bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial and Ethnic Disparities in Anemia and Severe Maternal Morbidity
Authors: Igbinosa Irogue I. , Leonard Stephanie A. , Noelette Francecsa , Davies-Balch Shantay , Carmichael Suzan L. , Main Elliott , Lyell Deirdre J.
Published: September 2023

OBJECTIVE:

To evaluate antepartum anemia prevalence by race and ethnicity, to assess whether such differences contribute to severe maternal morbidity (SMM), and to estimate the contribution of antepartum anemia to SMM and nontransfusion SMM by race and ethnicity.

METHODS:

We conducted a population-based cohort study using linked vital record and birth hospitalization data for singleton births at or after 20 weeks of gestation in California from 2011 through 2020. Pregnant patients with hereditary anemias, out-of-hospital births, unlinked records, and missing variables of interest were excluded. Antepartum anemia prevalence and trends were estimated by race and ethnicity. Centers for Disease Control and Prevention criteria were used for SMM and nontransfusion SMM indicators. Multivariable logistic regression modeling was used to estimate risk ratios (RRs) for SMM and nontransfusion SMM by race and ethnicity after sequential adjustment for social determinants, parity, obstetric comorbidities, delivery, and antepartum anemia. Population attributable risk percentages were calculated to assess the contribution of antepartum anemia to SMM and nontransfusion SMM by race and ethnicity.

RESULTS:

In total, 3,863,594 births in California were included. In 2020, Black pregnant patients had the highest incidence of antepartum anemia (21.5%), followed by Pacific Islander (18.2%), American Indian–Alaska Native (14.1%), multiracial (14.0%), Hispanic (12.6%), Asian (10.6%), and White pregnant patients (9.6%). From 2011 to 2020, the prevalence of anemia increased more than100% among Black patients, and there was a persistent gap in prevalence among Black compared with White patients. Compared with White patients, the adjusted risk for SMM was high among most racial and ethnic groups; adjustment for anemia after sequential modeling for known confounders decreased SMM risk most for Black pregnant patients (approximated RR 1.47, 95% CI 1.42–1.53 to approximated RR 1.27, 95% CI 1.22–1.37). Compared with White patients, the full adjusted nontransfusion SMM risk remained high for most groups except Hispanic and multiracial patients. Within each racial and ethnic group, the population attributable risk percentage for antepartum anemia and SMM was highest for multiracial patients (21.4%, 95% CI 17.5–25.0%), followed by Black (20.9%, 95% CI 18.1–23.4%) and Hispanic (20.9%, 95% CI 19.9–22.1%) patients. The nontransfusion SMM population attributable risk percentages for Asian, Black, and White pregnant patients were less than 8%.

CONCLUSION:

Antepartum anemia, most prevalent among Black pregnant patients, contributed to disparities in SMM by race and ethnicity. Nearly one in five to six SMM cases among Black, Hispanic, American Indian–Alaska Native, Pacific Islander, and multiracial pregnant patients is attributable in part to antepartum anemia.
Obstetric Clinical Trial Diversity
Authors: Steinberg Jecca R. , DiTosto Julia D. , Turner Brandon E. , Roque Dario R. , Yee Lynn M.
Published: September 2023

Inclusive clinical trials are necessary to improve maternal health equity. We aimed to analyze the current state of race and ethnicity reporting and representation in obstetric trials and the association with trial focus for all U.S.-based obstetric trials between 2007 and 2020. In this cross-sectional, multivariable regression analysis, the exposure variable was clinical trial focus (eg, prematurity), and the outcomes were race and ethnicity reporting and representation of diverse cohorts. Obstetric anesthesia trials reported race and ethnicity the least frequently of all trial foci (adjusted odds ratio 0.2, 95% CI 0.08–0.48). Hypertension and obstetric anesthesia trials enrolled the lowest proportion of Black participants, and prematurity trials enrolled the lowest proportion of Latinx and Asian participants. All researchers should strive to improve measurement and reporting of demographic data as well participation of diverse cohorts.
Living liver donor pain management
Authors: Kang Ryung A. , Ko Justin Sangwook
Published: September 2023

Purpose of review

Optimal pain control in living liver donors undergoing hepatectomy is strongly recommended considering their unique status as healthy individuals willingly undergoing surgery for the benefit of the recipient. This review aims to examine and evaluate different strategies aimed at ensuring effective postoperative pain management in living liver donors.

Recent findings

Enhanced recovery after surgery (ERAS) protocols have proven effective in optimizing patient outcomes, including in living liver donor hepatectomy. By implementing these protocols, healthcare professionals can enhance postoperative pain control and accelerate recovery. Multimodal analgesia, which combines different techniques and agents, is crucial in pain management for living liver donors. Regional analgesia techniques, such as spinal anesthesia and various peripheral nerve blocks, have shown efficacy in reducing pain and facilitating early recovery. Systemic nonopioid analgesics, including acetaminophen, nonsteroidal anti-inflammatory drugs, ketamine, lidocaine, and dexmedetomidine act synergistically to alleviate pain and reduce inflammation. Minimizing the use of opioids is important to avoid adverse effects, and they should be reserved for rescue medication or breakthrough pain.

