bluuebunny/crossref_metadata_2025 huggingface dataset:
GUNN DOTS IN CHILDREN AGED 11–12 YEARS FROM THE GENERAL COMMUNITY SAMPLE COPENHAGEN CHILD COHORT 2000 STUDY
Authors: Boberg-Ans Lars Christian , Munch Inger Christine , Olsen Else Marie , Skovgaard Anne Mette , Larsen Michael
Published: June 2024

Purpose:

To study characteristics and associations of Gunn dots in a cohort of healthy children aged 11 to 12 years.

Methods:

As part of the Copenhagen Child Cohort 2000 Study, red-free fundus photographs were taken on 761 healthy children aged 11 to 12 years. The photographs were centered on the optic disk. Gunn dots were annotated and counted within a disk-centered circular grid of 6 mm diameter. Data were analyzed in relation to age, sex, axial length, and retinal nerve fiber layer thickness.

Results:

Gunn dots were found in 716 of the 761 participants (94%). The majority of dots were located both inferior and superior to the optic disk, situated within a distance of 3 mm from its center. The median number of Gunn dots was 64 (range 0–574) in right eyes and 68 (range 0–532) in left eyes. Having more than the median number of Gunn dots in the right eye was associated with older age (odds ratio 2.12, 95% CI 1.56 to 2.89, P < 0.0001, adjusted for sex, axial length, and retinal nerve fiber layer thickness) and was less common among the children with a thinner retinal nerve fiber layer (odds ratio 0.40, 95% CI 0.26–0.60, P < 0.0001 comparing bottom and top quartiles).

Conclusion:

Gunn dots were visible in the majority of healthy children aged 11 to 12 years, and large numbers of dots were associated with a thicker nerve fiber layer and with older age, within the limited age range of 1 year. The clinical significance of Gunn dots is unknown. Their location at the vitreoretinal interface makes them a parameter of interest in the study of aging, epiretinal fibrosis, macular pucker and retinal detachment.
ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY AND PLACOID VARIANT DISEASES MASQUERADING AS AGE-RELATED MACULAR DEGENERATION IN THE ELDERLY
Authors: Cheng John Yu , Santina Ahmad , Margines J. Ben , Voichanski Shilo , Ramtohul Prithvi , Bousquet Elodie , Bijon Jacques , Freund K. Bailey , Yannuzzi Lawrence , Sarraf David
Published: June 2024

Purpose:

To report eight cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) or persistent placoid maculopathy (PPM) initially masquerading as age-related macular degeneration in elderly individuals.

Methods:

APMPPE or PPM eyes in patients above age 55 years with macular retinal pigment epithelium disruption including drusenoid lesions on macular examination and/or with multimodal imaging were included. At least one method of multimodal imaging including fluorescein angiography (FA), indocyanine green angiography, optical coherence tomography (OCT), and OCT angiography (OCTA) was performed in all eyes for diagnosis and to monitor for macular neovascularization.

Results:

Eight elderly male patients presented with vision loss and were all initially diagnosed with non-neovascular or neovascular age-related macular degeneration. With the aid of multimodal retinal imaging, a final diagnosis of either APMPPE or PPM was rendered. With FA and indocyanine green angiography, choroidal hypoperfusion was detected in all but one eye. With OCT, the angular sign of Henle fiber layer hyperreflectivity was identified in >50% of eyes. With OCTA, inner choroidal flow deficits were detected in all eyes. Macular neovascularization requiring anti–vascular endothelial growth factor injection therapy complicated three of eight cases.

Conclusion:

Both APMPPE and PPM may develop in elderly individuals and may masquerade as age-related macular degeneration on presentation. Multimodal imaging including FA, indocyanine green angiography, and OCTA are important diagnostic modalities to assess for inner choroidal hypoperfusion to arrive at an accurate diagnosis and to detect macular neovascularization, which frequently complicates APMPPE and PPM. In these patients, serial anti–vascular endothelial growth factor intravitreal injections are essential in treating macular neovascularization and in preventing significant vision loss.
Bilateral Aggressive Mooren Ulcer in the Setting of Bilateral Pterygia and Pregnancy: A Unique Case
Authors: Selvan Harathy , Samantaray Puja Prativa , Rana Mrinal
Published: June 2024

Purpose:

To report an unusual case of bilateral aggressive Mooren ulcer that occurred in the setting of bilateral pterygia and showed a relentless course during pregnancy.

Methods:

A 39-year-old woman of Black African ethnicity, 36-week pregnant, presented to the eye casualty with bilateral nasal corneal ulcer and associated melt around preexisting pterygia. A detailed workup including microbial evaluation, culture and sensitivity, polymerase chain reaction for herpes simplex virus, varicella zoster virus, and cytomegalovirus, inflammatory blood profile, autoimmune markers, and human leucocyte antigen (HLA) screening was undertaken. Treatment was initiated in a stepwise approach.

Results:

Infections and systemic autoimmune and rheumatologic conditions were ruled out. A diagnosis of bilateral Mooren ulcer was made by exclusion. The peripheral blood was positive for HLA DQ2. As the condition seemed refractory to medical management (topical steroids and intravenous pulse methylprednisolone followed by oral prednisolone and topical cyclosporine), urgent bilateral conjunctival resection with multilayered amniotic membrane transplantation was performed to reduce the inflammatory stimulus and keratolysis. Stabilization of the condition warranted the need for systemic immunosuppressive agents. Using a multidisciplinary approach, in liaison with Obstetricians and Rheumatologists, the patient was planned for an earlier elective Cesarean section and commencement of oral mycophenolate mofetil postpartum, which aided in successful control of the disease.

