bluuebunny/crossref_metadata_2025 huggingface dataset:
Carcinogenic Effects of Nitrosodimethylamine (NDMA) Contamination in Ranitidine: Defining the Relationship With Renal Malignancies
Authors: Gold Samuel A. , Margulis Vitaly
Published: October 2023

Purpose:

Ranitidine, a medication used to treat gastric ulcers and reflux, was once the highest selling drug in the world with over $1 billion in annual sales. However, in 2020, ranitidine, known more commonly by the brand name Zantac, virtually vanished from the market after multiple regulatory bodies including the US Food and Drug Administration recommended withdrawal. Their concern was based on detection of nitrosodimethylamine (NDMA), a known animal carcinogen, in ranitidine samples. NDMA has been shown to induce multiple tumor types, including renal tumors. The effects of human exposure, however, are not completely understood. This review aims to clarify what is known about NDMA contamination in ranitidine, the carcinogenic mechanisms of NDMA, and possible associations between ranitidine consumption and renal cancers.

Materials and Methods:

A comprehensive literature review was performed regarding ranitidine and NDMA, carcinogenesis, and associations with malignancy. Data were considered from environmental, preclinical, and clinical studies from various disciplines. Publications from governmental bodies, including the Food and Drug Administration and International Agency for Research on Cancer, were reviewed and included for analysis.

Results:

Multiple preclinical studies have demonstrated the carcinogenic effects of NDMA in animals with high rates of renal tumor development. NDMA has been detected in industrial, dietary, and pharmacologic sources. Regarding NDMA levels in ranitidine, evidence points to associations with storage conditions at elevated temperatures and/or prolonged duration as well as endogenous production facilitated by physiologic gastric conditions. Once metabolized, NDMA by-products form DNA adducts with established roles in carcinogenesis. Human data on ranitidine consumption and cancer development are derived from large population studies limited by their observational nature and inconsistent measure of NDMA exposure. To date, NDMA associations with renal malignancies—although evident in animal studies—is not clearly delineated in humans.

Conclusions:

Detection of NDMA in ranitidine has prompted governmental regulatory bodies to recommend withdrawal of ranitidine from US markets. Classification of NDMA as a “probable human carcinogen” is based on decades of animal studies with a notable rate of renal malignancies. Human observational studies do not clearly demonstrate an association with renal malignancies, but the available data have significant limitations and any conclusions drawn from these observational studies, whether supporting or challenging associations between ranitidine use and renal cancer, should be interpreted with caution.
Laryngeal verrucous cell carcinoma
Authors: Lechien Jerome R. , Vaira Luigi A. , Chiesa-Estomba Carlos M.
Published: October 2023

Purpose of review

To summarize the recent literature on epidemiology, clinical findings, treatment, and survival of laryngeal verrucous cell carcinoma (LVC).

Recent findings

Epidemiological studies report that LVC accounts for 1–3% of all laryngeal cancers. The incidence is decreasing, while most patients are male individuals and smokers. LVC are commonly detected in early stages because they are more frequently located in the glottic region. Tobacco, alcohol overuse, and, possibly, human papilloma virus are the main contributing factors. Recent studies confirm that surgery is the primary therapeutic approach with better prognosis when compared with other treatment modalities. Surgery alone is associated with 86.8% disease-free and 80.3% overall survival rates, while metastases are anecdotal.

LVC presents different clinical, pathological, and survival outcomes when compared with the classic laryngeal squamous cell carcinoma. Biopsies need often to be repeated before getting the most appropriate diagnosis; this supports the need of large-sample biopsy during the tumor diagnosis and staging. The glottic location of most LVC leads to detection of this lesion in its early stages, with ensuing better survival and outcomes after surgery compared with the classic form of squamous cell carcinoma. Future studies are needed to understand the biology of LVC and its related better prognostic outcomes when compared to other laryngeal malignancies.
Esophageal motility disorder – has Chicago classification v4.0 simplified our management?
Authors: Edeani Francis , Massey Benson
Published: October 2023

Review purpose

Addressing dysphagia is vital due to its prevalence and impact on healthcare expenditure. While high resolution manometry (HRM) effectively evaluates esophageal dysphagia, its role in oropharyngeal dysphagia and upper esophageal sphincter (UES) dysfunction remains debated. The fourth iteration of the Chicago classification (CC) offers an algorithmic approach for diagnosing abnormal motor patterns via HRM. This review assesses the CC's impact on dysphagia management.

Recent insights

The Chicago classification version 4.0 emphasizes auxiliary and provocative techniques when the algorithm falls short of a conclusive diagnosis. It introduces stricter criteria for previously ambiguous conditions like ineffective motility and esophagogastric junction outflow obstruction. This version also introduces the concept of conclusive and inconclusive classifications based on symptoms, provocation maneuvers, and supportive testing minimizing ambiguity.

