bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical Management of Polymethylmethacrylate-Collagen Gel Complications in the Lower Eyelid
Authors: Durkin Alan James , Catena Dominique , Woltjen Nick , Boyle Kathleen , Polling Maxwell , Weng John , Chim Jimmy H.
Published: December 2022

Background

As nonsurgical rejuvenation with fillers continues to grow in popularity, patients are increasingly interested in more durable results. Polymethylmethacrylate (PMMA)-collagen gel is unique among fillers in that the PMMA microspheres are not completely absorbed and phagocytosed by the body. This durability coupled with the biophysical properties of PMMA makes it a poor choice for periorbital rejuvenation, an unforgiving and highly complex anatomic area.

Methods

Between 2011 and 2018, 14 patients with PMMA granulomas in various facial areas self-referred to the senior author's practice. Of these patients, 11 were managed nonsurgically; however, all 3 patients who presented with granulomas in the infraorbital area required surgery to remove the filler and restore a natural aesthetic.

Results

The 3 patients with significant swelling and PMMA filler nodules in the infraorbital area with unacceptable cosmetic appearance were females between the ages of 50 and 55 years. Nonsurgical protocols were unsuccessful, and surgical removal was required. All subjects have been followed for a minimum of 2 years with no immediate- or long-term postoperative complications secondary to PMMA removal. Patients remain satisfied with the outcome of the surgery.

Conclusions

Despite the evidence that the periorbital area is prone to adverse events when injected with particulate fillers, misguided enthusiasm for PMMA-collagen gel as a durable treatment continues to lead to unnecessary and severe complications in patients. The case studies presented here highlight that this product should not be introduced into the periorbital area. We also describe a surgical treatment approach for its removal if complications arise.
Oncoplastic Augmentation Mastopexy in Breast Conservation Therapy
Authors: Salinas Harry M. , Ainuz Bar Y. , Pourmoussa Austin J. , Levitt Eli B. , Ali Aleeza , Bouz Antoun , Treiser Matthew D. , Medina Miguel A.
Published: December 2022

Background

Oncoplastic techniques, in conjunction with lumpectomy and adjuvant radiotherapy, have been demonstrated to achieve good aesthetic results and cancer outcomes in the treatment of patients with macromastia or significant ptosis. This study evaluated a series of patients undergoing breast conservation with concomitant oncoplastic-augmentation-mastopexy and a contralateral augmentation-mastopexy.

Methods

Patients undergoing lumpectomy for breast conservation were identified via a retrospective chart review. Inclusion criteria included patients with ptosis and preexisting breast implants or insufficient breast volume undergoing oncoplastic implant placement/exchange and mastopexy. Demographic characteristics, operative details, and complications were assessed.

Results

Thirty-four consecutive patients (64 breasts, 4 unilateral procedures) were included in the study. Average age was 51.4 years, average body mass index was 27, and 38.2% were smokers/former smokers. The average operative time was 2.5 hours. Furthermore, 38.2% of patients received chemotherapy, and 82.4% of patients received breast adjuvant radiotherapy. The average length of follow-up was 11.7 months. In the sample that received radiation, the capsular contracture rate was 25%, with a 7.1% contracture revision rate. For the entire group, a total of 8 patients (23.5%) underwent revisions for either positive margins (8.8%), capsular contracture (8.8%), implant loss (2.9%), or cosmetic concerns (2.9%). One patient developed a pulmonary embolism.

Conclusions

Oncoplastic-augmentation-mastopexy is a safe technique with acceptable complication rates. This technique is best used for breast cancer patients with breast ptosis and a paucity of breast volume or preexisting implants who wish to pursue breast-conserving therapy. The revision rates are acceptable compared with single-stage cosmetic augmentation procedures as well as other oncoplastic techniques described in the literature, but patients must be clearly counseled on contracture risk.
Prognostic Analysis of Skin Scar Loosening and Tissue-Expansive Autologous Skin Grafting in the Treatment of Skin Postburn Scars
Authors: Zhang Mengyao , Fang Yuan , Li Haibo , Shi Shupeng , Chen Jia , Tang Fengjie , Li Xu , Jiang Ming , Wang Shoubao , Li Shengli , Zhou Jianda
Published: December 2022

Background:

This study aims to observe and investigate the clinical value of scar loosening and tissue-expansive autologous skin grafting in the treatment of postburn scars and independent risk characteristics for surgery-related complications.

Methods:

We retrospectively analyzed 94 cases with postburn scars, and all patients were treated with scar loosening and autologous skin grafting. Overall therapeutic effects were evaluated using the standard of cure and improvement of clinical diseases. Burn Specific Health Scale-brief was used to analyze patients’ quality of life. The visual analog scale scores were used to analyze esthetic satisfaction. Surgery-related complications were recorded, and logistic regression model was used to analyze independent factors affecting surgery-related complications.

Results:

As for overall efficacy evaluation, 50 cases were cured, 19 cases were markedly improved, 17 cases improved, and 8 cases were detected and tested, and the overall effective rate was 91.4%. The Burn Specific Health Scale-brief and visual analog scale score showed a trend of increasing gradually. It indicated that the patients were satisfied with the operation and their quality of life was improved. The logistic regression model showed that history of skin disease (OR=1.53 (1.08–2.16), P=0.02) and skin area (OR=2.50 (1.22–4.50), P<0.01) were significantly associated with surgery-related complications.