Conclusions:

Mooren ulcer could follow an aggressive course during pregnancy, especially in the setting of preexisting pterygium. The complex hormonal and immunological changes during pregnancy and the delivery of inflammatory mediators directly onto the cornea by pterygium could contribute to the severity. A well-planned, stepwise, and multidisciplinary management is pivotal for the treatment of this condition.
A Standardized Protocol of Simultaneous Transepithelial Phototherapeutic Keratectomy (PTK) Followed by Corneal Collagen Crosslinking for Keratoconus
Authors: Patel Radhika Pooja , Kabbani Jamil , Angunawela Romesh , Bizrah Mukhtar
Published: June 2024

Purpose:

To report outcomes in patients with progressive keratoconus who underwent a standardized protocol of transepithelial phototherapeutic keratectomy (t-PTK) laser followed by accelerated corneal collagen crosslinking (CXL).

Methods:

All patients with progressive keratoconus undergoing our protocol at a London clinic between 2019 and 2023 were included. The protocol involved t-PTK at 58-μm central ablation depth at a 9-mm treatment zone on the Schwind Amaris 1050RS platform. Preoperative K readings of 43.0D (both K1 and K2) were inputted for all cases. Patients then underwent CXL with a pulsed-light accelerated protocol (30 mW/cm2 for 8 minutes of UVA exposure time with 1 second on/1 second off).

Results:

Seventy-nine eyes from 55 patients were included with an average follow-up of 12 months (range 6–24 months). Both mean uncorrected distance visual acuity (UDVA) and best spectacle-corrected visual acuity improved significantly from 0.42 preoperatively to 0.29 postoperatively (P < 0.01) and 0.11 to 0.06 postoperatively (P < 0.01), respectively. The refractive cylinder reduced significantly from −3.07D to −2.63D (P < 0.05). The mean Km improved from 46.15D to 45.44D (P < 0.01) and mean Kmax from 54.03D to 52.52D (P < 0.01). 77% of eyes (n = 61) exhibited Kmax improvement postoperatively, and 56% showed an improvement in UDVA (n = 44). 16% (n = 13) had worsening of vision, but of these, only 1 patient had visual loss of more than 2 lines. No eyes had corneal haze reported at the final follow-up, and none required additional treatment.

Conclusions:

This standardized simultaneous t-PTK and CXL protocol is safe and effective for the treatment of progressive keratoconus, providing visual, refractive, and topographic improvements.
Conjunctival Apocrine Hidrocystoma: A Case Report and Review of Literature
Authors: Mirzania Delaram , Jacobson Adam , McHugh Jonathan , Demirci Hakan
Published: June 2024

Purpose:

To describe the clinical features of a conjunctival apocrine hidrocystoma that developed 6 decades after a strabismus surgery and review existing literature on apocrine hidrocystomas of the conjunctiva and caruncle.

Methods:

Case report and review of literature on conjunctival apocrine hidrocystomas.

Results:

A 71-year-old man with a history of strabismus surgery as a child presented with a cystic lesion on the nasal conjunctiva and caruncle for 1 year. Excision of the lesion showed a unilocular cavity lined by a double layer of cells with the hallmark finding of apical decapitations, confirming a diagnosis of apocrine hidrocystoma. Seven additional cases of conjunctival and caruncular apocrine hidrocystomas were reviewed. All cases presented after 50 year of age. Most cases presented nasally or within the caruncle and had a pigmented appearance. No other reported cases had a history of trauma or surgery. All cases were treated with surgical excision without recurrence.

Conclusions:

History of strabismus surgery or conjunctival trauma may lead to ectopic deposition of apocrine glands that may contribute to the formation of an apocrine hidrocystoma.
Clinical Profile of Expanded Dengue Syndrome in Children
Authors: Mahajan Vidushi , Singh Jasmine , Guglani Vishal
Published: June 2024

The objective is to study the clinical profile and outcome of expanded dengue syndrome (EDS) in children. We conducted a retrospective cohort study and enrolled consecutive children (1 month to 18 years) who presented with dengue fever for over 1 year. The diagnosis of dengue fever was confirmed by the presence of dengue NS1 antigen and/or dengue IgM positivity. Subsequently, we identified children exhibiting EDS according to the revised World Health Organization guidelines (2011). We compared the clinical and laboratory profiles of children diagnosed with EDS and those without EDS. Of 178 children with dengue fever, 33 (18.5%) had EDS [95% confidence interval (CI): 13.1%–25.0%]. In these 33 children, neurological involvement was the most common manifestation [n = 16/33 (49%, 95% CI: 32%–65%)], namely encephalopathy, febrile seizures and encephalitis, respectively. Gastrointestinal involvement was the second most common [n = 10/33 (30%, 95% CI: 17%–47%)], which included fulminant hepatic failure, acalculous cholecystitis and acute pancreatitis. Renal presentation [n = 7 (21%, 95% CI: 10%–37%)] was limited to acute kidney injury. Children with EDS were significantly anemic and had leukocytosis, hyperkalemia, azotemia, hyperbilirubinemia, raised serum transaminases and fluid-refractory shock than their non-EDS counterparts. Children with EDS had a trend toward higher mortality (P = 0.07) and the survivors had a longer duration of hospital stay (5 days vs. 4 days in non-EDS, P = 0.001). In conclusion, we observed a high prevalence (18.5%) of EDS among children hospitalized for dengue fever. The common manifestations of EDS include neurological, renal and gastrointestinal involvement. Children with EDS showed a trend toward higher mortality and longer duration of hospital stay than children without EDS.
One- and Two-year Multidisciplinary Follow-Up of MIS-C at a Tertiary Hospital: A Retrospective Cohort Study
Authors: Johnson Sarah May , Penner Justin , Issitt Richard , Kmentt Laura , Grant Karlie , Pandey Ashwin , Champsas Dimitrios , Abdel-Mannan Omar , Maillard Sue , McKenzie Kim , Golding Emily , Kucera Filip , Hacohen Yael , Moshal Karyn
Published: June 2024

