Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer.

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 µM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2'-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.

Probing the Electrostatic Effects of H-Ras Tyrosine 32 Mutations on Intrinsic GTP Hydrolysis Using Vibrational Stark Effect Spectroscopy of a Thiocyanate Probe.

The wildtype H-Ras protein functions as a molecular switch in a variety of cell signaling pathways, and mutations to key residues result in a constitutively active oncoprotein. However, there is some debate regarding the mechanism of the intrinsic GTPase activity of H-Ras. It has been hypothesized that ordered water molecules are coordinated at the active site by Q61, a highly transforming amino acid site, and Y32, a position that has not previously been investigated. Here, we examine the electrostatic contribution of the Y32 position to GTP hydrolysis by comparing the rate of GTP hydrolysis of Y32X mutants to the vibrational energy shift of each mutation measured by a nearby thiocyanate vibrational probe to estimate changes in the electrostatic environment caused by changes at the Y32 position. We further compared vibrational energy shifts for each mutation to the hydration potential of the respective side chain and demonstrated that Y32 is less critical for recruiting water molecules into the active site to promote hydrolysis than Q61. Our results show a clear interplay between a steric contribution from Y32 and an electrostatic contribution from Q61 that are both critical for intrinsic GTP hydrolysis.

Multidimensional Widefield Infrared-Encoded Spontaneous Emission Microscopy: Distinguishing Chromophores by Ultrashort Infrared Pulses.

Photoluminescence (PL) imaging has broad applications in visualizing biological activities, detecting chemical species, and characterizing materials. However, the chemical information encoded in the PL images is often limited by the overlapping emission spectra of chromophores. Here, we report a PL microscopy based on the nonlinear interactions between mid-infrared and visible excitations on matters, which we termed MultiDimensional Widefield Infrared-encoded Spontaneous Emission (MD-WISE) microscopy. MD-WISE microscopy can distinguish chromophores that possess nearly identical emission spectra via conditions in a multidimensional space formed by three independent variables: the temporal delay between the infrared and the visible pulses (t), the wavelength of visible pulses (λvis), and the frequencies of the infrared pulses (ωIR). This method is enabled by two mechanisms: (1) modulating the optical absorption cross sections of molecular dyes by exciting specific vibrational functional groups and (2) reducing the PL quantum yield of semiconductor nanocrystals, which was achieved through strong field ionization of excitons. Importantly, MD-WISE microscopy operates under widefield imaging conditions with a field of view of tens of microns, other than the confocal configuration adopted by most nonlinear optical microscopies, which require focusing the optical beams tightly. By demonstrating the capacity of registering multidimensional information into PL images, MD-WISE microscopy has the potential of expanding the number of species and processes that can be simultaneously tracked in high-speed widefield imaging applications.

Giant optical second- and third-order nonlinearities at a telecom wavelength.

A material platform that excels in both optical second- and third-order nonlinearities at a telecom wavelength is theoretically and experimentally demonstrated. In this TiN-based coupled metallic quantum well structure, electronic subbands are engineered to support doubly resonant inter-subband transitions for an exceptionally high second-order nonlinearity and provide single-photon transitions for a remarkable third-order nonlinearity within the 1400-1600 nm bandwidth. The second-order susceptibility χ(2) reaches 2840 pm/V at 1440 nm, while the Kerr coefficient n2 arrives at 2.8 × 10-10 cm2/W at 1460 nm. The achievement of simultaneous strong second- and third-order nonlinearities in one material at a telecom wavelength creates opportunities for multi-functional advanced applications in the field of nonlinear optics.

Gym lifestyle factors and male reproductive health: a study into young adult usage and perceptions.

RESEARCH QUESTION: What level of awareness do young adults have regarding the potential impacts of gym lifestyle factors and supplementation on male infertility? DESIGN: Between February and March 2023 a questionnaire (n = 153) was employed to gauge attitudes to and awareness of the effects of male reproductive health and gym lifestyles on male fertility. Two semi-structured focus groups (n = 10 total), stratified by sex assigned at birth, were conducted using a set of discussion topics. RESULTS: The survey revealed a statistically significant difference between male and female awareness of the potential impacts of some forms of high-intensity exercise and protein supplementation on male reproductive health (P = 0.045). Many men do not think about fertility unprompted; the survey revealed that fewer men have thought about their fertility compared with those who are curious about their fertility (P = 4.7 â€¯×  10-5) and those who believe their personal fertility is important to them (P = 8.1 â€¯×  10-6). Men were more likely to make a change in their behaviour if it had a long-term compared with a short-term effect on their fertility (P < 10-5). Five focus group themes surrounding awareness of male reproductive health were extracted. CONCLUSIONS: This work has shown that there is a significant lack of awareness and information surrounding the effects of gym lifestyles on male infertility in a young adult UK population. Crucially, levels of awareness differ significantly between men and women. Men have a potentially alarming lack of concern over their own fertility and how factors such as gym supplements can have negative long-term impacts.