Conclusions:

Scar loosening and autologous skin grafting is a safe and effective treatment. The history of skin disease and skin area was the independent factors for surgery-related complications.
AMP-activated protein kinase phosphorylation mediated by Sirtuin 5 alleviates septic acute kidney injury
Authors: Wang Tingjie , Lin Bo , Qiu Weihuang , Yu Binmei , Li Jiaxin , An Sheng , Weng Lijun , Li Yuying , Shi Menglu , Chen Zhongqing , Zeng Zhenhua , Lin Xianzhong , Gao Youguang , Ouyang Jie
Published: December 2022

Background

Our previous studies have shown that ameliorating mitochondrial damage in renal tubular epithelial cells (RTECs) can alleviate septic acute kidney injury (SAKI). It is reported that AMPK phosphorylation (p-AMPK) could ameliorate mitochondrial damage in renal tissue and Sirtuin 5 (SIRT5) over-expression significantly enhanced the level of p-AMPK in bovine preadipocytes. However, the role of SIRT5- mediated phosphorylation of AMPK in SAKI needs to be clarified.

Methods

WT/SIRT5 gene knockout mouse model of cecal ligation and puncture (CLP)-induced SAKI and a human kidney (HK)-2 cell model of LPS-induced SAKI were constructed. An AMPK chemical activator and SIRT5 overexpression plasmid were employed. Indexes of mitochondrial structure and function, level of p-AMPK, and expression of SIRT5 protein in renal tissue and RTECs were measured.

Results

After sepsis stimulation, the p-AMPK level was decreased, mitochondrial structure was disrupted, and ATP content was decreased. Notably, an AMPK activator alleviated SAKI. SIRT5 gene knockout significantly aggravated SAKI, while SIRT5 overexpression alleviated mitochondrial dysfunction following LPS stimulation, as manifested by the increase of p-AMPK level, the alleviation of mitochondrial structure damage, the restoration of ATP content, the decrease of pro-apoptotic protein expression, as well as the reduction of reactive oxygen species generation.

Conclusion

Up-regulation of SIRT5 expression can attenuate mitochondrial dysfunction in RTECs and alleviate SAKI by enhancing the phosphorylation of AMPK.
Diagnostic yield of broad-range 16s rRNA gene PCR varies by sample type and is improved by the addition of qPCR panels targeting the most common causative organisms
Authors: Harris Kathryn A. , Brown Julianne R.
Published: December 2022

Introduction. Molecular techniques are used in the clinical microbiology laboratory to support culture-based diagnosis of infection and are particularly useful for detecting difficult to culture bacteria or following empirical antimicrobial treatment.

Hypothesis/Gap Statement. Broad-range 16S rRNA PCR is a valuable tool that detects a wide range of bacterial species. Diagnostic yield is low for some sample types but can be improved with the addition of qPCR panels targeting common bacterial pathogens.

Aim. To evaluate the performance of a broad-range 16S rRNA gene PCR and the additional diagnostic yield of targeted qPCR applied to specimens according to a local testing algorithm.

Methodology. In total, 6130 primary clinical samples were collected as part of standard clinical practice from patients with suspected infection during a 17 month period. Overall, 5497 samples were tested by broad-range 16S rRNA gene PCR and a panel of targeted real-time qPCR assays were performed on selected samples according to a local testing algorithm. An additional 633 samples were tested by real-time qPCR only. The 16S rRNA gene PCR was performed using two assays targeting different regions of the 16S rRNA gene. Laboratory developed qPCR assays for seven common bacterial pathogens were also performed. Data was extracted retrospectively from Epic Beaker Laboratory Information Management System (LIMS).

Results. Broad-range 16S rRNA gene PCR improves diagnostic yield in culture-negative samples and detects a large range of bacterial species.

Streptococcus

spp.,

Staphylococcu

s spp. and the Enterobacteriaceae family are detected the most frequently in samples with a single causative organism, but mixed samples frequently contained anaerobic species. The highest diagnostic yield was obtained from abscess, pus and empyema samples; 44.9 % were positive by 16S and 61 % were positive by the combined 16S and targeted qPCR testing algorithm. Samples with a particularly low diagnostic yield were blood, with 3.3 % of samples positive by 16S and CSF with 4.8 % of samples positive by 16S. The increased diagnostic yield of adding targeted qPCR is largest (~threefold) in these two sample types.