Background:

Although 6-month follow-up of patients with multisystem inflammatory syndrome in children (MIS-C) was reassuring, there is scant data on long-term sequelae, including whether changing variants affect clinical severity and outcomes.

Methods:

Children (<18 years of age) admitted to Great Ormond Street Hospital between April 4, 2020, and January 2023, meeting diagnostic criteria for MIS-C were included. Admission and follow-up data were categorized by the predominant SARS-CoV-2 circulating variant in the United Kingdom.

Results:

One hundred and sixty children [median age, 10.1 (interquartile range, 7.9-12.6) years] were included. There was no difference in the time of symptom onset to diagnosis between waves (P=0.23) or hospitalization days across all waves (P=0.32). Inflammatory markers were normal for up to 2 years in all patients except one. Eleven patients (6.9%) remain in follow-up: cardiology (n=5), gastroenterology (n=5) and nephrology (n=1). The main self-reported symptoms at 2 years were abdominal pain (n=5) and myalgia (n=2). Fatigue was present in approximately a quarter of patients at admission; this reduced to 14 (9%), (2%) and 1 (2%) at 6-month, 1-year and 2-year follow-ups, respectively. Chronic fatigue or long-COVID symptomatology was rare (n=1) even with high rates of concurrent Epstein–Barr virus positivity (49/134). All patients had sustained neurological recovery with no new neurological pathology observed.

Conclusions:

Patients with MIS-C have a sustained recovery, which is reassuring for positive long-term outcomes. Across waves, time from symptom onset to diagnosis and treatment, symptomatology and length of stay were similar. Sustained recovery is reassuring for clinicians and parents alike. Differentiating long-COVID symptomatology from that of MIS-C is important in formulating an individualized treatment plan.
Emerging Challenges of Mpox Transmission: An In-depth Scoping Review and Evidence Mapping on Breastfeeding Practices in South America
Authors: da Silva Kelly , Granzotti Raphaela Barroso Guedes , César Carla Patrícia Hernandez Alves Ribeiro , Barretto Renata Barros Sá , Santos Nathália Monteiro , Cruz Pablo Jordão Alcântara , Martins-Filho Paulo Ricardo
Published: June 2024

Background:

In 2022, a marked escalation in Monkeypox (Mpox) cases was observed in nonendemic regions, notably South America, despite the virus being traditionally endemic to Central and West Africa. This unexpected shift necessitated a deeper exploration of the novel transmission dynamics, including breastfeeding, given the emerging evidence of potential horizontal and vertical Mpox transmission during mother-infant interactions.

Research aim:

The study aimed to critically evaluate existing evidence on potential horizontal and vertical Mpox transmission related to breastfeeding and to assess guidelines in South American countries regarding Mpox prevention during breastfeeding.

Methods:

A scoping review and evidence mapping were conducted, adhering to the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guideline. Data extraction involved identifying primary studies evaluating breastfeeding as a transmission route. Additionally, official documents from South American Health Ministries detailing guidelines or policies on breastfeeding in the context of maternal Mpox infection were reviewed.

Results:

Three of 215 studies were found relevant; 2 were case reports, and 1 was a laboratory study. Available evidence suggests that contamination could likely occur horizontally through skin-to-skin contact. Six South American countries had issued guidelines on breastfeeding during Mpox infection, but the guidance varied and was not consistent across the region.

Conclusions:

The study emphasizes the need for clear and consistent guidelines on breastfeeding during Mpox outbreaks, particularly in South America. Collaborative strategies and regular research updates will be essential in addressing the ongoing public health challenge.
Acute Acalculous Cholecystitis Related to Hepatitis A Virus: Report of 3 Cases
Authors: Foles Ana Isabel , Valsassina Rita , Garcia Ana Margarida
Published: June 2024

Hepatitis A virus commonly affects children in developing countries. Usually, it presents as an asymptomatic infection or a self-limited acute hepatitis. We report 3 rare pediatric cases of acute acalculous cholecystitis associated with to hepatitis A virus. Conservative treatment was successful, with complete clinical, analytical and imaging remission.
Concurrent Klebsiella Bacteremia in Two Infants with Severe Respiratory Syncytial Virus Infection
Authors: Polat Meltem , Akçay Ayşe , Önal Betül , Öztürk Nihan , Şahin Elif Ayca , Demirdağ Tuğba Bedir , Tapısız Anıl
Published: June 2024

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in children. In most previously healthy infants, RSV infection is self-limited and resolves without complications. The risk of bacteremia is low in young febrile infants with RSV infection. Herein, we report two previously healthy infants with severe RSV infection who had concurrent Klebsiella bacteremia.
Management of vaginoplasty canal complications
Authors: Stojanovic Borko , Horwood Geneviève , Joksic Ivana , Bafna Sandeep , Djordjevic Miroslav L.
Published: June 2024

Purpose of review

Increasing uptake of gender affirming surgery has allowed for a wider breadth of publication examining complications associated with vaginoplasty. This review aims to provide a comprehensive overview of complications associated with vaginoplasty procedures, focusing on intraoperative, early postoperative, and delayed postoperative complications across different surgical techniques.