The Chicago classification v4.0 remains a useful tool for the diagnosis of well characterized esophageal motility disorders. However, major limitations include reliance on HRM and a focus on distal esophagus contractile characteristics without considering proximal esophagus or upper esophageal sphincter, both of which can sometimes be the only evident abnormality in patients with dysphagia. Despite efforts to reduce ambiguity, diagnostic challenges persist. These limitations can be addressed in future updates
Evaluation of the Impact and Outcomes of a Rapid Transition to Telehealth PrEP Delivery at a Sexual Health Clinic During the COVID-19 Pandemic
Authors: Higgins David M. , Riba Adrean , Alderton Lucy , Wendel Karen A. , Scanlon Jennifer , Weise Julia , Gibson Nathan , Obafemi Oluyomi
Published: October 2023

Background

Increasing HIV pre-exposure prophylaxis (PrEP) use is a critical part of ending the HIV epidemic. In response to the COVID-19 pandemic, many PrEP services transitioned to a telehealth model (telePrEP). This report evaluates the effect of COVID-19 and the addition of telePrEP on delivery of PrEP services at the Denver Sexual Health Clinic (DSHC), a regional sexual health clinic in Denver, CO.

Methods

Prior to COVID-19, DSHC PrEP services were offered exclusively in-clinic. In response to the pandemic, after March 15, 2020, most PrEP initiation and follow up visits were converted to telePrEP. A retrospective analysis of DSHC PrEP visits compared pre-COVID-19 (September 1, 2019 to March 15, 2020) to post-COVID-19 (March 16, 2020 to September 30, 2020) visit volume, demographics, and outcomes.

Results

The DSHC completed 689 PrEP visits pre-COVID-19 and maintained 96.8% (n = 667) of this volume post-COVID-19. There were no differences in client demographics between pre-COVID-19 (n = 341) and post-COVID-19 PrEP start visits (n = 283) or between post-COVID-19 in-clinic (n = 140) vs telePrEP start visits (n = 143). There were no differences in 3-4-month retention rates pre-COVID-19 (n = 17/43) and post-COVID-19 (n = 21/43) (P = 0.52) or between in-clinic (n = 12/21) and telePrEP clients (n = 9/22) in the post-COVID-19 window (P = 0.37). Also, there were no significant differences in lab completion rates between in-clinic (n = 140/140) and telePrEP clients (n = 138/143) (P = 0.06) and prescription fill rates between in-clinic (n = 115/136) and telePrEP clients (n = 116/135) in the post-COVID-19 window (P = 0.86).

Conclusions

Implementation of TelePrEP enabled the DSHC to sustain PrEP services during the COVID-19 pandemic without significant differences in demographics, engagement, or retention in PrEP services.
Choosing Wisely and Promoting High-Value Care and Staff Safety During the COVID-19 Pandemic in a Large Safety Net System
Authors: Krouss Mona , Israilov Sigal , Mestari Nessreen , Talledo Joseph , Alaiev Daniel , Moskovitz Joshua B. , Faillace Robert T. , Uppal Amit , Fagan Ian , Curcio Joan , Scott Jinel , Bouton Michael , Ford Kenra , Cohen Victor , Wei Eric K. , Cho Hyung J.
Published: October 2023

Background and Objectives:

As the COVID-19 pandemic brought surges of hospitalized patients, it was important to focus on reducing overuse of tests and procedures to not only reduce potential harm to patients but also reduce unnecessary exposure to staff. The objective of this study was to create a Choosing Wisely in COVID-19 list to guide clinicians in practicing high-value care at our health system.

Methods:

A Choosing Wisely in COVID-19 list was developed in October 2020 by an interdisciplinary High Value Care Council at New York City Health + Hospitals, the largest public health system in the United States. The first phase involved gathering areas of overuse from interdisciplinary staff across the system. The second phase used a modified Delphi scoring process asking participants to rate recommendations on a 5-point Likert scale based on criteria of degree of evidence, potential to prevent patient harm, and potential to prevent staff harm.

Results:

The top 5 recommendations included avoiding tracheal intubation without trial of noninvasive ventilation (4.4); not placing routine central venous catheters (4.33); avoiding routine daily laboratory tests and batching laboratory draws (4.19); not ordering daily chest radiographs (4.17); and not using bronchodilators in the absence of reactive airway disease (4.13).

Conclusion:

We successfully developed Choosing Wisely in COVID-19 recommendations that focus on evidence and preventing patient and staff harm in a large safety net system to reduce overuse.
Ictal EEG Source Imaging With Supplemental Electrodes
Authors: Loube Deanne Kennedy , Tan Yee-Leng , Yoshii-Contreras June , Kleen Jonathan , Rao Vikram R. , Chang Edward F. , Knowlton Robert C.
Published: October 2023

Introduction:

Noninvasive brain imaging tests play a major role in guiding decision-making and the usage of invasive, costly intracranial electroencephalogram (ICEEG) in the presurgical epilepsy evaluation. This study prospectively examined the concordance in localization between ictal EEG source imaging (ESI) and ICEEG as a reference standard.

Methods:

Between August 2014 and April 2019, patients during video monitoring with scalp EEG were screened for those with intractable focal epilepsy believed to be amenable to surgical treatment. Additional 10-10 electrodes (total = 31–38 per patient, “31+”) were placed over suspected regions of seizure onset in 104 patients. Of 42 patients requiring ICEEG, 30 (mean age 30, range 19–59) had sufficiently localized subsequent intracranial studies to allow comparison of localization between tests. ESI was performed using realistic forward boundary element models used in dipole and distributed source analyses.