Applying the principles of ERAS and multimodal analgesia to living liver donors can effectively control pain while promoting early recovery.
Is It Safe to Omit the 1-week Post-operative Examination after Uncomplicated Phacoemulsification?
Authors: McLaughlin Mallory , Salazar Patricia , Piser Danielle , Bands Tenley , Shpountova Kristina
Published: September 2023

SIGNIFICANCE

The incidence of cataract surgery is increasing, accounting for a large percentage of eye care expenses. Scientific evidence supporting the medical necessity of the traditional post-operative schedule is lacking. Further studies are needed to optimize post-operative care to reduce the burden on patients and medical providers.

PURPOSE

This study aimed to study the rate of complication 1 week after uncomplicated phacoemulsification to determine if the 1-week post-operative examination can be safely omitted.

METHODS

A retrospective record review was conducted on all consecutive patients who had uncomplicated phacoemulsification between February 1, 2019, and February 1, 2020, at a clinic in an urban setting with a predominantly Black and African American patient population. Subjects were included if they had no complications during the 1-day post-operative examination. Complications at the 1-week and 1-month post-operative examination were recorded and analyzed.

RESULTS

Omitting the 1-week post-operative examination would result in missed complications in 4.48 to 15.97% of patients and failure to make unexpected management changes in 1.78 to 13.84% of patients.

CONCLUSIONS

The results of this study do not support omitting the 1-week post-operative examination after uncomplicated phacoemulsification. Further studies are needed to determine whether telemedicine can be safely substituted for post-operative examinations.
Results of Pyrocarbon Disc Interposition Compared to Trapeziectomy with Ligament Reconstruction and Tendon Interposition
Authors: van Laarhoven Cecile M. C. A. , Donners Simone J. A. , van Laarhoven Constance J. H. C. M. , Teunissen Joris , Bieckmann Luc , Schuurman Arnold H. , van der Heijden Brigitte E. P. A.
Published: September 2023

Background:

To compare pyrocarbon disc interposition arthroplasty (PDI) with trapeziectomy plus ligament reconstruction tendon interposition (LRTI), the authors assessed whether PDI resulted in a higher pinch strength, and compared grip strength, range of motion (ROM), patient-reported outcomes, satisfaction, and complications between the approaches.

Methods:

Because of scarcity of preoperative hand measurements, the authors performed a descriptional cross-sectional cohort study of patients operated on between 2006 and 2014, with a minimum of 5 years of follow-up. Patients were treated with PDI or LRTI. The authors determined key pinch strength as the primary outcome, followed by tip and tripod pinch, grip strength, palmar abduction and opposition, Michigan Hand Outcomes Questionnaire (MHQ) and Patient-Reported Hand and Wrist Evaluation (PRWHE) scores, satisfaction level, and complications. Propensity score matching was used to match the study groups on demographic variables. A ratio of 2:1 was used, resulting in inclusion of 62 (of 154) PDI and 31 (of 31) LRTI thumbs.

Results:

Patients in the PDI group showed stronger key and tip pinch strength than did patients in the LRTI group (P = 0.027 and P = 0.036, respectively). Tripod pinch, grip strength, and ROM were equal between the groups. MHQ and PRWHE were comparable, with higher satisfaction levels in the PDI group. Eight patients with PDI were converted to LRTI because of pain.

Conclusions:

This study confirmed the hypothesis that key and tip pinch strength is stronger after PDI compared with LRTI for first carpometacarpal joint osteoarthritis. Both techniques have comparable outcomes considering patient-reported outcome (MHQ and PRWHE), ROM, and complications.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
A rare and fatal case of tubo-ovarian abscess due to Burkholderia pseudomallei presenting as puerperal sepsis
Authors: Bhaskar M Maanasa , Rajamanikam Soundarya , Raj Sruthi , Sistla Sujatha , Nichanahalli Kubera Siddappa
Published: September 2023

Introduction. Melioidosis is an emerging life-threatening infectious disease caused by the Gram-negative

Burkholderia pseudomallei

found in contaminated soil and surface ground water. It often presents with varied clinical manifestations and has a high mortality if left untreated due to lack of clinical suspicion. Here we report a rare and fatal case of tubo-ovarian abscess presenting as puerperal sepsis due to

B. pseudomallei

in a young woman.

Case report. A 25-year-old female presented for medical consultation at day 43 postpartum complaining of fever on and off for the past 40 days associated with vomiting. On per speculum examination, greenish discharge from the cervix was seen and a right adnexal mass was felt which was cystic in consistency, non-tender and pushing the cervix to the left side. An exploratory laparotomy was carried out and pus was drained from below the rectus sheath, and from the right tubo-ovarian mass. Peripheral blood and the pus samples collected intraoperatively grew

B. pseudomallei

. The patient died on the fifth post-operative day due to septic shock with disseminated intravascular coagulation secondary to puerperal sepsis.