Conclusion. Broad-range PCR is a powerful technique that can detect a very large range of bacterial pathogens but has limited diagnostic sensitivity. The data in this report supports a testing strategy that combines broad-range and targeted bacterial PCR assays for maximizing diagnosis of infection in culture-negative specimens. This is particularly justified for blood and CSF samples. Alternative approaches, such as metagenomic sequencing, are needed to provide the breadth of broad-range PCR and the sensitivity of targeted qPCR panels.
Small multidrug resistance protein EmrE phenotypically associates with OmpW, DcrB and YggM for osmotic stress protection by betaine in Escherichia coli
Authors: Pushpker Rajnigandha , Bay Denice C. , Turner Raymond J.
Published: December 2022

The small multidrug resistance (SMR) protein EmrE resides in the inner membrane and provides resistance against a wide range of antiseptic quaternary cationic compounds (QCCs) for the Gram-negative bacterium

Escherichia coli

. We have reported previously that overexpression of the emrE gene results in the reduction of pH and osmotic tolerance, likely through EmrE-mediated biological QCC-based osmoprotectant efflux, indicating a potential physiological role for EmrE beyond providing drug resistance. EmrE is the most studied member of SMR transporter family; however, it is not known how the substrates translocated by EmrE move across the periplasm and through the outer membrane (OM). We have shown that the OM protein OmpW participates in the EmrE-mediated substrate efflux process and provided a hypothesis for the present study that additional OM and periplasmic proteins participate in the translocation process. To test the hypothesis, we conducted alkaline pH-based growth phenotype screens under emrE overexpression conditions. This screen identified 10 additional genes that appear to contribute to the EmrE-coupled osmoprotectant efflux: gspD, hofQ, yccZ, acrA, emrA, emrB, proX, osmF, dcrB and yggM. Further screening of these genes using a hyperosmotic growth phenotype assay in the presence and the absence of the osmoprotectant glycine betaine identified ompW and two periplasmic protein genes, dcrB and yggM, are mechanistically linked to EmrE.
Extending Finlay-Wilkinson regression with environmental covariates
Authors: Piepho Hans-Peter
Published: December 2022

Finlay-Wilkinson regression is one of the most popular methods for analysing genotype-environment interaction in series of plant breeding and variety trials. The method involves a regression on the environmental mean, computed as the average of all genotype means. The environmental mean is an index for the productivity of an environment. Productivity is driven by a wide array of environmental factors. Increasingly, it is becoming feasible to characterize environments explicitly using quantitative measurements of these factors. Hence, there is mounting interest to replace the environmental index with an explicit regression on such observable environmental covariates. This paper reviews the development of such methods. The focus is on parsimonious models that allow replacing the environmental index by regression on synthetic environmental covariates formed as linear combinations of a larger number of observable environmental covariates. Two new methods are proposed for obtaining such synthetic covariates, which may be integrated into genotype-specific regression models. The main advantage of such explicit modelling is that predictions can be made also for new environments where trials have not been conducted. A published dataset is employed to illustrate the proposed methods.
Impact of Sars-Cov-2 on access to healthcare by person with disabilities
Authors: Nkosi Nkosi Botha , Fortune Selase Atsu , Edward Wilson Ansah , Cynthia Esinam Segbedzi , Sarah Annim
Published: December 2022

Background

The Sars-Cov-2 pandemic has ravaged societies at their very core and deepened pre-existing inequalities. Meanwhile, persons with disabilities (PwDs), the most oppressed group in Ghana that live in poor and deplorable conditions are most like to be negatively impacted by the Sars-Cov-2 crisis. Therefore, the aim of this study is to explore how the Sars-Cov-2 pandemic is influencing access to healthcare by PwDs in the Sekondi-Takoradi Metropolis (STM).

Methods

We collected data from 17 participants, nine from the Ghana Blind Union (GBU), five from Ghana Society for the Physically Challenged (GSPC), and three from the Ghana National Association of the Deaf (GNAD). An interview guide containing 25 items was used to gather data from the participants and we employed Phenomenological Analysis (PA) approach in making sense of the data.

Result

PWDs encounter many different barriers like; i) stigma and discrimination, ii) cost and availability of transport, iii) poor attitude of healthcare staff, iv) poor communication, v) hospital environment and equipment, vi) handwashing and sanitizing facilities, vii) unsuitable washrooms, viii) cost of healthcare, ix) registration and renewal of NHIS cards, and x) loss of income as they attempt to seek healthcare during this Covid-19 era in the STM.

Conclusion

Covid-19 pandemic has widened the disproportionate and inequality gaps against PWDs in the STM when they attempt to seek healthcare. in the face of this, STM may lead Ghana to lag in achieving the Sustainable Development Goal (SDG) 3.8, which entreats nations to provide quality healthcare for all persons including PWDs. PWDs need education and empowerment to enable them demand for their rights when accessing healthcare. The findings highlight existing gaps in the implementation of the disability law by healthcare facilities in STM and, re-focus the attention of hospital managers in STM to the healthcare needs of PWDs in STM.
New insights into the role ofCutibacterium acnes-derived extracellular vesicles in inflammatory skin disorders
Authors: Cros Maria Pol , Mir-Pedrol Júlia , Toloza Lorena , Knödlseder Nastassia , Güell Marc , Maruotti Julien , Zouboulis Christos C. , Fernández Maria-José Fábrega
Published: December 2022

Background

Cutibacterium acnes(C. acnes) is one of the most prevalent bacteria that form the human skin microbiota and, depending on multifactorial conditions it can help to maintain the skin homeostasis. Actually, different phylotypes ofC. acneshave been associated with different degrees of acne vulgaris development, while others, such as the H1 subtype, have been detected in patients with non-acneic skin. However, due to the physiology of the skin, the skin microbiota neither has direct access to the skin’s sebaceous glands nor to the main immune cells, as they are protected by a sebum layer. Therefore, the inter-kingdom communication relies on secreted factors and bacterial extracellular vesicles (EVs). In this context, the purpose of this project was to study the role of EVs secreted by three different phylotypes ofC. acnes(A1 as pathogenic, H1 as beneficial and H2 as commensal).