Recent findings

Intraoperative complications such as bleeding, injury of the rectum, urethra and prostate, and intra-abdominal injury are discussed, with insights into their incidence rates and management strategies. Early postoperative complications, including wound dehiscence, infection, and voiding dysfunction, are highlighted alongside their respective treatment approaches. Moreover, delayed postoperative complications such as neovaginal stenosis, vaginal depth reduction, vaginal prolapse, rectovaginal fistula, and urinary tract fistulas are assessed, with a focus on their etiology, incidence rates, and management options.

Vaginoplasty complications range from minor wound issues to severe functional problems, necessitating a nuanced understanding of their management. Patient counseling, surgical approach, and postoperative care optimization emerge as crucial strategies in mitigating the impact of complications. Standardizing complication reporting and further research are emphasized to develop evidence-based strategies for complication prevention and management in vaginoplasty procedures.
Primary chylous peritonitis: a rare case report from Syria
Authors: Haj Osman Osama
Published: June 2024

Introduction and importance:

Chylous peritonitis is characterized by a sudden accumulation of chyle in the peritoneal cavity, leading to symptoms of an acute abdomen. This condition is quite rare, with less than 100 cases documented in the medical literature, and is often misdiagnosed.

Case presentation:

The authors present a case of an acute abdomen in a young man who was initially suspected to have a perforated peptic ulcer. After laparotomy, the diagnosis of chylous peritonitis was confirmed. Despite extensive investigations, no underlying cause was identified. Treatment involved peritoneal lavage and placement of a pelvic drainage tube, with discharge after three days on a low-fat.

Clinical discussion:

Chylous peritonitis is a relatively rare condition, occurring in ~1 in 20 000 individuals. Chyle leakage can be detected through various diagnostic modalities including ultrasound, computed tomography, laparoscopy, or exploratory laparotomy. In cases where a definitive etiology is not identified, treatment typically involves peritoneal lavage and drainage. Postoperative management focuses on a low-fat diet and somatostatin administration to prevent recurrence.

Conclusion:

The present case highlights the importance of considering primary chylous peritonitis as a potential cause of acute abdomen in young patients. Future research should focus on identifying risk factors and establishing evidence-based guidelines for approaching this condition.
Epidemiology and clinical characteristics of acute malnutrition among under-5 children attending a rural hospital in the Democratic Republic of Congo: a cross-sectional study
Authors: Bavurhe Rodrigue Fikiri , Ahmad Bilal , Naaz Farheen , Oduoye Malik Olatunde , Rugendabanga Excellent , Nkundakozera Marie , Bianga Viviane Feza , Farhan Kanza , Kioma Josline , Biamba Chrispin , Bisimwa Jospin , Banyanga David , Opondjo Fernand Manga , Colombe Moise Mbaluku , Bucangende Eric Ndagano , Shamamba Peniel Kundo , Cirhuza Eric Cibambo , Isonga Stéphanie Sifa , Akilimali Aymar , Birindwa Archippe Muhandule ,   and the collaborators,   Collaborators
Published: June 2024

Background:

Malnutrition, a public health problem in a low-income country such as the Democratic Republic of Congo (DR Congo), is a major killer among children under 5 who are most at risk of acute malnutrition. This study aims to describe the epidemiological and clinical characteristics of acute malnutrition in children under 5 years old.

Methods:

The authors conducted a retrospective and descriptive cross-sectional study on children under 5 with acute malnutrition from April 2022 to April 2023. A total of 287 malnourished children were consulted, hospitalized in a rural hospital, and registered for participation in this study.

Results:

Two hundred eighty-seven (25%) children were victims of acute malnutrition. The age group between 13 and 24 months is the most affected by acute malnutrition with 30%. The male-to-female(M/F) sex ratio was 1.17. Kwashiorkor is the most common form of acute malnutrition with 171 (59.6%) cases. Abdominal bloating, weight loss as well as diarrhea and vomiting were the more frequent clinical signs. Shock is the most complication of acute malnutrition. Therapeutic milk (Food 75 and Food 100) was the most effective in management. Twenty-nine (10.1%) other children died from acute malnutrition and 258 (89.9%) children progressed to full recovery.

