endogenous opioid peptide dynorphin and its receptor κ-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and motivational drive in mice. On one hand, dynorphin acts postsynaptically via KORs on local GABAergic neurons in the VP to promote disinhibition of cholinergic neurons, which release acetylcholine into the amygdala to invigorate reward-seeking behaviors. On the other hand, dynorphin also acts presynaptically via KORs on dynorphinergic terminals to limit its own release. Such autoinhibition keeps cholinergic neurons from prolonged activation and release of acetylcholine, and prevents perseverant reward seeking. Our study reveals how dynorphin exquisitely modulate motivation through cholinergic system, and provides an explanation for why these neuromodulators are involved in motivational disorders, including depression and addiction.
Depletion of endomembrane reservoirs drives phagocytic appetite exhaustion in macrophages
Authors: Fountain Aaron , Mansat Mélanie , Soffiaturo Sierra , Gimenez Maria C. , Moussaoui Serene , Ezzo Maya , Verdawala Munira B. , Fung Karen , Lancaster Charlene , Somerville Elliott , Hinz Boris , Terebiznik Mauricio R. , Botelho Roberto J.
Published: August 2024

During phagocytosis, F-actin and local membrane secretion grows a phagocytic cup around a bound particle ultimately entrapping the particle within a phagosome. The phagosome then fuses with endosomes and lysosomes to digest the particle. After particle degradation, phagosomes fragment to reform lysosomes and maintain phagocyte degradative capacity. As finite systems, phagocytes have a maximal phagocytic capacity, which should blunt further phagocytosis. However, the processes responsible for appetite exhaustion are not known. We found that macrophages at capacity retained Fcγ receptors levels and did not shrink in size. Instead, surface membrane in-folding, membrane tension, and cortical F-actin were reduced in exhausted macrophages. Moreover, exhausted macrophages were depleted for both endosomes and lysosomes, and consequently, focal endosome exocytosis in remaining externally bound particles was blunted. In comparison, if phagosome resolution was permitted macrophages regained the phagocytic appetite. Altogether, we propose that depletion of the endomembrane pools is a major determinant of phagocytic fatigue as macrophages reach their phagocytic capacity, though other processes are also at play.
Cascaded Antithetic Integral Feedback for Enhanced Stability and Performance
Authors: Zand Armin M. , Gupta Ankit , Khammash Mustafa
Published: August 2024

Precise intracellular regulation and robust perfect adaptation can be achieved using biomolecular integral controllers and it holds enormous potential for synthetic biology applications. In this letter, we consider the cascaded implementation of a class of such integrator motifs. Our cascaded integrators underpin proportional-integral-derivative (PID) control structures, which we leverage to suggest ways to improve dynamic performance. Moreover, we demonstrate how our cascaded strategy can be harnessed to enhance robust stability in a class of uncertain reaction networks. We also discuss the genetic implementation of our controllers and the natural occurrence of their cascaded sequestration pairs in bacterial pathogens.
Extensive admixture among karst-obligate salamanders reveals evidence of recent divergence and gene exchange through aquifers
Authors: Nice Chris C. , Bell Katherine L. , Gompert Zachariah , Lucas Lauren K. , Ott James R. , Tovar Ruben U. , Crump Paul , Diaz Peter H.
Published: August 2024

Karst ecosystems often contain extraordinary biodiversity, but the complex underground aquifers of karst regions present challenges for assessing and conserving stygobiont diversity and investigating their evolutionary history. We examined the karst-obligate salamanders of theEurycea neotenesspecies complex in the Edwards Plateau region of central Texas using population genomics data to address questions about population connectivity and the potential for gene exchange within the underlying aquifer system. TheEurycea neotenesspecies complex has historically been divided into three nominal species, but their status, and spatial extent of species ranges, have remained uncertain. We discovered evidence of extensive admixture within the species complex and with adjacent lineages. We observed relatively low levels of differentiation among all sampling localities which supports the hypothesis of recent divergence. Nominal taxonomy, aquifer region and geography accounted for a modest amount of the overall population genomic variation, but these predictors were largely collinear and difficult to disentangle. Importantly, the taxonomy of the three nominal species does not reflect the admixture apparent in clustering analyses. Inference of migration events revealed a complex pattern of gene exchange, suggesting thatEuryceasalamanders have a dynamic history of dispersal through the aquifer system. These results highlight the need for greater understanding of how stygobiont populations are connected via dispersal and gene exchange through karst aquifers.
Recurrent breakpoints in theBRD4locus reduce toxicity associated with gene amplification
Authors: Wala Jeremiah , Dalin Simona , Webster Sophie , Shapira Ofer , Busanovich John , Beroukhim Rameen , Bandopadhayay Pratiti , Rendo Veronica
Published: August 2024

Structural variants (SVs) represent a mechanism by which cancer cells activate oncogenes or disrupt the function of genes with tumor suppressor roles. A recent study by the PCAWG Consortium investigated structural variants in 30 tumor types, identifying focal rearrangements in the oncogenic BRD4 gene in ovarian, endometrial and breast cancers. These rearrangements resulted in decreased BRD4 expression despite increased copy number, suggesting a novel mechanism to finetune gene over-expression. In this study, we show that focal deletions of BRD4 disrupt genomic regulatory regions and impact gene isoform expression in breast and ovarian tumors when compared to their expression across normal tissues. To determine the functional impact of these concomitant amplification and focal deletion events, we first leveraged open-reading-frame (ORF) screen data from 16 cancer cell lines, where we observed that overexpression of BRD4-long and BRD4-short isoforms is toxic for cancer cell growth. We confirmed these results in OVSAHO ovarian cancer cells, where overexpression of both isoforms significantly reduced tumor growth. Next, we mimicked the focal deletions occurring in BRD4 regulatory regions by CRISPR-Cas9 technology, and observed that their depletion functionally ablates tumor cell growth. We finally show that these focal deletions rescue ovarian carcinoma cells from the toxicity effects associated with gene overexpression, suggesting that global BRD4 gene expression levels must be fine tuned to ensure proper cancer cell proliferation. Our study provides experimental evidence for BRD4 deletions constituting the first example of a driver SV alteration reducing toxicity in cancer, therefore expanding the landscape of cancer progression mechanisms.
Preferential assimilation, metabolism, and transfer of organic nitrogen to host plants by Mucoromycotina ‘fine root endophytes’
Authors: Howard Nathan OA , Williams Alex , Durant Emily , Pressel Silvia , Daniell Tim J , Field Katie J
Published: August 2024

Mucoromycotina ‘fine root endophytes’ (MFRE) are an understudied group of plant fungal symbionts that usually co-occur with arbuscular mycorrhizal fungi. The functional significance of MFRE in plant nutrition remains under-explored, particularly their role in plant N assimilation from the variety of sources typically found in soils.

Using four15N-labelled N sources to track N transfer between MFRE andPlantago lanceolata,applied singly and in tandem, we investigated N source discrimination, preference, and transfer to host plants by MFRE. We traced movement of14C from plants to MFRE to determine the impact of N source type on plant C allocation to MFRE.

We found MFRE preferentially transferred N derived from glycine and ammonium to plant hosts over that derived from nitrate and urea, regardless of other N sources present. MFRE mycelium supplied with glycine and ammonium contained more plant-derived carbon than those supplied with other N sources.

We show that MFRE directly assimilates and metabolises organic compounds, retaining C to meet its own metabolic requirements and transferring N to plant hosts. Our findings highlight diversity in function of endomycorrhizal associations with potentially profound implications for our understanding of the physiology and ecology of plant-fungal symbioses.