Results

Main findings showed that the proteomic profile of the cargo embodied in the EVs reflects unique characteristics of the differentC. acnesphylotypes in terms of lifestyle, survival and virulence. Moreover,in vitroskin models showed an extended pro-inflammatory modulation of A1 EVs, while H1 EVs displayed a high sebum-reducing potential.

Conclusions

This study has highlighted the role ofC. acnesEVs as key modulators during skin alterations, specially H1 EVs as an alternative based-natural treatment to fight acne vulgaris symptomatology.
Logging alters tropical forest structure, while conversion to agriculture reduces biodiversity and functioning
Authors: Marsh Charles J. , Turner Edgar C. , Blonder Benjamin Wong , Bongalov Boris , Both Sabine , Cruz Rudi S. , Elias Dafydd M. O. , Hemprich-Bennett David , Jotan Palasiah , Kemp Victoria , Kritzler Ully H. , Milne Sol , Milodowski David T. , Mitchell Simon L. , Pillco Milenka Montoya , Nunes Matheus Henrique , Riutta Terhi , Robinson Samuel J. B. , Slade Eleanor M. , Bernard Henry , Burslem David F. R. P. , Chung Arthur Y. C. , Clare Elizabeth L. , Coomes David A. , Davies Zoe G. , Edwards David P. , Johnson David , Kratina Pavel , Malhi Yadvinder , Majalap Noreen , Nilus Reuben , Ostle Nicholas J. , Rossiter Stephen J. , Struebig Matthew J. , Tobias Joseph A. , Williams Mathew , Ewers Robert M. , Lewis Owen T. , Reynolds Glen , Teh Yit Arn , Hector Andy
Published: December 2022

The impacts of degradation and deforestation on tropical forests are poorly understood, particularly at landscape scales. We present an extensive ecosystem analysis of the impacts of logging and conversion of tropical forest to oil palm from a large-scale study in Borneo, synthesizing responses from 82 variables categorized into four ecological levels spanning a broad suite of ecosystem properties: 1) structure and environment, 2) species traits, 3) biodiversity, and 4) ecosystem functions. Responses were highly heterogeneous and often complex and non-linear. Variables that were directly impacted by the physical process of timber extraction, such as soil structure, were sensitive to even moderate amounts of logging, whereas measures of biodiversity and ecosystem functioning were generally resilient to logging but more affected by conversion to oil palm plantation.

One-Sentence Summary

Logging tropical forest mostly impacts structure while biodiversity and functions are more vulnerable to habitat conversion.
Activation of the P2RX7/IL-18 pathway in immune cells attenuates lung fibrosis
Authors: Janho dit Hreich Serena , Juhel Thierry , Leroy Sylvie , Ghinet Alina , Brau Frederic , Hofman Véronique , Hofman Paul , Vouret-Craviari Valérie
Published: December 2022

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. We show here that theP2RX7/IL-18/IFNGaxis is downregulated in IPF patients and that P2RX7 has immunoregulatory functions. Using our positive modulator of P2RX7, we show that activation of the P2RX7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an anti-fibrotic immune environment, with notably an enhanced IL-18-dependent IFN-γ production by lung T cells leading to a decreased production of IL-17 and TGFβ. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. Hence, treatment with a small activator of P2RX7 may represent a promising strategy to help patients with lung fibrosis.
Functional mRNA delivery to hematopoietic stem and progenitor cellsin vivo
Authors: Alvarez David , Masse-Ranson Guillemette , Sedimbi Saikiran K. , Wisti Phylicia , Rodriguez Lisa , Santana Jordan , Manning Taylor , Towner Tim , Geilich Ben , Mihai Cosmin , Mishra Ankita , Gurumurthy Sushma , Frederick Josh , von Andrian Ulrich H. , Hoggatt Jonathan , Moore Melissa J. , Mora J. Rodrigo
Published: December 2022

Gene correction of hematopoietic stem cells (HSC) is a promising therapeutic approach for multiple disorders. Current methods, however, require HSC collection from patients, gene correction duringex vivoculture, and re-infusion of corrected HSC into patients conditioned with chemotherapeutic agents. These approaches are complex, and the conditioning creates toxicities. We show that a lipid nanoparticle (LNP) can deliver mRNA encoding a reporter or a gene editing protein to HSC, with one injection transfecting ∼25% of mouse HSC, and repeated doses resulting in higher editing efficiencies. We also demonstrate LNP-drivenin vivomRNA delivery to HSC in non-human primates and humanized mice. These results demonstrate a translatable approach to deliver mRNA encoding therapeutic proteins, or gene correcting tools, to HSC that do not require cell culture or toxic conditioning.