Results:

At least partial sublobar concordance between ESI and ICEEG solutions was obtained in 97% of cases, with 73% achieving complete agreement. Median Euclidean distances between ESI and ICEEG solutions ranged from 25 to 30 mm (dipole) and 23 to 38 mm (distributed source). The latter was significantly more accurate with 31+ compared with 21 electrodes (P < 0.01). A difference of ≤25 mm was present in two thirds of the cases. No significant difference was found between dipole and distributed source analyses.

Conclusions:

A practical method of ictal ESI (nonuniform placement of 31–38 electrodes) yields high accuracy for seizure localization in epilepsy surgery candidates. These results support routine clinical application of ESI in the presurgical evaluation.
Enhanced specific loss power of hematite–chitosan nanohybrid synthesized by hydrothermal method
Authors: Deb Nandita , Rashid Rimi , Das H. , Syed Ishtiaque M. , Hoque S. Manjura
Published: October 2023

We used a hydrothermal technique to develop nano-scale α-Fe
2
O
3
particles and functionalized them with chitosan. An X-ray diffraction study revealed α-Fe
2
O
3
nanoparticles were of single-phase, lattice constants were
a
= 5.07 Å and
c
= 13.68 Å, and the grain size was 27 nm. The presence of lattice fringes in the HRTEM image confirmed the crystalline nature of the α-Fe
2
O
3
. The Mössbauer spectra reveal a mixed relaxation state, which supports the PPMS studies. Zero-field cooled studies revealed the existence of a Morin transition and blocking temperature. The z-average value of the coated particles by DLS was between 218 and 235 nm, PDI ranged from 0.048 to 0.119, and zeta potential was +46.8 mV. We incubated the Vero and HeLa cell lines for 24 h to study the viability of the nanohybrids at different concentrations. Hyperthermia studies revealed the maximum temperature and specific loss power attained by the hematite–chitosan nanohybrid solution of a concentration between 0.25–4 mg ml
−1
. The
T
max
at the lowest and highest concentrations of 0.25 and 4 mg ml
−1
were 42.9 and 48.3°C, while the SLP were 501.6 and 35.5 W g
−1
, which are remarkably high when the maximum magnetization of α-Fe
2
O
3
nanoparticles was as small as 1.98 emu g
−1
at 300 K.
Quantum chemical investigation of predominant conformation of the antibiotic azithromycin in water and DMSO solutions: thermodynamic and NMR analysis
Authors: Hernandes Isabel S. , Da Silva Haroldo C. , Dos Santos Hélio F. , Ávila Eloah P. , De Almeida Mauro V. , De Almeida Wagner B.
Published: October 2023

Azithromycin (AZM) is a macrolide-type antibiotic used to prevent and treat serious infections (mycobacteria or MAC) that significantly inhibit bacterial growth. Knowledge of the predominant conformation in solution is of fundamental importance for advancing our understanding of the intermolecular interactions of AZM with biological targets. We report an extensive density functional theory (DFT) study of plausible AZM structures in solution considering implicit and explicit solvent effects. The best match between the experimental and theoretical nuclear magnetic resonance (NMR) profiles was used to assign the preferred conformer in solution, which was supported by the thermodynamic analysis. Among the 15 distinct AZM structures, conformer
M14
, having a short intramolecular C6-OH … N H-bond, is predicted to be dominant in water and dimethyl sulfoxide (DMSO) solutions. The results indicated that the X-ray structure backbone is mostly conserved in solution, showing that large flexible molecules with several possible conformations may assume a preferential spatial orientation in solution, which is the molecular structure that ultimately interacts with biological targets.
Effects of environmental colours in virtual reality: Physiological arousal affected by lightness and hue
Authors: Weijs Marieke Lieve , Jonauskaite Domicele , Reutimann Ricarda , Mohr Christine , Lenggenhager Bigna
Published: October 2023

It is a popular belief that colours impact one's psychological and affective functioning. However, clear-cut scientific evidence is still lacking, largely due to methodological challenges. Virtual reality (VR) enabled us to control and modify the environment. We exposed 60 participants to red or blue environments varying in lightness and saturation. We assessed participants' physiological responses (i.e. arousal) with heart rate and skin conductance measures, and their self-reported levels of valence and arousal in response to the coloured environments. The results revealed physiological effects of lightness and hue. When compared with the baseline measures, heart rate increased, and heart rate variability decreased more in the dark than the medium lightness rooms. Both measures signalled higher arousal in the darker room, irrespective of hue. Also, when compared with the baseline measures, skin conductance increased more in the red than the blue rooms, again signalling higher arousal in the red condition. The difference between the red and the blue conditions was detectable only on some saturation and lightness combinations. We conclude that being immersed in environments of different colours can change physiological arousal. However, not all changes are driven by hue and not all the effects are measurable on all physiological parameters.
Unveiling evolutionary cradles and museums of flowering plants in a neotropical biodiversity hotspot
Authors: González-Orozco Carlos E.
Published: October 2023