Conclusion. Melioidosis is a fatal but treatable disease when it is promptly diagnosed. In countries such as India, where tuberculosis is highly endemic, underdiagnosis of melioidosis can be common. Clinicians and microbiologists should have a high index of suspicion of melioidosis especially in individuals with underlying illness.
Ancient mitogenomes reveal evidence for the late Miocene dispersal of mergansers to the Southern Hemisphere
Authors: Rawlence Nicolas J. , Verry Alexander J. F. , Cole Theresa L. , Shepherd Lara D. , Tennyson Alan J. D. , Williams Murray , Wood Jamie R. , Mitchell Kieren J.
Published: September 2023

Mergansers are riverine and coastal piscivorous ducks that are widespread throughout North America and Eurasia but uncommon in the Southern Hemisphere. One species occurs in South America and at least two extinct species from New Zealand. It has been proposed that Southern Hemisphere mergansers were founded by independent dispersal events from the Northern Hemisphere. However, some morphological and behavioural evidence suggests that Southern Hemisphere mergansers may be closely related to one another. They share several characteristics that differ from Northern Hemisphere mergansers (e.g., non-migratory vs. migratory, sexual monochromatism vs. sexual dichromatism, long vs. short pair bonds). We sequenced complete mitogenomes from the Brazilian merganser and an extinct merganser from New Zealand—the Auckland Island merganser. Our results show the Brazilian and Auckland Island mergansers form a monophyletic clade with the common merganser, and that a sister relationship between Southern Hemisphere mergansers cannot be rejected. We cannot exclude the possibility that the Brazilian and Auckland Island mergansers descend from a single dispersal event from the Northern Hemisphere at least seven million years ago. Nuclear (palaeo)genomic data may help to resolve the relationship between living and extinct mergansers, including merganser fossils from New Zealand that have not been subjected to palaeogenetic analysis.
From Bimodal to Unimodal: The Transformed Incidence of Osteosarcoma in the United States
Authors: Kar Emma , Ammanamanchi Amrit , Yousif Miranda , Geetha Saroja Devi , Schwartz Kendall , Mishra Arya , Ling Jiali , Nonyelu Kristie Nneoma , Kannadath Bijun Sai
Published: September 2023

Background

Osteosarcoma is the most common primary bone malignancy. It has classically been described as having a bimodal incidence by age, with the first peak in the second decade of life and the second peak after 65 years of age. We sought to identify whether the bimodal incidence distribution still exists for osteosarcoma using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) and the National Inpatient Sample (NIS) (Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality) databases.

Methods

Incidence rates of osteosarcoma between 1975-2020 were analyzed by age, year of occurrence, sex, race, and primary tumor site using the SEER program data. The age of maximum incidence in patients 40 years of age and older was analyzed by calendar year to observe for a consistent second peak. Fisher’s Exact test was also conducted with the SEER data to assess if there was a significant association between the occurrence of osteosarcoma in patients 35-64 years old and those 65+ years old. Incidence of tumors of the long bones of the lower limbs using ICD-9 and 10 diagnosis codes from the NIS discharge database 2012-2019 were also analyzed for comparison.

Results

A total of 1,779 cases of osteosarcoma were reported in the SEER database from 1975-2020. Across the 46 calendar year span, a consistent first peak appeared in the second decade of life alternating between the 10-14 and 15-19 age groups. In the 40+ cohort, the age of the highest incidence varied widely each calendar year: being found in age groups 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, & 85+ years old (5, 3, 5, 1, 2, 1, 2, 1, & 1 times respectively). For 25 years of the 46-year span, the max was shared by more than one age group. Overall, no single age group from the 40+ age group held a consistent maximum from 1975-2020.

Using the NIS program and similar methodology, we analyzed 86,100 discharges of lower limb long bone tumors from 2012-2019 as a reference. The NIS data exhibited nearly identical patterns, with a unimodal incidence in adolescence and no obvious second peak.

Conclusion

Our analysis shows that the incidence of osteosarcoma is no longer bimodally distributed. This may be due to the increased use of bisphosphonates in recent years for the effective management of Paget’s disease, leading to a decline in late-age bone tumors. Our findings suggest the need to update our understanding of the epidemiology of osteosarcoma, as it should be considered more as a disease of adolescence with only sporadic incidence later on in older age.
Associating with kin selects against disease tolerance
Authors: Walsman Jason Cosens , Lambe Madalyn , Stephenson Jessica F
Published: September 2023

Behavioural and physiological immunity are key to slowing epidemic spread. Here, we explore the evolutionary and epidemic consequences of their different costs for the evolution of tolerance vs. resistance: behavioural resistance affects social cohesion, with associated group-level costs, while physiological resistance costs should accrue to the individual. Further, the transmission-reduction benefits of resistance accrue differently to susceptible hosts and those already infected; infected hosts only benefit indirectly, by reducing transmission to kin. We therefore model the coevolution of transmission-reducing defences expressed in susceptible hosts with those expressed in infected hosts, as a function of kin association, and analyse the effect on population-level outcomes. Using parameter values for guppies,Poecilia reticulata, and their gyrodactylid parasites, we find that: 1) either susceptible or infected hosts should invest heavily in preventing infection, but not both; 2) kin association drives investment in physiological resistance more strongly than in behavioural resistance; 3) even weak levels of kin association can favour altruistic infected hosts that invest heavily in resistance (vs. selfish tolerance), eliminating the disease. Overall, our finding that weak kin association affects the coevolution of infected and susceptible investment in both behavioural and physiological immunity suggests that kin selection may affect disease dynamics across systems.
The immunoglobulin A isotype of the Arabian camel (Camelus dromedarius) preserves the dualistic structure of unconventional single-domain and canonical heavy chains
Authors: Conca Walter , Salih Soad , Al-Rabiah Rana , Parhar Ranjit , Abd-Elnaeim Mahmoud , Al-Hindas Hussein , Tinson Alexander , Collison Kate , Kishore Uday , Al-Mohanna Futwan
Published: September 2023