One-Sentence Summary

LNP can deliver functional mRNA to mouse, non-human primate, and human HSC.
The effect of COVID-19 lockdowns on fertility in the Democratic Republic of the Congo
Authors: Feng Shuo , Kyomba Gabriel , Mayaka Serge Manitu , Grépin Karen Ann
Published: December 2022

Most countries implemented public health measures, including lockdowns, during the COVID-19 pandemic. It has been speculated that the pandemic will affect fertility, but the direction, magnitude, and mechanisms of these effects are not well understood. Using data from the national health management information system and an augmented synthetic control methodology, we examined the impact of a lockdown of Kinshasa in April 2020 on the subsequent fertility of women, which we proxy by the number of births in health facilities months after the policy was implemented. Seven months after the lockdown, we see a large increase in births in Kinshasa, as compared to control areas, which at its peak represents an additional 5000 monthly births, or a 45% increase relative to baseline. We also observe increases in complimentary maternal health services but not in other health services. Increased births were observed among women both older and younger than 20. Lockdown policies have likely affected fertility and future pandemic preparedness plans should anticipate the effects find strategies to mitigate any negative unintended effects.
Pre-Diagnostic Circulating RNAs Networks Identify Testicular Germ Cell Tumour Susceptibility Genes
Authors: Burton Joshua , Rounge Trine B. , Haugen Trine B. , Wojewodzic Marcin W.
Published: December 2022

Testicular germ cell tumour (TGCT) is a malignancy with known inherited risk factors, affecting young men. We have previously identified several hundred circulating RNAs that were differentially expressed in pre-diagnostic serum samples from TGCT cases when compared to healthy controls. In this study we performed network preservation analyses of pre-diagnostic serum mRNA and miRNA. Hub genes, enriched functional pathways, and regulatory feature prediction were identified for all TGCT, seminoma, and non-seminoma cases separately, compared to controls. We identifiedUBCA1, RCC1, FMR1, OSA3,andUBE2Was hub genes associated with TGCT. The genesOSA3andUBE2Whave previously been associated with testicular dysgenesis syndrome (TDS) disorders. Previously described TGCT susceptibility genesTEX14,NARS2,andG3BP2were identified as hub genes in both seminoma and non-seminoma networks. Furthermore, network module analysis showed prediction of transcription factors for oestrogen-related receptors. The overlap between network hub genes and TGCT susceptibility genes indicates a role in the progression from germ cell neoplasia in situ (GCNIS) to TGCT that should be further investigated.
Immunogenicity and reactogenicity of mRNA COVID-19 vaccine booster administered by intradermal or intramuscular route in Thai Older adults
Authors: Assantachai Prasert , Niyomnaitham Suvimol , Chatthanawaree Wichai , Intalapaporn Somboon , Muangpaisan Weerasak , Phannarus Harisd , Saichompoo Rangsimatiti Binda , Sura-amonrattana Unchana , Wongprompitak Patimaporn , Toh Zheng Quan , Licciardi Paul V , Srisutthisamphan Kanjana , Chokephaibulkit Kulkanya
Published: December 2022

Introduction

Intradermal (ID) vaccination may alleviate COVID-19 vaccine shortages and vaccine hesitancy due to systemic reactogenicity among older adults.

Objectives

To compare the immunogenicity and reactogenicity of fractional ID and standard intramuscular (IM) booster vaccination of mRNA-1273 and BNT162b2 vaccines in older adults.

Methods

Participants aged ≥65 years who previously vaccinated with 2-dose ChAdOx1 were randomized to receive one of the four booster vaccinations: 0.1mL ID mRNA-1273, 0.5mL IM mRNA-1273, 0.1mL ID BNT162b2 and 0.3mL IM BNT162b2. Immunogenicity as measured by anti-receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NAb) against Wuhan and Omicron BA.1, BA.2 and BA.4/5, and IFNγ-producing cells. Local and systemic adverse effects (AEs) were self-reported via an electronic diary card.

Results

Of the 210 participants enrolled, 70.5% were female and median age was 77.5 years (interquartile range (IQR): 71.0-84.0). Following the booster dose, both ID vaccination induced 37% lower levels of anti-RBD IgG than IM vaccination of the same vaccine. NAb against ancestral and Omicron BA.1 strains was highest following IM mRNA-1273 (1,718 and 617), followed by ID mRNA-1273 (1,212 and 318), IM BNT162b2 (713 and 230), and ID BNT162b2 (587 and 148), respectively. Spike-specific IFNγ responses were similar or higher in the ID groups when compared with their respective IM groups. Vaccine delivery through ID route tended to have lower systemic AEs, although more local AEs reported in ID mRNA-1273 group.

Conclusions

Fractional ID vaccination induced immunogenicity and reactogenicity comparable to IM and may be an alternative option for older people.

Key points

Fractional dose intradermal mRNA COVID-19 booster vaccination induces robust immunogenicity in adults aged ≥65 years.

For each vaccine, intradermal route induced lower humoral but similar or higher cellular immune responses than IM route.

Intradermal mRNA-1273 vaccination induced similar immunogenicity to intramuscular BNT162b2 vaccination.

Immune responses were marginally lower among participants aged ≥80 years than among participants aged 65-79 years.