Conclusion:

Acute malnutrition in children remains a public health problem worldwide and particularly in low-income countries such as DR Congo. It is associated with multiple physiological vulnerabilities and has many short- and long-term complications in children who have suffered from it.
Spatial Perspective Taking is Distinct from Cognitive and Affective Perspective Taking
Authors: Brucato Maria , Newcombe Nora S. , Chein Jason
Published: June 2024

Perspective taking (PT) is the ability to imagine viewpoints different from our own. However, the nature of PT as a construct, and its underlying cognitive mechanisms, are not well established. Some researchers propose that understanding what others believe (cognitive PT), feel (affective PT), and see (spatial PT) form a single behavioral dimension, relying on the orienting of attention between competing frame-of-reference representations. Others propose that PT mechanisms are dissociable, although there are three different proposals about such dissociations. The present study examined behavioral associations among measures of spatial, cognitive, and affective PT and attentional control in neurotypical young adults. There was a lack of convergent validity for measures of cognitive and affective PT, pointing to the need for more psychometric work on these dimensions. Much better convergence was found for spatial PT measures. There was little to no behavioral association between spatial PT and either social forms of PT (cognitive or affective) or attentional control measures. This pattern suggests support for a dissociated model in which spatial PT is a distinct cognitive construct.
Modeling neural coding in the auditory midbrain with high resolution and accuracy
Authors: Drakopoulos Fotios , Sabesan Shievanie , Xia Yiqing , Fragner Andreas , Lesica Nicholas A
Published: June 2024

Computational models of auditory processing can be valuable tools for research and technology development. Models of the cochlea are highly accurate and widely used, but models of the auditory brain lag far behind in both performance and penetration. Here, we present ICNet, a model that provides accurate simulation of neural dynamics in the inferior colliculus across a wide range of sounds, including near-perfect simulation of responses to speech. We developed ICNet using deep learning and large-scale intracranial recordings from gerbils, addressing three key modeling challenges that are common across all sensory systems: capturing the full statistical complexity of neuronal response patterns; accounting for physiological and experimental non-stationarity; and extracting features of sensory processing that are common across different brains. ICNet can be used to simulate activity from thousands of neural units or to provide a compact representation of central auditory processing through its latent dynamics, facilitating a wide range of hearing and audio applications.
Distinctive Transcriptional and Microbial Signature in Cutaneous Acute Graft-vs-Host-Disease
Authors: El Jurdi Najla , Shabaneh Ashraf , Schultz Brittney , Dean Owen , Wang Jinhua , Holtan Shernan G.
Published: June 2024

Skin acute graft-vs-host disease (aGVHD) is often first manifestation of GVHD, yet very few preclinical and clinical studies have focused on this target organ, leaving a critical information gap in the pathophysiology of GVHD. We hypothesized that analysis of host and microbiome gene expression could yield novel insights into the molecular and immunologic mechanisms underlying skin GVHD. Our objectives were to determine the differential host gene expression and microbiome profile of human skin aGVHD samples compared to normal skin, and aGVHD corticosteroid responders to non-responders. We performed RNA-Sequencing on lower arm biopsies from 45 patients compared to 10 healthy controls. Our findings suggest a distinctive transcriptional signature of cutaneous aGVHD, that could identify potentially actionable targets for prevention or treatment corticosteroid refractory disease. Our analysis suggests a key role of dendritic cells and macrophages, potentially mediated by differential expression of MIF, in the development of cutaneous aGVHD and corticosteroid responsiveness. Additionally, we describe a unique microbial signature in cutaneous aGVHD that includes skin microbes not previously described in this population.
The DiffInvex evolutionary model for conditional somatic selection identifies chemotherapy resistance genes in 10,000 cancer genomes
Authors: Khalil Ahmed , Supek Fran
Published: June 2024

Tumors often show an initial response to chemotherapy, but then develop resistance, leading to relapse and poor prognosis. We hypothesized that a genomic comparison of mutations in pre-treated versus treatment-naive tumors would serve to identify genes that confer resistance. A challenge in such an analysis is that therapy alters mutation burdens and signatures, confounding association studies and complicating identifying causal, selected mutations. We developed DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes. Crucially, DiffInvex draws on a mutation rate baseline that accounts for these shifts in neutral mutagenesis during cancer evolution. We applied DiffInvex to 9,953 cancer whole-genomes from 29 cancer types from 8 studies, containing both WGS of treatment-naive tumors and tumors pre-treated by various drugs, identifying genes where point mutations are under conditional positive or negative selection for a certain chemotherapeutic, suggesting resistance mechanisms occurring via point mutation. DiffInvex confirmed well-known chemoresistance-driver mutations inEGFR,ESR1,KITandARgenes as being under conditional positive selection, with additional cancer types identified forEGFRandKIT. Additionally, DiffInvex identified 11 genes with treatment-associated selection for different classes of therapeutics. In most cases, these genes were common cancer genes includingPIK3CA,APC,MAP2K4andMAP3K1. This suggests that tumor resistance to therapy via mutation often occurs via selective advantages conferred by known driver genes, rather than via mutations in specialized resistance genes. Various gene-chemotherapy associations were further supported in tests for functional impact of mutations, again implemented in a conditional selection setting, as well as replicating in independent panel or exome sequencing data. In addition to nominating drug resistance genes that could be targeted by future therapeutics, DiffInvex can also be applied to diverse analysis in cancer evolution, such as comparing normal and tumoral tissues, or analyzing subclonal evolution, identifying changes in selection over time.
Antiviral insulin signaling during West Nile virus infection results in viral mutations
Authors: Char Aditya B. , Trammell Chasity E. , Fawcett Stephen , Ahlers Laura R.H. , Patel Dharmeshkumar , Luckhart Shirley , Goodman Alan G.
Published: June 2024