Good practice in clinical embryology laboratories: Association of Reproductive and Clinical Scientists Guidelines 2024.

Clinical embryology is a dynamic and ever-evolving field, and as such clinical practice guidelines must be regularly reviewed and updated. Accordingly, this document supersedes previous good clinical practice in clinical embryology guidance, developing, and updating where necessary, existing good practice guidelines. The Association of Reproductive and Clinical Scientists (ARCS) suggests this Good Laboratory Practice framework as appropriate and effective to ensure the best possible care for all individuals undertaking fertility treatment. Efforts have been made to ensure that the language used is inclusive and reflective of the wide range of patients who seek treatment. The guidance provided within this document aims to be relevant within an international context and to consider the range of regulatory considerations affecting clinical embryology laboratories. This guideline was written to guide best practice but is not intended as a tool to judge the practice of centres within the UK or beyond.

Good practice in laboratory diagnostic andrology: Association of Reproductive and Clinical Scientists guidelines 2024.

These guidelines update and clarify items relating to diagnostic andrology in the 2012 Association of Biomedical Andrologists Laboratory Andrology Guidelines for Good Practice Version 3. The main change separates diagnostic and therapeutic andrology into individual documents; post-vasectomy semen analysis still references the 2016 guideline. These guidelines seek to incorporate and clarify internationally agreed methodology following the World Health Organization Laboratory Manual for the Examination and Processing of Human Semen 6th edition and publication of ISO 23162:2021. Significant updates include: requiring four-category grading for motility (A, rapidly progressive; B, slowly progressive; C, non-progressive; D, immotile); a four-part morphology assessment (head, midpiece, tail, cytoplasmic droplets) as essential for quality assurance (even if only the percentage of 'normal' is reported); and specifying sperm toxicity testing procedures for diagnostic andrology. These guidelines include a section on haematospermia, an observation requiring rapid onward referral. An Association of Reproductive and Clinical Scientists (ARCS) working group wrote these guidelines, with review by ARCS members. The aim is to guide good practice in laboratories but they are not intended as a tool to judge the practice of centres within the UK or beyond.

The Hidden Risks of Perioperative Transfusions in Traumatic Lower Extremity Free Flap Reconstruction.

BACKGROUND: Blood transfusions have been associated with surgical complications; however, these studies are not specific to lower extremity (LE) reconstruction. We evaluated the effect of perioperative packed red blood cell (PRBC) transfusions on LE free flap outcomes in trauma patients. METHODS: Patients undergoing LE free flap reconstruction following acute injuries from 2016 to 2021 were retrospectively analyzed. The perioperative period for transfusions was defined as ± 3 days from the procedure. Parameters included demographics, perioperative characteristics, and outcomes. Major complications were complications requiring reoperation. Univariate and multivariate analyses were performed to identify associations. RESULTS: Of the 205 patients, 48% received PRBCs perioperatively. There was a trend toward higher major complications rate in the transfusion group (19 vs. 10%, p = 0.09). Wound size, injury severity score (ISS), and intraoperative estimated blood loss were greater in the transfusion group (p < 0.01). Preoperative hemoglobin/hematocrit were lower in the transfusion group (p < 0.001). Units of PRBCs transfused were independently associated with major complications on multivariate analysis (odds ratio [OR] = 1.34, confidence interval [CI]: 1.06-1.70, p = 0.015) and length of hospital stay (LOS; OR = 1.05, CI: 1.02-1.08, p = 0.002). Infection, wound size, ISS, and preoperative hemoglobin/hematocrit were independently associated with increased LOS (p < 0.05) but not with major complications. CONCLUSION: The number of units of PRBCs given perioperatively was the only variable independently associated with major complications on multivariate analysis and was one of many variables associated with increased LOS. These findings suggest the usage of restrictive transfusion protocols in trauma patients requiring LE reconstruction.

Surgical Complications after Targeted Muscle Reinnervation at a Safety-Net Hospital.