Evolutionary processes of adaptive immunity inCamelidaeand some cartilaginous fishes resulted in the concurrent expression of classic heavy-light chain heterotetrameric antibodies together with unconventional heavy chain-only homodimeric antibodies of the IgG class. Heavy chain-only IgG bears a single variable domain and lacks the constant heavy (CH) γ1 domain required for the covalent pairing with the light chain. It has so far not been reported whether this distinctive feature of IgG is also observed in the IgA isotype. Therefore, gene-specific primers were used to generate a library of IgA heavy chain cDNA derived from RNA extracted from the third eyelid of the dromedary where isolated lymphoid follicles and plasma cells abound at inductive and effector sites, respectively. Majority of the cDNA clones revealed the hallmarks of heavy chain-only antibodies,i.e.camelid-specific amino acid substitutions in framework region 1 and 2, broad length distribution of complementarity determining region 3, and the absence of the CHα1 domain. In a few clones, however, the cDNA of canonical IgA heavy chain was amplified which included the CHα1 domain, analogous to CHγ1 domain in dromedary IgG1 subclass. Moreover, we noticed a short, proline-rich hinge, similar to that in human IgA2, and, at the N-terminal end of the CHα3 domain, a unique, camelid-specific pentapeptide consisting of serine, glutamic acid, aspartic acid, alanine or threonine, and isoleucine, of undetermined function, designated as the inter-α region. Immunoblots using rabbit anti-camel IgA antibodies raised against CHα2 and CHα3 domains as well as the inter-α region revealed the expression of a ∼52 kDa and a ∼60 kDa IgA species, corresponding to unconventional and canonical IgA heavy chain, respectively, in tissue extracts of the third eyelid,trachea, small and large intestine. In contrast, the leporine anti-CHα1 antibody detected canonical, but not unconventional IgA heavy chain, in all the examined tissues, milk, and serum, in addition to another hitherto unexplored species of ∼45 kDa in milk and serum. Immunohistology using anti-CHα domain antibodies confirmed the expression of both variants of IgA heavy chains in plasma cells in the third eyelid’s lacrimal gland, and in thelamina propriaofconjunctiva, bronchial and intestinalmucosa. We conclude that in the dromedary, the IgA isotype has expanded the immunoglobulin repertoire by co-expressing single-domain unconventional as well as canonical IgA heavy chains, comparable to the IgG class, thus underscoring the crucial role of heavy chain-only antibodies in immune defense not only in circulation but also at the mucosal frontiers.
Abca4 inhibition in a cone-rich rodent leads to Stargardt Disease type 1-like retinal degeneration
Authors: Sassone Fabiana , Roux Michel J. , Ciocca Dominique , Rossolillo Paola , Birling Marie-Christine , Sparrow Janet R. , Hicks David
Published: September 2023

Mutations in the geneABCA4coding for photoreceptor-specificATP-bindingcassette subfamilyAmember4, are responsible for the most common form of inherited macular degeneration known as Stargardt Disease type 1 (STGD1). STGD1 typically declares early in life and leads to severe visual handicap.Abca4gene deletion mouse models of STGD1 show increased accumulation of lipofuscin, a hallmark of the disease, but unlike the human disease show mostly no photoreceptor degeneration or functional decline (an albinoAbca4-/-mouse exhibits photoreceptor degeneration although functional parameters were not studied). Reasoning that the small cone population of mice (<3%) might compromise more faithful modelling of human maculopathies, we performed subretinal injections of CRISPR/Cas9-Abca4 recombinant Adeno-Associated Virus constructs into young Fat Sand Rats (Psammomys obesus), a diurnal rodent containing >30% cones. Sanger sequencing of the CRISPR-targeted sequence showed clear edition of theAbca4gene. At 2 months post- injection, non-invasive fundus imaging showed widespread photoreceptor loss, confirmed by optical coherence tomography. Functional recording by scotopic and photopic single flash, and photopic flicker electroretinography, showed significant decline in photopic (cone) but not scotopic (rod) light responses. Post-mortem real-time PCR, immunohistochemistry and western blotting showed significant decrease of cone-specific (MW cone opsin) but not rod- specific (rhodopsin) markers. Transmission electron microscopy showed large numbers of lipid inclusions in treated but not control retinal pigmented epithelium. Finally, ultrahigh performance liquid chromatographic analysis of wholeP. obesuseyes showed the presence ofall-transretinal-dimer, also seen inAbca4-/-mice but not normal rod-rich mouse or rat eyes. In conclusion, this animal model of STGD1 more accurately reflects human STGD1 and should be valuable for characterizing pathogenic pathways and exploring treatment options.
Deep learning enables accurate soft tissue deformation estimationin vivo
Authors: Huff Reece D. , Houghton Frederick , Earl Conner C. , Ghajar-Rahimi Elnaz , Dogra Ishan , Yu Denny , Harris-Adamson Carisa , Goergen Craig J. , O’Connell Grace D.
Published: September 2023