Arthropod-borne viruses or arboviruses, including West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV) pose significant threats to public health. It is imperative to develop novel methods to control these mosquito-borne viral infections. We previously showed that insulin/insulin-like growth factor-1 signaling (IIS)-dependent activation of ERK and JAK-STAT signaling has significant antiviral activity. Continuous immune pressure can lead to adaptive mutations of viruses during infection. We aim to elucidate how IIS-signaling in mosquitoes selects for West Nile virus escape variants, to help formulate future transmission blocking strategies. We hypothesize that passage of WNV under activation of IIS will induce adaptive mutations or escape variants in the infecting virus. To test our hypothesis, WNV was serially passaged throughCulex quinquefasciatusHsu cells in the presence or absence of bovine insulin to activate IIS antiviral pressure. We sequenced WNV genes encoding for E, NS2B, NS3, and NS5 and identified variants inEandNS5arising from IIS antiviral pressure. In parallel to the genetic analyses, we also report differences in the levels of virus replication and Akt activation in human cells using virus passaged in the presence or absence of insulin. Finally, using adultCulex quinquefasciatus, we demonstrated the enhancement of immune response gene expression in virus-infected mosquitoes fed on insulin, compared to control. Notably, virus collected from insulin-fed mosquitoes contained a non-synonymous mutation inNS3. These results contribute towards achieving our long-term goal of manipulating mosquito IIS-dependent antiviral immunity to reduce WNV or other flavivirus transmission to mammalian hosts.
Altered Dynamics and Characterization of Functional Networks in Cocaine Use Disorder: A Coactivation Pattern Analysis of Resting-State fMRI data
Authors: Klugah-Brown Benjamin , Yao Xing , Yang Hang , Wang Pan , Biswal Bharat B.
Published: June 2024

Background

Cocaine Use Disorder (CUD) poses significant neurobiological and neuropsychiatric challenges, often resulting in severe cognitive and behavioral impairments. This study aims to explore the neural dynamics of CUD using a dynamic coactivation pattern (CAP) analysis approach to provide a deeper understanding of the transient neurobiological mechanisms of the disorder.

Methods

Resting-state functional MRI data (SUDMEX_CONN) from 56 CUD patients and 57 healthy controls (HC) were analyzed. CAP analysis was employed to capture transient brain states and their coactivation patterns. Temporal dynamic metrics such as Fraction of Time, Persistence (PST), and Counts were computed to assess differences between groups. Stationary functional connectivity (sFC) was also examined, and meta-analytic term mapping from the Neurosynth database was used to characterize functional associations.

Results

CAP analysis revealed six distinct coactivation patterns, with five showing high spatial similarity between CUD and HC groups. Notable differences were observed in State 6, which displayed inverse activation patterns between the groups. CUD individuals exhibited significantly reduced PST across all brain states and altered transition probabilities, particularly increased transitions from the default mode network (DMN) to the somatomotor network and decreased transitions from DMN to attentional/executive networks. Clinical correlations indicated that prolonged cocaine use was associated with altered PST in specific brain states. sFC analysis identified significant alterations in regions such as the right supramarginal gyrus, left superior frontal gyrus, right precentral gyrus, and right lingual gyrus, each linked to distinct cognitive and behavioral functions.

Conclusions

This study highlights the utility of CAP analysis in capturing the dynamic neural underpinnings of CUD. The findings provide insights into the neurobiological mechanisms of the disorder, suggesting potential biomarkers for CUD. These results have implications for developing an enhanced approach for substance use disorders, as well as improving our understanding and management of CUD.
Improving Tuberculosis Control: Assessing the Value of Medical Masks and Case Detection – A Multi-Country Study with Cost-Effectiveness Analysis
Authors: Aldila Dipo , Fardian Basyar Lauzha , Chukwu Chidozie Williams , Noor Aziz Muhamad Hifzhudin , Kamalia Putri Zahra
Published: June 2024

Tuberculosis (TB) remains a significant global health concern, necessitating effective control strategies. This paper presents a mathematical model to evaluate the comparative effectiveness of medical mask usage and case detection in TB control. The model is constructed as a system of ordinary differential equations and incorporates crucial aspects of TB dynamics, including slow-fast progression, medical mask utilization, case detection, treatment interventions, and differentiation between symptomatic and asymptomatic cases. A key objective of TB control is to ensure that the reproduction number, ℛc, remains below unity to achieve TB elimination or persistence if ℛcexceeds one. Our mathematical analysis reveals the presence of a transcritical bifurcation when the ℛc= 1 signifies a critical juncture in TB control strategies. These results confirm that the effectiveness of case detection in diminishing the endemic population of symptomatic individuals within a TB-endemic equilibrium depends on exceeding a critical threshold value. Furthermore, our model is calibrated using TB yearly case incidence data per 100,000 population from Indonesia, India, Lesotho, and Angola, and we employ the Bootstrap Resampling Residual Approach to assess the uncertainty inherent in our parameter estimates and provide a comprehensive distribution of parameter values. Despite a declining trend in new incidence, these four countries exhibit a reproduction number greater than one, indicating persistent TB cases in the presence of ongoing TB control programs. We employ the Partial Rank Correlation Coefficient (PRCC) in conjunction with the Latin Hypercube Sampling (LHS) method to conduct global sensitivity analysis of theℛcparameter for each fitted parameter in every country. We find that the medical mask use is more sensitive to reduce ℛccompared to the case detection implementation. To further gain insight into the necessary control strategy, we formulated an optimal control and studied the cost-effectiveness analysis of our model to investigate the impact of case detection and medical mask use as control measures in TB spread. Cost-effectiveness analysis demonstrates that combining these interventions emerges as the most cost-effective strategy for TB control. Our findings highlight the critical importance of medical masks and their efficacy coupled with case detection in shaping TB control dynamics, elucidating the primary parameter of concern for managing the control reproduction number. We envisage our findings to have implications and be vital for TB control if implemented by policymakers and healthcare practitioners involved in TB control efforts.
Comparison of clinical metagenomics with 16S rDNA Sanger sequencing for the bacteriological diagnosis of culture-negative samples
Authors: d’Humières Camille , Haviari Skerdi , Petitjean Marie , Deconinck Laurène , Gueye Signara , Peiffer-Smadja Nathan , Chalal Lynda , Beldjoudi Naima , Rossi Geoffrey , Nguyen Yann , Burdet Charles , Perrineau Ségolène , Le Pluart Diane , Rahli Roza , Thy Michael , Szychowiak Piotr , Lescure Xavier , Leflon-Guibout Véronique , de Lastours Victoire , Ruppé Etienne
Published: June 2024