Systemic reaction was lower following intradermal mRNA COVID-19 vaccination compared with intramuscular vaccination.
Identification of novel PGRP3 protein -protein interactions using yeast two hybrid system
Authors: Lin Li-jung , Lee Clarence , Ranganathan Srivathsan , Kreth Jens , Merritt Justin , Prakasam Sivaraman
Published: December 2022

Background

Peptidoglycan recognition protein-3 (PGRP3) is a pattern recognition receptor that binds peptidoglycan to elicit an immune response. How PGRP3 mediates these immunomodulatory effects remains unknown. Identifying the proteins that interact with PGRP3 will help begin to address this important knowledge gap. Therefore, in this study our objective was to identify and validate novel PGRP3-protein interactions.

Methods

PGRP3-protein interactions were identified using a yeast two-hybrid system. PGRP3 cloned into a pGBKT7 DNA-BD vector and transformed into a Y2HGold yeast strain served as the bait. A normalized universal human cDNA library cloned in a pGADT7 AD vector and pre-transformed into an Y187 yeast strain served as the prey. Y2HGold and Y187 yeast strains were mated and diploids were plated on selective media. True positive clones were sent in for DNA sequencing and corresponding proteins were identified through NCBI Blast. Two proteins were selected for validation. His-tagged PGRP3 expressing 293T cells were then co-transfected with expression vectors containing the identified proteins tagged with c-Myc. Lysates from co-transfected cells were subjected to anti-His and anti-Myc co-immunoprecipitation and analyzed with western blots.

Results

Four unique proteins— MBNL3, RBP5, ATXN2, and GPATCH8—were identified from our yeast two-hybrid screen. Co-transfection and co-immunoprecipitation assays successfully confirmed MBNL3 and RBP5 as positive interactors with PGRP3.

Conclusions

Based on the known functions of MBNL3, RBP5, ATXN2, and GPATCH8, we hypothesize that PGRP3 may be involved in RNA processing, endocytic trafficking, and PPARγ pathways related to innate immunity.
High-Throughput Discovery and Characterization of Viral Transcriptional Effectors in Human Cells
Authors: Ludwig Connor H. , Thurm Abby R. , Morgens David W. , Yang Kevin J. , Tycko Josh , Bassik Michael C. , Glaunsinger Britt A. , Bintu Lacramioara
Published: December 2022

Viruses encode transcriptional regulatory proteins critical for controlling viral and host gene expression. Given their multifunctional nature and high sequence divergence, it is unclear which viral proteins can affect transcription and which specific sequences contribute to this function. Using a high-throughput assay, we measured the transcriptional regulatory potential of over 60,000 protein tiles across ∼1,500 proteins from 11 coronaviruses and all nine human herpesviruses. We discovered hundreds of new transcriptional effector domains, including a conserved repression domain in all coronavirus Spike homologs, dual activation-repression domains in VIRFs, and an activation domain in six herpesvirus homologs of the single-stranded DNA-binding protein that we show is important for viral replication and late gene expression in KSHV. For the effector domains we identified, we investigated their mechanisms via high-throughput sequence and chemical perturbations, pinpointing sequence motifs essential for function. This work massively expands viral protein annotations, serving as a springboard for studying their biological and health implications and providing new candidates for compact gene regulation tools.
Resting-state functional connectivity in children cooled for neonatal encephalopathy
Authors: Spencer Arthur P C , Goodfellow Marc , Chakkarapani Ela , Brooks Jonathan C W
Published: December 2022

Therapeutic hypothermia improves outcomes following neonatal hypoxic-ischaemic encephalopathy (HIE), reducing cases of death and severe disability such as cerebral palsy compared to normothermia management. However, when cooled children reach early school-age they have cognitive and motor impairments which are associated with underlying alterations to brain structure and white matter connectivity. It is unknown whether these differences in structural connectivity are associated with differences in functional connectivity between cooled children and healthy controls. Resting-state fMRI has been used to characterise static and dynamic functional connectivity in children, both with typical development and those with neurodevelopmental disorders. Previous studies of resting-state brain networks in children with HIE have focussed on the neonatal period. In this study, we used resting-state fMRI to investigate static and dynamic functional connectivity in children aged 6-8 years who were cooled for neonatal HIE without cerebral palsy (n = 22, median age [IQR] 7.08 [6.85-7.52] years), and healthy controls matched for age, sex and socioeconomic status (n = 20, median age [IQR] 6.75 [6.48-7.25] years). Using group independent component analysis, we identified 31 intrinsic functional connectivity networks consistent with those previously reported in children and adults. We found no case-control differences in the spatial maps of these intrinsic connectivity networks. We constructed subject-specific static functional connectivity networks by measuring pairwise Pearson correlations between component time courses, and found no case-control differences in functional connectivity after FDR correction. To study the time-varying organisation of resting-state networks, we used sliding-window correlations and deep clustering to investigate dynamic functional connectivity characteristics. We found k = 4 repetitively occurring functional connectivity states, which exhibited no case-control differences in dwell time, fractional occupancy, or state functional connectivity matrices. In this small cohort, the spatiotemporal characteristics of resting-state brain networks in cooled children without severe disability were too subtle to be differentiated from healthy controls at early school-age, despite underlying differences in brain structure and white matter connectivity, possibly reflecting a level of recovery of healthy resting-state brain function. To our knowledge, this is the first study to investigate resting-state functional connectivity in children with HIE beyond the neonatal period, and the first to investigate dynamic functional connectivity in any children with HIE.
A realist interview study of a participatory public mental health project “#KindnessByPost”
Authors: Scott Hannah Rachel , Warran Katey , Fraser Kathleen , Chipp Beverley , McGinnes Gail , Towers Mike , Lloyd-Evans Brynmor , Rains Luke Sheridan
Published: December 2022