Image-based deformation estimation is an important tool used in a variety of engineering problems, including crack propagation, fracture, and fatigue failure. These tools have been instrumental in biomechanics research where measuringin vitroandin vivotissue deformations help evaluate tissue health and disease progression. However, accurately measuring tissue deformationin vivois particularly challenging due to limited image signal-to-noise ratio. Therefore, we created a novel deep-learning approach for measuring deformation from a sequence ofin vivoimages calledStrainNet. Utilizing a training dataset that incorporates image artifacts,StrainNetwas designed to maximize performance in challengingin vivosettings. Artificially generated image sequences of human flexor tendons undergoing known deformations were used to compareStrainNetagainst two conventional image-based strain measurement techniques.StrainNetoutperformed the traditional techniques by nearly 90%. High-frequency ultrasound imaging was then used to acquire images of the flexor tendons engaged during contraction. OnlyStrainNetwas able to track tissue deformations under thein vivotest conditions. Findings revealed strong correlations between tendon deformation and contraction effort, highlighting the potential forStrainNetto be a valuable tool for assessing preventative care, rehabilitation strategies, or disease progression. Additionally, by using real-world data to train our model,StrainNetwas able to generalize and reveal important relationships between the effort exerted by the participant and tendon mechanics. Overall,StrainNetdemonstrated the effectiveness of using deep learning for image-based strain analysisin vivo.
An experimental approach towards untangling the role of nature versus nurture in shaping the microbiome of social insects
Authors: Cohen Tali Magory , Bodner Levona , Turjeman Sondra , Sharon Efrat , Cohen Alisa , Bouchebti Sofia , Tikhonov Evgeny , Koren Omry , Levin Eran
Published: September 2023

The gut microbiota is intimately related to host wellbeing, in terms of physiology, immune function, and even social interactions. The strength of this relationship is dynamic, but the extent to which the microbiome is shaped by the identity of the host (nature) or its environment (nurture) remains largely unknown. Here we aimed to identify factors shaping the microbiomes of nursing workers and larvae of two Vespidae species, using a cross-species experimental design to control for effects of environment, host identity and their interactions. We found that the microbiome composition of adults depended principally on the environment. Conversely, larval microbiome composition differed more between host species, regardless of treatment. We also found distinct microbiota profiles between the two species, across life stages and independently. These findings further elucidate the complexity of the host-microbiome relationship shaped by the environment while retaining symbionts that benefit the host. These results suggest that holobiont evolution may have promoted the rise of social behavior in animals.
MAGPIE: an interactive tool for visualizing and analyzing protein-ligand interactions
Authors: Rodriguez Daniel C. Pineda , Weber Kyle C. , Sundberg Belen , Glasgow Anum
Published: September 2023

Quantitative tools to compile and analyze biomolecular interactions among chemically diverse binding partners would improve therapeutics design and aid in the study of molecular evolution. Here we present MAGPIE (Mapping Areas of Genetic Parsimony In Epitopes), a publicly available software package for simultaneously visualizing and analyzing thousands of interactions between a single protein or small molecule ligand (the "target") and all of its protein binding partners ("binders"). MAGPIE generates an interactive 3D visualization from a set of protein complex structures that share the target ligand, as well as sequence logo-style amino acid frequency graphs that show all the amino acids from the set of protein binders that interact with user-defined target ligand positions or chemical groups. MAGPIE highlights all the salt bridge and hydrogen bond interactions made by the target in the visualization and as separate amino acid frequency graphs. Finally, MAGPIE collates the most common target-binder interactions as a list of "hotspots," which can be used to analyze trends or guide the de novo design of protein binders. As an example of the utility of the program, we used MAGPIE to probe how two ligands bind orthologs of a well-conserved glycolytic enzyme for a detailed understanding of evolutionarily conserved interactions involved in its activation and inhibition. MAGPIE is implemented in Python 3 and freely available at https://github.com/glasgowlab/MAGPIE, along with sample datasets, usage examples, and helper scripts to prepare input structures.
Antibody Humanization via Protein Language Model and Neighbor Retrieval
Authors: Zou Honggang , Yuan Rongqing , Lai Boqiao , Dou Yang , Wei Li , Xu Jinbo
Published: September 2023

Antibody (Ab), also known as immunoglobulin (Ig), is an essential macromolecule involved in human immune response and plays an increasingly vital role in drug discovery. However, the development of antibody drugs heavily relies on humanization of murine antibodies, which often necessitates multiple rounds of sequence optimizations through laborious experimental processes. In recent years, the remarkable capabilities of machine learning have revolutionized the field of natural sciences and have also demonstrated promising applications in the field of antibody humanization. Here, we present Protein-LAnguage-model-knN (PLAN), a machine learning model leveraging protein language model and information retrieval for improving humanization of antibodies. Further, we proposeDE, a computed value shows a positive correlation with antigen-binding affinity. Ourin silicoexperimental results demonstrate that 1) the PLAN-humanized sequences’ average humanness score reaches 0.592, improving over the best existing method by 44.7%; 2) a 63% overlap between the PLAN-proposed mutations and the mutations validated through wet lab experiments, which is 16.7% higher than the best existing result; 3) comparable antigen-binding affinity afterDEguided back mutation.
Blood transfusion in care of patients with Visceral Leishmaniasis: a review of practices in therapeutic efficacy studies
Authors: Dahal Prabin , Singh-Phulgenda Sauman , Wilson James , Cota Glaucia , Ritmeijer Koert , Musa Ahmed , Alves Fabiana , Stepniewska Kasia , Guerin Philippe J
Published: September 2023