Background

Currently, diagnosis of bacterial infections is based on culture, possibly followed by the amplification and sequencing (Sanger method) of the 16S rDNA - encoding gene when cultures are negative. Clinical metagenomics (CMg), i.e. the sequencing of a sample’s entire nucleic acids, may allow for the identification of bacteria not detected by conventional methods. Here, we tested the performance of CMg compared to 16S rDNA sequencing (Sanger) in 50 patients with suspected bacterial infection but negative cultures.

Methods

This is a prospective cohort study. Fifty patients (73 samples) with negative culture and a 16S rDNA sequencing demand (Sanger) were recruited from two sites. On the same samples, CMg was also performed and compared to 16S rDNA Sanger sequencing. Bacteria were identified using MetaPhlAn4.

Results

Among the 73 samples, 20 (27.4%, 17 patients) had a clinically significant 16S rDNA Sanger sequencing result (used for patient management) while 11 (15.1%, 9 patients) were considered contaminants. At the patient level, the sensitivity of CMg was 70.1% (12/17) compared to 16S rDNA. In samples negative for 16S rDNA Sanger sequencing (n=53), CMg identified clinically-relevant bacteria in 10 samples (18.9%, 10 patients) with 14 additional bacteria.

Conclusions

CMg was not 100% sensitive when compared to 16S, supporting that it may not be a suitable replacement. However, CMg did find additional bacteria in samples negative for 16S rDNA Sanger. CMg could therefore be positioned as a complementary to 16S rDNA Sanger sequencing.
Adverse sequelae of the COVID-19 pandemic on mental health care in seven low- and middle-income countries: MASC study
Authors: Hanlon Charlotte , Lempp Heidi , Alem Atalay , Alemu Azeb Asaminew , Alvarado Rubén , Ayinde Olatunde , Adesola Adekunle , Brohan Elaine , Davies Thandi , Fekadu Wubalem , Gureje Oye , Jalagania Lucy , Makhashvili Nino , Mihretu Awoke , Misganaw Eleni , Milenova Maria , Mujirishvili Tamar , Myshakivska Olha , Pinchuk Irina , Solis-Araya Camila , Sorsdahl Katherine , Soto-Brandt Gonzalo , Susser Ezra , Toro-Devia Olga , Votruba Nicole , Wickramasinghe Anuprabha , Williams Shehan , Thornicroft Graham
Published: June 2024

A WHO rapid assessment of early impact of the COVID-19 pandemic on mental health services worldwide found a consistent pattern of degradation. In this context the MASC study aimed to: identify the consequences of the pandemic for mental health services and people with pre- existing mental health conditions (MHCs) in 7 low- and middle-income countries; and (2) identify good practice to mitigate these impacts. The study was conducted in Chile, Ethiopia, Georgia, Nigeria, South Africa, Sri Lanka and Ukraine. This was an observational study, using a mixed- methods convergent design, triangulating data from: (1) 144 key informants participating in semi- structured interviews or focus groups and/or a self-completed survey; (2) routine service utilization data; (3) local grey literature; and (4) expert consultation. We found clear evidence in all sites that the pandemic exacerbated pre-existing disadvantages experienced by people with MHCs and led to a deterioration in the availability and quality of care, especially for psychosocial care. Alongside increased vulnerability to COVID-19, people with MHCs faced additional barriers to accessing prevention and treatment interventions compared to the general population. To varying extents, sites showed accelerated implementation of digital technologies, but with evidence of worsening inequities in access. Where primary care-based mental health care was more developed or prioritised, systems seemed more resilient and adaptive. Our findings have the following implications. First, mental health service reductions are clear examples of ‘structural stigma’, namely policy level decisions in healthcare which place a low priority upon services for people with MHCs. Second, integration of mental health care into all general health care settings is key to ensuring accessibility and parity of physical and mental health care. Third, digital innovations should be designed to strengthen and not fragment systems. We discuss these findings in terms of anticipating such challenges in future and preparing layers of resilience.
Seasonal and comparative evidence of adaptive gene expression in mammalian brain size plasticity
Authors: Thomas William R. , Richter Troy , O’Neil Erin T. , Baldoni Cecilia , Corthals Angelique P. , von Elverfeldt Dominik , Nieland John , Dechmann Dina K. N. , Hunter Richard G. , Dávalos Liliana M.
Published: June 2024