Colombia, renowned as an important centre of global biodiversity, continues to harbour undiscovered evolutionary hotspots of flowering plants. The altitude-dependent hypothesis suggests that richness patterns are determined by altitude and probably influenced by climate variables. This study employs null models based on a species-level phylogeny of Colombia's flowering plants and their geographical distributions to identify evolutionary hotspots. We explore the potential correlation between elevation, climate variables such as temperature and rainfall, and the location and nature of these hotspots. The findings reveal that evolutionary cradles, which house young endemic species, are predominantly located in the mountainous regions of the Andes. Conversely, evolutionary museums, hosting older endemic species, are found in lowland regions spanning the Caribbean, Orinoco, Amazon and Pacific areas. These results demonstrate a clear elevational segregation of evolutionary hotspots, primarily influenced by temperature, thereby supporting the hypothesis under examination. Furthermore, this study identifies previously unrecognized evolutionary regions, highlighting the limited understanding of Colombia's biodiversity distribution and evolutionary history.
The social microbiome: gut microbiome diversity and abundance are negatively associated with sociality in a wild mammal
Authors: Pfau Madison , Degregori Sam , Johnson Gina , Tennenbaum Stavi R. , Barber Paul H. , Philson Conner S. , Blumstein Daniel T.
Published: October 2023

The gut microbiome has a well-documented relationship with host fitness. Greater microbial diversity and abundance of specific microbes have been associated with improved fitness outcomes. Intestinal microbes also may be associated with patterns of social behaviour. However, these associations have been largely studied in captive animal models; we know less about microbiome composition as a potential driver of individual social behaviour and position in the wild. We used linear mixed models to quantify the relationship between fecal microbial composition, diversity and social network traits in a wild population of yellow-bellied marmots (
Marmota flaviventer
). We focused our analyses on microbes previously linked to sociability and neurobehavioural alterations in captive rodents, primates and humans. Using 5 years of data, we found microbial diversity (Shannon–Wiener and Faith's phylogenetic diversity) has a modest yet statistically significant negative relationship with the number of social interactions an individual engaged in. We also found a negative relationship between
Streptococcus
spp. relative abundance and two social network measures (clustering coefficient and embeddedness) that quantify an individual's position relative to others in their social group. These findings highlight a potentially consequential relationship between microbial composition and social behaviour in a wild social mammal.
Flies adaptively control flight to compensate for added inertia
Authors: Salem Wael , Cellini Benjamin , Jaworski Eric , Mongeau Jean-Michel
Published: October 2023

Animal locomotion is highly adaptive, displaying a large degree of flexibility, yet how this flexibility arises from the integration of mechanics and neural control remains elusive. For instance, animals require flexible strategies to maintain performance as changes in mass or inertia impact stability. Compensatory strategies to mechanical loading are especially critical for animals that rely on flight for survival. To shed light on the capacity and flexibility of flight neuromechanics to mechanical loading, we pushed the performance of fruit flies (
Drosophila
) near its limit and implemented a control theoretic framework. Flies with added inertia were placed inside a virtual reality arena which permitted free rotation about the vertical (yaw) axis. Adding inertia increased the fly's response time yet had little influence on overall gaze stabilization performance. Flies maintained stability following the addition of inertia by adaptively modulating both visuomotor gain and damping. By contrast, mathematical modelling predicted a significant decrease in gaze stabilization performance. Adding inertia altered saccades, however, flies compensated for the added inertia by increasing saccade torque. Taken together, in response to added inertia flies increase reaction time but maintain flight performance through adaptive neural control. Overall, adding inertia decreases closed-loop flight robustness. Our work highlights the flexibility and capacity of motor control in flight.
Metabolic stress as a driver of life-history plasticity: flight promotes longevity and antioxidant production in monarch butterflies
Authors: Shephard Alexander M. , Hund Amanda K. , Snell-Rood Emilie C.
Published: October 2023

Life-history theory predicts that increased investment in traits related to reproduction will be associated with a reduced ability to invest in survival or longevity. One mechanistic explanation for this trade-off is that metabolic stress generated from current fitness activities (e.g. reproduction or locomotion) will increase somatic damage, leading to reduced longevity. Yet, there has been limited support for this damage-based hypothesis. A possible explanation is that individuals can respond to increases in metabolic stress by plastically inducing cellular maintenance responses, which may increase, rather than decrease, longevity. We tested this possibility by experimentally manipulating investment in flight activity (a metabolic stressor) in the migratory monarch butterfly (
Danaus plexippus
), a species whose reproductive fitness is dependent on survival through a period of metabolically intensive migratory flight. Consistent with the idea that metabolic stress stimulated investment in self-maintenance, increased flight activity enhanced monarch butterfly longevity and somatic tissue antioxidant capacity, likely at a cost to reproductive investment. Our study implicates a role for metabolic stress as a driver of life-history plasticity and supports a model where current engagement in metabolically stressful activities promotes somatic survival by stimulating investment in self-maintenance processes.
Evaluation of kit-based loop-mediated isothermal amplification (TB-LAMP) assay in the diagnosis of tubercular lymphadenitis
Authors: Das Saurav , Nischal Neeraj , Singh Binit Kumar , Ray Animesh , Jorwal Pankaj , Soneja Manish , Khan Maroof Ahmad , Sikka Kapil , Sinha Sanjeev , Wig Naveet
Published: October 2023