Anaemia is a common presentation feature in patients with visceral leishmaniasis (VL). Blood transfusion remains an important aspect of patient management in VL. However, triggers considered for making decisions on transfusion are poorly understood. This review is based on the Infectious Diseases Data Observatory (IDDO) VL clinical trials library, a database of all published efficacy studies since 1980 and has indexed 160 published trials (1980–2021). Description of blood transfusion was reported in 16 (10.1%) trials (n=3,459 patients). Transfusion was initiated solely based on haemoglobin (Hb) measurement in 9 studies, using a combination of Hb and other health conditions (epistaxis, poor health, or clinical instability) in 3 studies, and the criteria was unclear in 4 studies; Hb threshold ranged from 3-8 g/dL. Overall, the number of patients receiving transfusion was explicitly reported in 10 trials (n=2,421 patients enrolled). Of these, 217 patients underwent transfusion; 58 before treatment initiation and 46 during treatment or the follow-up phase, and the time of transfusion was unclear in 113. The median proportion of patients who received a transfusion in a study was 8.0% [Interquartile range (IQR): 4.7% to 47.2%; range: 0-100%; n=10 studies]. This review describes the variation in current clinical practice and is an important initial step in policy/guideline development, where both the patient’s haemoglobin concentration and clinical status must be considered.
Framingham risk score prediction at 12 months in the STANDFIRM randomised control trial
Authors: Phan Thanh G , Srikanth Velandai K , Cadilhac Dominique A , Nelson Mark , Kim Joosup , Olaiya Muideen T , Fitzgerald Sharyn M , Bladin Christopher , Gerraty Richard , Ma Henry , Thrift Amanda G
Published: September 2023

Background

The Shared Team Approach between Nurses and Doctors For Improved Risk factor Management (STANDFIRM, ACTRN12608000166370) trial was designed to test the effectiveness of chronic disease care management for modifying the Framingham risk score (FRS) among patients with stroke or transient ischemic attack. The primary outcome of change in FRS between baseline and 12 months was not met. We aimed to determine characteristics of participants at baseline that predict reduction in FRS at 12 months and whether future FRS is predetermined at the time of randomization

Method

Data included 35 variables encompassing demographics, risk factors, psychological, social and education status, and laboratory tests. Five supervised machine learning (ML) methods were used: random forest (RF), extreme gradient boosting (XGBoost), support vector regression (SVR), multilayer perceptron artificial neural network (MLP) and K-nearest neighbor (KNN). We split data for training (80%, n=406) and testing (20%, n=102).

Results

Training and test data were evenly matched for age, sex, baseline and 12-month FRS. Following tuning of the five ML methods, the optimal model for predicting FRS at 12 months was SVR (R2=0.763, root mean squared error or RMSE=8.52). The five most important variables for SVR were: baseline FRS, age, male sex, sodium/potassium excretion and proteinuria. All ML methods were poor at determining change in FRS at 12 months (R2<0.161).

Conclusion

Our findings suggest that change in FRS as an endpoint in trials may have limited value as it is largely determined at baseline. In this cohort, Support Vector Regression was the optimal method to predict future but not change in FRS.
Preliminary study of transcranial Doppler observation of cerebral herniation in acute internal carotid artery occlusion
Authors: Chen Jin , Su Jun , Chang Hong , Bai Peng
Published: September 2023

Background and Purpose

The purpose of this study was to attempt early detection of the risk of cerebral herniation after acute internal carotid artery occlusion (AICAO) using transcranial Doppler.

Methods

Twenty-four patients were enrolled within 6 hours of symptom onset. All patients underwent transcranial Doppler (TCD), head computed tomography (CT), magnetic resonance angiography (MRA) or computed tomography angiography (CTA). The National Institutes of Health Stroke Scale (NIHSS) score and the Alberta Stroke Program Early CT Score (ASPECTS) were performed in emergency department and 24 hours after the onset of acute ischemic stroke (AIS) (designated as NIHSS1 and ASPECTS1, respectively). TCD to determine collateral circulation was performed immediately after patient admission.

Results

Sex, risk factors, hemisphere, intravenous recombinant tissue plasminogen activator (rt-PA), and time from onset of symptoms to initiation treatment showed no difference between patients with or without cerebral herniation. The age of the group with cerebral hernia was significantly younger than that of the group without cerebral hernia (P=0.000). Assessment of the anterior communicating artery (ACoA) by TCD was in high agreement with assessment by MRA or CTA (kappa=0.625, P=0.002). Correlation analysis showed that the likelihood of a cerebral herniation event was positively correlated with absence of a communicating artery (rn=0.660, P=0.002) and negatively correlated with ACoA (rn=0.513, P=0.003) and ASPECTS1 (rs=0.528, P=0.008), but was not correlated with NIHSS score, NIHSS1 score, △NIHSS (NIHSS1-NIHSS), admission awareness, and stroke volume (P > 0.05).