Contrasting almost all other mammalian wintering strategies, Eurasian common shrews,Sorex araneus, endure winter by shrinking their brain, skull, and most organs, only to then regrow to breeding size the following spring. How such tiny mammals achieve this unique brain size plasticity while maintaining activity through the winter remains unknown. To discover potential adaptations underlying this trait, we analyzed seasonal differential expression in the shrew hypothalamus, a brain region that both regulates metabolic homeostasis and drastically changes size, and compared hypothalamus expression across species. We discovered seasonal variation in suites of genes involved in energy homeostasis and apoptosis, shrew-specific upregulation of genes involved in the development of the hypothalamic blood brain barrier and calcium signaling, as well as overlapping seasonal and comparative gene expression divergence in genes implicated in the development and progression of human neurological and metabolic disorders, includingCCDC22. With high metabolic rates and facing harsh winter conditions,Sorex araneushave evolved both adaptive and plastic mechanisms to sense and regulate their energy budget. Many of these expression changes mirrored those identified in human neurological and metabolic disease, highlighting the interactions between metabolic homeostasis, brain size plasticity, and longevity.
Policies on Artificial Intelligence Chatbots Among Academic Publishers: A Cross-Sectional Audit
Authors: Bhavsar Daivat , Duffy Laura , Jo Hamin , Lokker Cynthia , Haynes R. Brian , Iorio Alfonso , Marusic Ana , Ng Jeremy Y.
Published: June 2024

Background

Artificial intelligence (AI) chatbots are novel computer programs that can generate text or content in a natural language format. Academic publishers are adapting to the transformative role of AI chatbots in producing or facilitating scientific research. This study aimed to examine the policies established by scientific, technical, and medical academic publishers for defining and regulating the responsible authors’ use of AI chatbots.

Methods

This study performed a cross-sectional audit on the publicly available policies of 163 academic publishers, indexed as members of the International Association of the Scientific, Technical, and Medical Publishers (STM). Data extraction of publicly available policies on the webpages of all STM academic publishers was performed independently in duplicate with content analysis reviewed by a third contributor (September 2023 - December 2023). Data was categorized into policy elements, such as ‘proofreading’ and ‘image generation’. Counts and percentages of ‘yes’ (i.e., permitted), ‘no’, and ‘N/A’ were established for each policy element.

Results

A total of 56/163 (34.4%) STM academic publishers had a publicly available policy guiding the authors’ use of AI chatbots. No policy allowed authorship accreditations for AI chatbots (or other generative technology). Most (49/56 or 87.5%) required specific disclosure of AI chatbot use. Four policies/publishers placed a complete ban on the use of AI tools by authors.

Conclusions

Only a third of STM academic publishers had publicly available policies as of December 2023. A re-examination of all STM members in 12-18 months may uncover evolving approaches toward AI chatbot use with more academic publishers having a policy.
Top-Down Proteomics Identifies Plasma Proteoform Signatures of Liver Cirrhosis Progression
Authors: Forte Eleonora , Sanders Jes M. , Pla Indira , Kanchustambham Vijaya Lakshmi , Hollas Michael A. R. , Huang Che-Fan , Sanchez Aniel , Peterson Katrina N. , Melani Rafael D. , Huang Alexander , Polineni Praneet , Doll Julianna M. , Dietch Zachary , Kelleher Neil L. , Ladner Daniela P.
Published: June 2024

Cirrhosis, advanced liver disease, affects 2-5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and experience life-threatening complications such as gastrointestinal bleeding, confusion (hepatic encephalopathy), and ascites, reducing life expectancy from 12 to less than 2 years. Among patients with compensated cirrhosis, identifying patients at high risk of decompensation is critical to optimize care and reduce morbidity and mortality. Therefore, it is important to preferentially direct them towards specialty care which cannot be provided to all patients with cirrhosis. We used discovery Top-down Proteomics (TDP) to identify differentially expressed proteoforms (DEPs) in the plasma of patients with progressive stages of liver cirrhosis with the ultimate goal to identify candidate biomarkers of disease progression. In this pilot study, we identified 209 DEPs across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated), of which 115 derived from proteins enriched in the liver at a transcriptional level and discriminated the three stages of cirrhosis. Enrichment analyses demonstrated DEPs are involved in several metabolic and immunological processes known to be impacted by cirrhosis progression. We have preliminarily defined the plasma proteoform signatures of cirrhosis patients, setting the stage for ongoing discovery and validation of biomarkers for early diagnosis, risk stratification, and disease monitoring.

Graphical Abstract

Highlights

Performed a pilot top-down LC-MS/MS analysis to identify proteoforms (PFRs) in the plasma of patients with 3 progressive stages of liver cirrhosis.

Identified 2867 proteoforms (PFRs) and 209 differentially regulated proteoforms (DRPs) in the different stages of the disease.

Identified DRP profiles able to potentially distinguish early from late stages of the disease, including 115 liver-derived DRPs.

Fibrinogen alpha chain, haptoglobin, and Apo A-I are the proteins with the highest number of DRPs and represent potential candidate biomarkers of liver cirrhosis progression.