Background: The rapid and accurate diagnosis of tubercular lymphadenitis remains a challenging task today.WHO endorsed LoopAMP™ MTBC kit (TB-LAMP) as a replacement for sputum-smear microscopy in the diagnosis of pulmonary tuberculosis (PTB). However, no prospective diagnostic accuracy study of TB-LAMP in tubercular lymphadenitis in adults has been done yet. Current study evaluated the diagnostic performance of TB-LAMP in tubercular lymphadenitis (LNTB).Material & Methods: In a prospective observational study conducted at a tertiary care hospital in India, 90 subjects (age>18years) suspected of LNTB were consecutively recruited and followed up till six months between January 2019 and December 2020. Samples were processed for microscopy, culture, GeneXpert®, histopathology and TB-LAMP. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TB-LAMP against composite reference standard (CRS) and culture were determined.Results : TB-LAMP showed a sensitivity of 83.78% (95% CI, 73.76-90.47) and specificity of 81.25% (95% CI, 56.99-93.41) respectively against CRS. The PPV and NPV were 95.38% (95% CI, 87.29-98.42) and 52.00% (95% CI, 33.50-69.97) respectively. TB-LAMP showed a sensitivity of 88.89% (95% CI, 71.94-96.15) and specificity of 36.17% (95% CI, 23.97-50.46) respectively against culture. The PPV and NPV were 44.44% (95% CI, 32-57.62) and 85% (95% CI, 63.96-94.76) respectively.Conclusion: TB-LAMP can be used over conventional microscopy for the diagnosis of TB in lymph node specimens at primary health care centres. This is the rapid and cost-effective diagnosis of LNTB in resource-limited settings due to good sensitivity and NPV.
Case Series on Trichomonas vaginalis Infections: Impact of Proper Sample Collection and Diagnostic Stewardship
Authors: Agarwal Ashwini , Padhi Abhishek , Chaudhary Anil , Bhise Mayuri , Chauhan Kinjal , Sharma Medhavi , Krishan Ramotra Rohini , Dubey Pankhuri
Published: October 2023

This paper elucidates the transformative impact of a strategic shift in diagnostic practices in the detection of Trichomonas vaginalis (T. vaginalis). It explores five cases where the implementation of a specific diagnostic protocol led to effective identification of the infection. In-depth discussions and a comprehensive literature review underline the necessity for precise diagnosis and the paramount importance of diagnostic stewardship in managing sexually transmitted infections.
Clinical Presentation and Outcome of Enteric Fever in Adult Patients with Cancer –A Perspective from Pakistan
Authors: Aslam Seemal , Nizamuddin Summiya , Abbas Salma , Raza Aun , Shehbaz Muhammad , Parveen Azra , Sultan Faisal
Published: October 2023

Introduction:
Enteric fever is a significant health concern in endemic countries. While extensive research has been conducted to understand its presentation and outcomes in non-cancer patients, limited data exist on its impact on cancer patients. This descriptive study aims to investigate the clinical presentation and outcome in cancer patients.
Methodology:
This retrospective observational study analysed 90 adult cancer patients from a single centre in Pakistan from January 2017 to December 2022. Inclusion criteria involved documented blood culture infections with Salmonella typhi or paratyphi A, B, or C. We examined clinical presentation, laboratory parameters, antimicrobial resistance, complications, and outcomes. Additionally, we explored the effects of chemotherapy, comorbidities, type of malignancy, and patient age on complications and mortality.
Results:
Salmonella typhi was the most prevalent organism (72.2%), followed by Salmonella paratyphi A (22.2%) and B (5.5%). Non-resistant isolates constituted 51.5%, multi-drug resistant (MDR) isolates accounted for 20%, extensively drug resistant (XDR) for 14.4% and ESBL-producing for 15.5%, of all enteric fever infections.. Enteric fever-associated complications were observed in 21.1% of cases. Chemotherapy in the preceding month did not affect mortality, nor did age, gender, or malignancy type. However, comorbidities were statistically significant for mortality (p-value 0.03). A total of 8.8% of patients required ICU care, and the all-cause 30-day mortality rate was 13.3%
Conclusion:
Enteric fever remains prevalent in our geographical region. Unlike Non-Typhoidal Salmonella (NTS), enteric fever does not behave differently in an immunocompromised population, including cancer patients.
Saliva as an alternative sample type for detection of pneumococcal carriage in young children
Authors: Wyllie Anne L. , Rots Nynke Y. , Wijmenga-Monsuur Alienke J. , van Houten Marlies A. , Sanders Elisabeth A. M. , Trzciński Krzysztof
Published: October 2023

For children, the gold standard for the detection of pneumococcal carriage is conventional culture of a nasopharyngeal swab. Saliva, however, has a history as one of the most sensitive methods for surveillance of pneumococcal colonization and has recently been shown to improve carriage detection in older age groups. Here, we compared the sensitivity of paired nasopharyngeal and saliva samples from PCV7-vaccinated 24-month-old children for pneumococcal carriage detection using conventional and molecular detection methods. Nasopharyngeal and saliva samples were collected from 288 24-month-old children during the autumn/winter, 2012/2013. All samples were first processed by conventional diagnostic culture. Next, DNA extracted from all plate growth was tested by qPCR for the presence of the pneumococcal genes piaB and lytA and a subset of serotypes. By culture, 161/288 (60 %) nasopharyngeal swabs tested positive for pneumococcus, but detection was not possible from saliva due to abundant polymicrobial growth on culture plates. By qPCR, 155/288 (54 %) culture-enriched saliva samples and 187/288 (65 %) nasopharyngeal swabs tested positive. Altogether, 219/288 (76 %) infants tested positive for pneumococcus, with qPCR-based carriage detection of culture-enriched nasopharyngeal swabs detecting significantly more carriers compared to either conventional culture (P<0.001) or qPCR detection of saliva (P=0.002). However, 32/219 (15 %) carriers were only positive in saliva, contributing significantly to the overall number of carriers detected (P=0.002). While testing nasopharyngeal swabs by qPCR proved most sensitive for pneumococcal detection in infants, saliva sampling could be considered as complementary to provide additional information on carriage and serotypes that may not be detected in the nasopharynx and may be particularly useful in longitudinal studies, requiring repeated sampling of study participants.
TENDINopathy Severity assessment – Achilles (TENDINS-A): Evaluation of reliability and validity in accordance with COSMIN recommendations
Authors: Murphy Myles C , McCleary Fergus , Hince Dana , Chimenti Ruth L , Chivers Paola T , Vosseller J. Turner , Nimphius Sophia , Mkumbuzi Nonhlanhla , Malliaras Peter , Maffuli Nicola , De Vos Robert-Jan , Rio Ebonie
Published: October 2023