Conclusions

TCD assessment of collateral status could more rapidly indicate the risk of cerebral herniation. Lack of collateral flow may predict the occurrence of cerebral hernia. Compensation of ACoA may indicate a lower risk of cerebral hernia.
De novo genome assembly and annotation of the saw-scaled viperEchis carinatus, a medically important venomous snake in the Indian Subcontinent
Authors: Blotra Avni , Sharma Anukrati , Sowpati Divya Tej , Vasudevan Karthikeyan
Published: September 2023

Echis carinatusis a widely distributed venomous snake in the Indian subcontinent. It is one of the “Big Four” snake species responsible for mortality and severe health complications caused by envenomations. Given the significance of the species for human health, we assembled and annotated the whole genome ofE. carinatus. Using long reads for assembly and short reads for correction, we achieved a highly contiguous 1.57Gb assembly, with a contig N50 of 17.1 Mb and scaffold N50 of 23.5 Mb. We could map 96.58% of our reads back to the assembled genome, and Benchmarking Universal Single-Copy Orthologs (BUSCO) score of 97.4%, indicates near completeness. 48.59% of the genome had repeat elements. The predominant types of repeats include retrotransposons (LINEs, SINEs and LTR elements), DNA transposons and satellite DNA (SSRs). Additionally, we conducted a gene prediction analysis, identifying a total of 26,711 protein-coding genes. These genes included alternatively spliced products, leading to the prediction of 31,106 proteins, 77.6% of which were successfully annotated usingBlastpandInterProScan. Out of the total predicted gene set, we identified 119 toxin-coding genes, crucial for venom toxin production in the species. The acquisition of toxin sequence-based information resulted in a valuable dataset of genes that are involved in venom production inE. carinatus. This dataset advances our understanding of the biological processes underlying venom production and lays the foundation for the development of new antivenom formulations.
GametesOmics: A Comprehensive Multi-Omics Database for Exploring the Gametogenesis in Humans and Mice
Authors: An Jianting , Wang Jing , Kong Siming , Song Shi , Chen Wei , Yuan Peng , He Qilong , Chen Yidong , Li Ye , Yang Yi , Wang Wei , Li Rong , Yan Liying , Yan Zhiqiang , Qiao Jie
Published: September 2023

Gametogenesis plays an important role in the reproduction and evolution of species. The transcriptomic and epigenetic alterations in this process can influence the reproductive capacity, fertilization, and embryonic development. The rapidly increasing single-cell studies have provided valuable multi-omics resources. However, data from different layers and sequencing platforms have not been uniformed and integrated, which greatly limits their use for exploring the molecular mechanisms that underlie oogenesis and spermatogenesis. Here, we developed GametesOmics, a comprehensive database that integrated the data of gene expression, DNA methylation, and chromatin accessibility during oogenesis and spermatogenesis in humans and mice. GametesOmics provides a user-friendly website and various tools, includingSearchandAdvanced Searchfor querying the expression and epigenetic modification of each gene;Analysis ToolswithDifferentially Expressed Gene (DEG) analysisfor identifying DEGs,Correlation analysisfor demonstrating the genetic and epigenetic changes,Visualizationfor displaying single-cell cluster and screening marker genes as well as master transcription factors (TFs), andMethylViewfor studying the genomic distribution of epigenetic modifications. GametesOmics also providesGenome BrowserandOrthologsfor tracking and comparing gene expression, DNA methylations, as well as chromatin accessibilities between humans and mice. GametesOmics offers a comprehensive resource for biologists and clinicians to decipher the cell fate transition in germ cell development, and can be accessed athttp://gametesomics.cn/.
NetAn: A Python Toolbox Leveraging Network Topology for Comprehensive Gene Annotation Enrichments
Authors: Magnusson Rasmus
Published: September 2023

Gene annotation enrichment analysis is the gold standard for studying the biological context of a set of genes, but available tools often overlook important network properties of the underlying gene regulatory system. This paper introduces the NETwork ANnotation enrichment package, NetAn, which augments annotation analysis with approaches such as the inference of closely related genes to include local neighbors in the analysis, and the separation of over-representation analyses based on network clustering, cliques, and the extraction of separate components. By using NetAn, an example of how such approaches enhance the identification of pertinent annotations in human gene sets is demonstrated.

Availability and Implementation

The software is implemented in Python under a GNU GENERAL PUBLIC LICENSE V3, and can be downloaded fromhttps://github.com/rasma774/netan.

Contact

rasmus.magnusson@his.se

Supplementary Information

The code relevant to this article is available in the doc/article material folder of the NetAn repository.
CD45-antibody-drug conjugate clears tissue resident myeloid cells from their niches enabling therapeutic adoptive cell transfer
Authors: Gustafsson Karin , Rhee Catherine , Frodermann Vanessa , Scadden Elizabeth W. , Li Dan , Iwamoto Yoshiko , Palchaudhuri Rahul , Hyzy Sharon L. , Boitano Anthony E. , Nahrendorf Matthias , Scadden David T.
Published: September 2023