Background

#KindnessByPost (KbP) is a participatory public health initiative in which people anonymously send and receive cards containing messages of goodwill with others also taking part in the programme. Quantitative evaluations of KbP consistently find evidence of improvements to people’s mental wellbeing and feelings of loneliness after participation and three months later. Our aim in the present study is to develop a programme theory of KbP, which describes for whom the KbP intervention improves mental wellbeing, other reported impacts, in which contexts it has these effects, and the mechanisms by which it works

Methods

We use a realist interviewing methodology to develop the programme theory. We conducted a focus group with the KbP executive team, and 20 one-to-one interviews with KbP participants. During analysis, a co-production working group iteratively developed a Theory of Change model comprising context-mechanism-outcome statements [CMOs] to map out the mechanisms present in KbP.

Results

We developed 145 CMO statements, which we condensed and categorized into 32 overarching CMOs across nine thematic topics: access to scheme; pathways to involvement; resources; culture; giving post; receiving post; content of received post; community; long term impact. These CMOs set out pathways through which KbP benefited participants, including from doing something kind for someone else, of receiving post and appreciating the effort that went into it, and from the creative process of creating post and writing the messages inside them. Effects were sustained in part through people keeping the cards and through the social media communities that emerged around KbP.

Discussion

Both giving and receiving post and the sense of community benefited participants and improved their mood and feelings of connectedness with others. Connection with a stranger, rather than friends and family, was also an important feature of the initiative for participants. Our wide range of CMO pathways by which KbP produced positive outcomes may mean that the intervention is applicable or adaptable across many communities and settings. Taken together with evidence from the quantitative evaluations, KbP is potentially an effective, low-cost, and highly scalable public health intervention for reducing loneliness and improving wellbeing.
Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology
Authors: Chauhan Nishant Ranjan , Kundu Soumya , Bal Ramyasingh , Chattopadhyay Diya , Mehto Subhash , Sahu Rinku , Yadav Rina , Krishna Sivaram , Jena Kautilya Kumar , Satapathy Sameekshya , Murmu Krushna C , Singh Bharati , Das Saroj Kumar , Jena Sarita , Harshan Krishnan H , Syed Gulam Hussain , Prasad Punit , Chauhan Santosh
Published: December 2022

Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2;Irgm1−/−) and the other with dampened IFN-I response (hACE2;Ifnar1−/−) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2;Irgm1−/−mice were resistant to lethal SARS-CoV-2 infection with substantially reduced cytokine storm and immunopathology. In striking contrast, a severe SARS-CoV-2 infection along with immune cells infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2;Ifnar1−/−mice. Additionally, hACE2;Ifnar1−/−mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2;Irgm1−/−Ifnar1−/−double knockout mice or hACE2;Irgm1−/−mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2;Irgm1−/−mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, andIrgm1(IRGM) could be an excellent therapeutic target.

GRAPHICAL ABSTRACT
A monkeypox mRNA-lipid nanoparticle vaccine targeting virus binding, entry, and transmission drives protection against lethal orthopoxviral challenge
Authors: Freyn Alec W. , Atyeo Caroline , Earl Patricia L. , Americo Jeffrey L. , Chuang Gwo-Yu , Natarajan Harini , Frey Tiffany , Gall Jason , Moliva Juan I , Hunegnaw Ruth , Arunkumar Guha Asthagiri , Ogega Clinton , Nasir Arshan , Bennett Hamilton , Johnson Joshua , Durney Michael A. , Stewart-Jones Guillaume , Hooper Jay W , Colpitts Tonya , Alter Galit , Sullivan Nancy J. , Carfi Andrea , Moss Bernard
Published: December 2022

Monkeypox virus (MPXV) caused a global outbreak in 2022, fueled by behaviorally-altered and enhanced human-to-human transmission. While smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the imminent threat of additional zoonotic events as well as the virus’ evolving ability to drive human-to-human transmission, there is an urgent need for the development of a MPXV-specific vaccine that is able to also confer broad protection against evolving strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared to Modified Vaccinia Virus Ankara (MVA), which forms the basis for the current MPXV vaccine, mRNA-vaccination generated superior neutralizing and cellular spread-inhibitory activities against MPXV and VACV as well as greater Fc-effector Th1-biased humoral immunity to the four MPXV antigens and the four VACV homologs. Single MPXV antigen mRNA vaccines provided partial protection against VACV challenge, while combinations of two, three or four MPXV antigen expressing mRNAs protected against disease-related weight loss and death. Remarkably, the cross-protection by multivalent MPXV mRNAs was superior to the homologous protection by MVA, associated with a combination of neutralizing and non-neutralizing antibody functions. These data reveal robust protection against VACV using an mRNA-based vaccine targeting four highly conserved viral surface antigens, linked to the induction of highly functional antibodies able to rapidly control viral infection.
STING-dependent cytosolic DNA sensing pathway drives the progression to leukemia in TET2-mutated HSPCs
Authors: Xie Jiaying , Sheng Mengyao , Rong Shaoqin , Wang Chao , Wu Wanling , Huang Jingru , Sun Yue , Chen Pingyue , Wu Yushuang , Wang Yuanxian , Wang Lan , Zhou Bo O. , Huang Xinxin , Walsh Colum P. , Bohlander Stefan K. , Huang Jian , Wang Xiaoqin , Gao Hai , Zhou Dan , Shi Yuheng , Xu Guo-Liang
Published: December 2022