Objectives

Evaluate the construct validity (structural validity and hypothesis-testing), reliability (test-retest reliability, measurement error and internal consistency) and minimal detectable change (MDC) of the 13-item TENDINopathy Severity assessment–Achilles (TENDINS-A).

Methods

Participants with Achilles pain completed an online survey: demographics, TENDINS-A, Foot and Ankle Outcome Score (FAOS) and Victorian Institute of Sport Assessment-Achilles (VISA-A). Exploratory factor analysis (EFA) assessed dimensionality. Confirmatory Factor Analysis (CFA) assessed structural validity [root-mean-squared error of approximation (RMSEA); Comparative Fit Index (CFI); Tucker-Lewis Index (TLI); Standardised Root Measure Square (SRMS)]. Correlations between TENDINS-A and the FAOS/ VISA-A assessed hypothesis-testing. Intraclass correlation (ICC) assessed test-retest reliability. Cronbach’s α assessed internal consistency. Standard error of the measurement (SEM) assessed measurement error. A distribution-based approach assessed MDC.

Results

Seventy-nine participants (51% female) with a mean (SD) age=42.6 (13.0)years, height=175.0 (11.7)cm and body mass=82.0 (19.1)kg were included. EFA identified three meaningful factors, proposed to be pain, symptoms and function. The best model identified using CFA had adequate structural validity (CFI= 0.959, TLI= 0.947, RMSEA= 0.101, SRMS=0.068) excluded three items from the original TENDINS-A, included three factors (Pain, Symptoms, and Function). TENDINS-A exhibited moderate positive correlation with FAOS (rho=0.598,p<0.001), moderate, negative correlation with VISA-A (r=-0.639,p<0.001). Reliability of the TENDINS-A is excellent (ICC=0.930; Cronbach’s α=0.808; SEM=6.54 units) and has an MDC of 12 units.

Conclusions

Our evaluation of the revised 10-item TENDINS-A has determined it has adequate validity and reliability. Thus, the TENDINS-A can be recommended for immediate use, being the preferred tool over other PROMs to assess disability in Achilles tendinopathy.
A phase I/II clinical trial of intradermal, controllable self-replicating RNA vaccine EXG-5003 against SARS-CoV-2
Authors: Koseki Takenao , Teramachi Mayumi , Koga Minako , Ko Minoru S.H. , Amano Tomokazu , Yu Hong , Amano Misa , Leyder Erica , Badiola Maria , Ray Priyanka , Kim Jiyoung , Ko Akihiro C. , Achour Achouak , Weng Nan-ping , Imai Takumi , Yoshida Hisako , Taniuchi Satsuki , Shintani Ayumi , Fujigaki Hidetsugu , Kondo Masashi , Doi Yohei
Published: October 2023

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID-19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG-5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG-5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNP). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 µg per dose, n = 16; placebo, n = 4) and Cohort 2 (25 µg per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG-5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG-5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG-5003 showed higher cellular responses compared to equivalently vaccinated participants in the placebo group. The findings suggest a priming effect by EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.
Foveolar drusen decrease fixation stability in pre-symptomatic AMD
Authors: Murari J. , Gautier J. , Daout J. , Krafft L. , Senée P. , Mecê P. , Grieve K. , Seiple W. , Sheynikhovich D. , Meimon S. , Paques M. , Arleo A.
Published: October 2023

Purpose

This study aims at linking subtle changes of fixational eye movements (FEM) in controls and in patients with foveal drusen using adaptive optics retinal imaging in order to find anatomo-functional markers for pre-symptomatic Age-related Macular Degeneration (AMD).

Methods

We recruited 7 young controls, 4 older controls and 16 presymptomatic AMD patients with foveal drusen from the Silversight Cohort. A high speed research-grade adaptive optics flood illumination ophthalmoscope (AO-FIO) was used for monocular retinal tracking of fixational eye movements. The system allows for sub-arcminute resolution, high-speed and distortion-free imaging of the foveal area. Foveal drusen position and size were documented using gaze-dependent imaging on a clinical-grade AO-FIO.

Results

FEM were measured with high precision (RMS-S2S=0.0015° on human eyes) and small foveal drusen (median=60µm) were detected with high contrast imaging. Microsaccade amplitude, drift diffusion coefficient and ISOline Area (ISOA) were significantly larger for patients with foveal drusen compared with controls. Among the drusen participants, microsaccade amplitude was correlated to drusen eccentricity from the center of the fovea.