Tissue resident myeloid cells (TRM) in adults have highly variable lifespans and may be derived from early embryonic yolk sac, fetal liver or bone marrow. Some of these TRM are known pathogenic participants in congenital and acquired diseases. Myeloablative conditioning and hematopoietic stem cell transplant can replace long-lived brain TRM resulting in clinical improvements in metabolic storage diseases. With the advent of antibody-drug-conjugate (ADC) targeted cell killing as a cell selective means of transplant conditioning, we assessed the impact of anti-CD45-ADC on TRM in multiple tissues. Replacement of TRM ranged from 40 to 95 percent efficiencies in liver, lung, and skin tissues, after a single anti-CD45-ADC dose and bone marrow hematopoietic cell transfer. Of note, the population size of TRM in tissues returned to pre-treatment levels suggesting a regulated control of TRM abundance. As expected, brain, microglia were not affected, but brain monocytes and macrophages were 50% replaced. Anti-CD45-ADC and adoptive cell transfer were then tested in the chronic acquired condition, atherosclerosis exacerbated byTet2mutant clonal hematopoiesis. Plaque resident myeloid cells were efficiently replaced with anti-CD45-ADC and wild-type bone marrow cells. Notably, this reduced existent atherosclerotic plaque burden. Overall, these results indicate that anti-CD45-ADC clears both HSC and TRM niches enabling cell replacement to achieve disease modification in a resident myeloid cell driven disease.
Phagocytosis in macrophages is regulated by the ATP-binding cassette family gene ABCF1
Authors: Arora Hitesh , Choi Kyung Bok , Munro Lonna , Pfeifer Cheryl G. , Jefferies Wilfred A.
Published: September 2023

Phagocytosis is a conserved biological mechanism that is integral to tissue remodeling, clearance of apoptotic cells, and immune defense in animals. Additionally, it serves as a pivotal means of sustenance for diverse unicellular eukaryotes. In the context of mammals, this crucial role is fulfilled by specific cell types such as macrophages, monocytes, dendritic cells, and neutrophils. It is orchestrated by an array of receptors, kinases, cytoskeletal elements, and enzymes, working collaboratively to enable the recognition, engulfment, and internalization of particles. Despite its profound significance, the intricate mechanisms underpinning the regulation of this phenomenon remains enigmatic. In this study, we present compelling evidence indicating the involvement of ABCF1, a member of the ATP-binding cassette family, in the FcγRIIA phagocytic pathway. ABCF1’s contribution lies in facilitating downstream signal activation through interactions with Src family members and SYK, pivotal players in this cascade. Additionally, our findings highlight ABCF1’s essentiality in the biosynthesis of various SFKs (Src family kinases) and MAPKs (mitogen-activated protein kinases). These molecules collectively oversee the orchestration of phagocytic cup formation, a pivotal step governing the engulfment process within macrophages. Consequently, the regulation of ABCF1 presents a potential avenue for modulating phagocytosis, allowing for the precise modulation of this fundamental process to either enhance or attenuate according to the specific physiological demands.
Dynamics and quantitative contribution of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] to amikacin resistance
Authors: d’Acoz Ophélie d’Udekem , Hue Fong , Ye Tianyi , Wang Louise , Leroux Maxime , Rajngewerc Lucila , Tran Tung , Phan Kimberly , Ramirez Maria S. , Reisner Walter , Tolmasky Marcelo E. , Reyes-Lamothe Rodrigo
Published: September 2023

Aminoglycosides are essential components in the available armamentarium to treat bacterial infections. The surge and rapid dissemination of resistance genes strongly reduce their efficiency, compromising public health. Among the multitude of modifying enzymes that confer resistance to aminoglycosides, the aminoglycoside acetyltransferase AAC(6′)-Ib is the most prevalent and relevant in the clinical setting as it can inactivate numerous aminoglycosides, such as amikacin. Although the mechanism of action, structure, and biochemical properties of the AAC(6′)-Ib protein have been extensively studied, the contribution of the intracellular milieu to its activity remains unclear. In this work, we used a fluorescent-based system to quantify the number of AAC(6′)-Ib per cell inEscherichia coli,and we modulated this copy number with the CRISPR interference method. These tools were then used to correlate enzyme concentrations with amikacin resistance levels. Our results show that resistance to amikacin increases linearly with a higher concentration of AAC(6′)-Ib until it reaches a plateau at a specific protein concentration.In vivoimaging of this protein shows that it diffuses freely within the cytoplasm of the cell, but it tends to form inclusion bodies at higher concentrations in rich culture media. Addition of a chelating agent completely dissolves these aggregates and partially prevents the plateau in the resistance level, suggesting that AAC(6′)-Ib aggregation lowers resistance to amikacin. These results provide the first step in understanding the cellular impact of each AAC(6′)-Ib molecule on aminoglycoside resistance. They also highlight the importance of studying its dynamic behavior within the cell.

Importance

Antibiotic resistance is a growing threat to human health. Understanding antibiotic resistance mechanisms can serve as foundation for developing innovative treatment strategies to counter this threat. While numerous studies clarified the genetics and dissemination of resistance genes and explored biochemical and structural features of resistance enzymes, their molecular dynamics and individual contribution to resistance within the cellular context remain unknown. Here, we examined this relationship modulating expression levels of AAC(6′)-Ib, an enzyme of clinical relevance. We show a linear correlation between copy number of the enzyme per cell and amikacin resistance levels up to a threshold where resistance plateaus. We propose that at concentrations below the threshold, the enzyme diffuses freely in the cytoplasm but aggregates at the cell poles at concentrations over the threshold. This research opens promising avenues for studying enzyme solubility’s impact on resistance, creating opportunities for future approaches to counter resistance.
PKA regulation of neuronal function requires the dissociation of catalytic subunits from regulatory subunits
Authors: Xiong Wei-Hong , Qin Maozhen , Zhong Haining
Published: September 2023

Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the β-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.