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain largely unknown. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in leukemogenesis in mouse models. DNA damage arising inTet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn induces the development of CH and myeloid transformation. Notably, both pharmacological inhibition and genetic deletion of STING suppressesTet2mutation-induced aberrant myelopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the hematopoietic transformation associated with TET2 mutations is powered through sterile inflammation dependent on the activated cGAS-STING pathway, and that STING may represent a potential target for intervention of relevant hematopoietic malignancies.

Key points

Tet2deficiency leads to DNA damage which in turn activates the cGAS-STING pathway to induce an inflammatory response

Blocking STING in TET2-mutated hematopoietic stem/progenitor cells suppresses clonal hematopoiesis in mice and leukemogenesis in patient-derived xenograft models
Changes in cancer prevention and management and patient needs during the COVID-19 pandemic: An umbrella review of systematic reviews
Authors: Muka Taulant , Li Joshua J X , Farahani Sahar J. , Ioannidis John P.A.
Published: December 2022

Introduction

The COVID-19 pandemic led to relocation and reconstruction of health care resources and systems, and to a decrease in healthcare utilization, and this may have affected the treatment, diagnosis, prognosis, and psychosocial well-being of cancer patients.

Objective

To summarize and quantify the evidence on the impact of the COVID-19 pandemic on the full spectrum of cancer care.

Methods

We performed an umbrella review to summarize and quantify the findings from systematic reviews on impact of the COVID-19 pandemic on cancer treatment modification, delays, and cancellations; delays or cancellations in screening and diagnosis; psychosocial well-being, financial distress, and use of telemedicine as well as on other aspects of cancer care. PubMed was searched for relevant systematic reviews with or without meta-analysis published before November 29th, 2022. Abstract, full text screening and data extraction were performed by two independent reviewers. AMSTAR-2 was used for critical appraisal of included systematic reviews.

Results

45 systematic reviews evaluating different aspects of cancer care were included in our analysis. Most reviews were based on observational studies judged to be at medium and high risk of bias. Only 2 of the included reviews had high or moderate scores based on AMSTAR-2. Findings suggest treatment modifications in cancer care during the pandemic versus the pre-pandemic period were based on low level of evidence. Different degrees of delays and cancellations in cancer treatment, screening and diagnosis were observed, with low-and-middle income countries and countries that implemented lockdowns being disproportionally affected. A shift from in-person appointments to telemedicine use was observed, but utility of telemedicine, challenges in implementation and cost-effectiveness in different areas of cancer care were little explored. Evidence was consistent in suggesting psychosocial well-being (e.g., depression, anxiety, and social activities) of cancer patients deteriorated, and cancer patients experienced financial distress, albeit results were in general not compared to pre-pandemic levels. Impact of cancer care disruption during the pandemic on cancer prognosis was little explored.

Conclusion

Substantial but heterogenous impact of COVID-19 pandemic on cancer care has been observed. Evidence gaps exist on this topic, with mid- and long-term impact on cancer care being most uncertain.
Evidence for a functional interaction between the respiratory syncytial virus fusion and attachment proteins in the envelope of infectious virus particles
Authors: Huong Tra Nguyen , Tan Boon Huan , Sugrue Richard J.
Published: December 2022

We have examined the interaction between the respiratory syncytial virus (RSV) F and G proteins on the surface of infected cells during multiple cycle infection using a low multiplicity of infection (MOI) model, and on the surface of virus particles that were isolated from infected cells. A combination of the proximity ligation assay (PLA) and confocal microscopy was used to demonstrate the interaction between the F and G proteins within the virus filaments on infected cells. Co-precipitation of the F and G proteins was confirmed using detergent extracts prepared from infected cells and in detergent extracts prepared from purified virus particles. The influence of the G protein in mediating virus spread in the low MOI model was further examined using the recombinant virus isolates rg224RSV (that expresses all virus proteins) and rg224RSV-ΔG (which does not express the G protein). While cells could be initially infected by both viruses, the rg224RSV-ΔG virus exhibited severely impaired localised virus transmission in the multiple cycle infection assay. Collectively these data provide evidence that the F and G proteins interact within the envelope of RSV particles, and suggests that this interaction may promote virus transmission. The interaction between these proteins in a single protein complex represents a potential new target for the development of antivirus strategies and in the development of RSV vaccine candidates.