Conclusions

A novel high-speed high-precision retinal tracking technique allowed for the characterization of FEM at the microscopic level. Foveal drusen altered fixation stability, resulting in compensatory FEM changes. Particularly, drusen at the foveolar level seemed to have a stronger impact on microsaccade amplitudes and ISOA. The unexpected anatomo-functional link between small foveal drusen and fixation stability opens up a new perspective of detecting oculomotor signatures of eye diseases at the presymptomatic stage.
Telomeres control human telomerase (hTERT) expression through non-telomeric TRF2
Authors: Sengupta Antara , Vinayagamurthy Soujanya , Soni Drishti , Deb Rajlekha , Mukherjee Ananda Kishore , Dutta Subhajit , Jaiswal Jushta , Yadav Mukta , Sharma Shalu , Bagri Sulochana , Roy Shuvra Shekhar , Poonia Priya , Singh Ankita , Khanna Divya , Bhatt Amit Kumar , Sharma Akshay , Saurav Suman , Motiani Rajender K , Chowdhury Shantanu
Published: October 2023

The function of the human telomerase reverse transcriptase (hTERT) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influencehTERTregulation is relatively less studied. We foundhTERTwas transcriptionally up/downregulated depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and thehTERTpromoter.hTERTpromoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to thehTERTpromoter. Cell lines from different tissue types (fibrosarcoma (HT1080), colon cancer (HCT116), and breast cancer (MDA-MB-231), engineered for either telomere elongation/shortening gave increase/decrease inhTERT, respectively. Mechanistically, we showhTERTpromoter-bound non-telomeric TRF2 recruits the canonical PRC2-complex inducing repressor histone H3K27-trimethylation in a TL-dependent fashion. This was further supported by TL-dependent promoter activity from an exogenously insertedhTERTreporter. Increase in TL over days followed by gradual decline, resulted in activation followed by repression ofhTERTin a concerted manner, further implicating TL as a key factor forhTERTregulation. Notably on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from thehTERTpromoter was evident along with telomere elongation andhTERTupregulation. Conversely, on telomere shortening in iPSCs,hTERTpromoter-bound TRF2 was restored with marked reduction inhTERTfurther supporting the causal role of TL inhTERTtranscription. Mechanisms of tight control ofhTERTby TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing and pluripotency.

Teaser

Telomere length controlshTERTexpression by modulating TRF2 distribution and PRC2-mediated repression, highlighting a self-regulatory mechanism in cancer.
SHIFTR enables the unbiased and multiplexed identification of proteins bound to specific RNA regions in live cells
Authors: Aydin Jens , Gabel Alexander , Zielinski Sebastian , Ganskih Sabina , Schmidt Nora , Hartigan Christina R. , Schenone Monica , Carr Steven A. , Munschauer Mathias
Published: October 2023

RNA-protein interactions determine the cellular fate of RNA and are central to regulating gene expression outcomes in health and disease. To date, no method exists that is able to identify proteins that interact with specific regions within endogenous RNAs in live cells. Here, we develop SHIFTR (Selective RNaseH-mediated interactome framing for target RNA regions), an efficient and scalable approach to identify proteins bound to selected regions within endogenous RNAs using mass spectrometry. Compared to state-of-the-art techniques, SHIFTR is superior in accuracy, captures close to zero background interactions and requires orders of magnitude lower input material. We establish SHIFTR workflows for targeting RNA classes of different length and abundance, including short and long non-coding RNAs, as well as mRNAs and demonstrate that SHIFTR is compatible with sequentially mapping interactomes for multiple target RNAs in a single experiment. Using SHIFTR, we comprehensively identify interactions ofcis-regulatory elements located at the 5ʹ and 3ʹ- terminal regions of the authentic SARS-CoV-2 RNA genome in infected cells and accurately recover known and novel interactions linked to the function of these viral RNA elements. SHIFTR enables the systematic mapping of region-resolved RNA interactomes for any RNA in any cell type and has the potential to revolutionize our understanding of transcriptomes and their regulation.
ABTrans: A Transformer-based model for predicting interaction between anti-Aß antibodies and peptides
Authors: Su Yuhong , Zhang Lingfeng , Wang Yangjing , Ma Buyong
Published: October 2023

Understanding the recognition of antibodies and Aβ peptide is crucial for the development of more effective therapeutic agents. Here we studied the interaction between anti-Aβ antibodies and different peptides by building a deep learning model, using the dodecapeptide sequences elucidated from phage display and known anti-Aβ antibody sequences collected from public sources. Our multi-classification model, ABTrans was trained to determine the four levels of binding ability between anti-Aβ antibody and dodecapeptide: not binding, weak binding, medium binding, and strong binding. The accuracy of our model reached 0.8278. Using the ABTrans, we examined the cross-reaction of anti-Aβ antibodies with other human amyloidogenic proteins, and we found that Aducanumab and Donanemab have the least cross-reactions with other human amyloidogenic proteins. We also systematically screened all human proteins interaction with eleven selected anti-Aβ antibodies to identify possible peptide fragments that could be an off-target candidate.

Key Points

ABTrans is a Transformer-based model that was developed for the first time to predict the interaction between anti-Aß antibodies and peptides.

ABTrans was trained using a dataset with 1.5 million peptides and 110 anti-Aβ antibodies.

ABTrans achieved an accuracy of 0.8278 and is capable of determining the four levels of binding ability between antibody and Aß: not binding, weak binding, medium binding, and strong binding.

ABTrans has potential applications in predicting off-target and cross-reactivity effects of antibodies and in designing new anti-Aß antibodies.
Urea excreted by tropical frogs is explained by their body mass and the mass of insects consumed
Authors: Dev Akash M , Sreedharan Gayathri , Panwar Yashwant Singh , Vasudevan Karthikeyan
Published: October 2023

Frog insect interactions are prominent and they result in services that are crucial in the ecosystem. The primary nitrogenous waste that frogs produce is urea. However, the role of biotic variables on urea excretion, has not been fully investigated. Frogs comprising of sixPolypedates maculatusand sevenMinervarya agricolawere maintained in controlled condition after tagging them with passive integrated transponders. Thirteen experiments were performed to test whether, frog species or frogs’ body mass or insect body mass, or a combination of these explained the amount of urea excreted by the frogs. We found that body mass of the frogs and the amount of insect biomass consumed explained the amount of urea excreted in the two species. In the light of these findings, we discuss the role of frogs in converting insect biomass into urea in the ecosystem.
Hindlimb Unloading Induces Bone Microarchitectural and Transcriptomic Changes in Murine Long Bones in an Age-Dependent Manner
Authors: Meas Steven J. , Daire Gabriella M. , Friedman Michael A. , DeNapoli Rachel , Ghosh Preetam , Farr Joshua N. , Donahue Henry J.
Published: October 2023

Age and disuse-related bone loss both result in decreases in bone mineral density, cortical thickness, and trabecular thickness and connectivity. Disuse induces physiological changes in bone like those seen with aging.

Bone microarchitecture and biomechanical properties were compared between 6- and 22-month-old C57BL/6J male control mice and 6-month-old mice that were hindlimb unloaded (HLU) for 3 weeks. Epiphyseal trabecular bone was the compartment most affected by HLU and demonstrated an intermediate bone phenotype between age-matched controls and aged controls.

RNA extracted from whole-bone marrow-flushed tibiae was sequenced and analyzed. Differential gene expression analysis additionally included 4-month-old male mice unloaded for 3 weeks compared to age-matched controls. Gene ontology analysis demonstrated that there were age-dependent differences in differentially expressed genes. Genes related to downregulation of cellular processes were most affected in 4-month-old mice after disuse whereas those related to mitochondrial function were most affected in 6- month-old mice. Cell-cycle transition was downregulated with aging.

A publicly available dataset (GSE169292) from 3-month female C57BL/6N mice unloaded for 7 days was included in ingenuity pathway analysis with the other datasets. IPA was used to identify the leading canonical pathways and upstream regulators in each HLU age group. IPA identified “Senescence Pathway” as the second leading canonical pathway enriched in mice exposed to HLU. HLU induced activation of the senescence pathway in 3- month and 4-month-old mice but inhibited it in 6-month-old mice.

In conclusion, we demonstrate that hindlimb unloading and aging initiate similar changes in bone microarchitecture and gene expression. However, aging is responsible for more significant transcriptome and tissue-level changes compared to hindlimb unloading.

Highlights

Epiphyseal trabecular bone is most susceptible to hindlimb unloading.

Hindlimb unloaded limbs resemble an intermediate phenotype between age-matched and aged controls.

Hindlimb unloading induces gene expression changes that are age dependent and may lead to inflammation and/or mitochondrial dysfunction depending on context.

Younger mice (3-4 months) activate the senescence pathway upon hindlimb unloading, whereas skeletally mature (6 months) mice inhibit it.
Saltational episodes of reticulate evolution in theDrosophila saltansspecies group
Authors: Prediger Carolina , Ferreira Erina A. , Zorzato Samara Videira , Hua-Van Aurélie , Klasson Lisa , Miller Wolfgang J. , Yassin Amir , Madi-Ravazzi Lilian
Published: October 2023

Phylogenomics reveals reticulate evolution to be widespread across taxa, but whether reticulation is due to low statistical power or it is a true evolutionary pattern remains a field of investigation. Here, we investigate the phylogeny and quantify reticulation in theDrosophila saltansspecies group, a Neotropical clade of the subgenusSophophoracomprising 23 species whose relationships have long been problematic. Phylogenetic analyses revealed conflicting topologies between the X chromosome, autosomes and the mitochondria. We extended the ABBA-BABA test of asymmetry in phylogenetic discordance to cases where no “true” species tree could be inferred, and applied our new test (called 2A2B) to whole genome data and to individual loci. We used four strategies, two of which consisted of windows from pseudo-reference genomes aligned to either an outgroup or ingroup species, and two based on our new assemblies using either conserved genes or ≥50 kb-long syntenic blocks with conserved collinearity across NeotropicalSophophora. Evidence for reticulation varied among the strategies, being lowest in the synteny-based approach, where it did not exceed ∼7% of the blocks in the most conflicting species quartets. High incidences of low phylogenetic resolution (polytomy) were restricted to three nodes on the tree, that coincided with major paleogeographical events in South America. Our results identify possible technical biases in quantifying reticulate evolution and indicate that episodic rapid radiations have played a major role in the evolution of a largely understudied Neotropical clade.