BACKGROUND: Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) can reduce neuroma formation and phantom limb pain (PLP) after lower extremity (LE) amputation. These techniques have not been studied in safety-net hospitals. This study aims to examine the surgical complication rates after TMR and/or RPNI at an academic safety-net hospital in an urban setting. METHODS: This was a retrospective review of patients older than 18 years who had prior above-knee guillotine amputation (AKA) or below-knee guillotine amputation (BKA) and underwent stump formalization with TMR and/or RPNI from 2020 to 2022. Demographics, medical history, and operative and postoperative characteristics were collected. The primary outcome was any surgical complication, defined as infection, dehiscence, hematoma, neuroma, or reoperation. Univariate analysis was conducted to identify variables associated with surgical complications and PLP. RESULTS: Thirty-two patients met the inclusion criteria. The median age was 52 years, and 75% were males. Indications for amputation included diabetic foot infection (71.9%), necrotizing soft tissue infection (25.0%), and malignancy (3.1%). BKA was the most common indication for formalization (93.8%). Most patients (56.3%) had formalization with TMR and RPNI, 34.4% patients had TMR only, and 9.4% had RPNI alone. The incidence of postoperative complications was 46.9%, with infection being the most common (31.3%). The median follow-up time was 107.5 days. There was no significant difference in demographics, medical history, or operative characteristics between patients who did and did not have surgical complications. However, there was a trend toward higher rates of PLP in patients who had a postoperative wound infection (p = 0.06). CONCLUSION: Overall complication rates after LE formalization with TMR and/or RPNI at our academic safety-net hospital were consistent with reported literature. Given the benefits, including reduced chronic pain and lower health care costs, we advocate for the wider adoption of these techniques at other safety-net hospitals.

Perillyl alcohol reduces parasite sequestration and cerebrovascular dysfunction during experimental cerebral malaria.

Cerebral malaria (CM) is a severe immunovasculopathy which presents high mortality rate (15-20%), despite the availability of artemisinin-based therapy. More effective immunomodulatory and/or antiparasitic therapies are urgently needed. Experimental Cerebral Malaria (ECM) in mice is used to elucidate aspects involved in this pathology since manifests many of the neurological features of CM. In the present study, we evaluated the potential mechanisms involved in the protection afforded by perillyl alcohol (POH) in mouse strains susceptible to CM caused by Plasmodium berghei ANKA (PbA) infection through intranasal preventive treatment. Additionally, to evaluate the interaction of POH with the cerebral endothelium using an in vitro model of human brain endothelial cells (HBEC). Pharmacokinetic approaches demonstrated constant and prolonged levels of POH in the plasma and brain after a single intranasal dose. Treatment with POH effectively prevented vascular dysfunction. Furthermore, treatment with POH reduced the endothelial cell permeability and PbA s in the brain and spleen. Finally, POH treatment decreased the accumulation of macrophages and T and B cells in the spleen and downregulated the expression of endothelial adhesion molecules (ICAM-1, VCAM-1, and CD36) in the brain. POH is a potent monoterpene that prevents cerebrovascular dysfunction in vivo and in vitro, decreases parasite sequestration, and modulates different processes related to the activation, permeability, and integrity of the blood brain barrier (BBB), thereby preventing cerebral oedema and inflammatory infiltrates.

Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Spatially dependent H-bond dynamics at interfaces of water/biomimetic self-assembled lattice materials.

Understanding hydrogen-bond interactions in self-assembled lattice materials is crucial for preparing such materials, but the role of hydrogen bonds (H bonds) remains unclear. To gain insight into H-bond interactions at the materials' intrinsic spatial scale, we investigated ultrafast H-bond dynamics between water and biomimetic self-assembled lattice materials (composed of sodium dodecyl sulfate and ß-cyclodextrin) in a spatially resolved manner. To accomplish this, we developed an infrared pump, vibrational sum-frequency generation (VSFG) probe hyperspectral microscope. With this hyperspectral imaging method, we were able to observe that the primary and secondary OH groups of ß-cyclodextrin exhibit markedly different dynamics, suggesting distinct H-bond environments, despite being separated by only a few angstroms. We also observed another ultrafast dynamic reflecting a weakening and restoring of H bonds between bound water and the secondary OH of ß-cyclodextrin, which exhibited spatial uniformity within self-assembled domains, but heterogeneity between domains. The restoration dynamics further suggest heterogeneous hydration among the self-assembly domains. The ultrafast nature and meso- and microscopic ordering of H-bond dynamics could contribute to the flexibility and crystallinity of the material--two critically important factors for crystalline lattice self-assemblies--shedding light on engineering intermolecular interactions for self-assembled lattice materials.

It's Hip to Go Home: An Evaluation of Outpatient Alveolar Bone Grafting in Patients With Cleft Palate.

INTRODUCTION: Secondary alveolar bone grafting (ABG) is a common procedure performed at cleft care centers used to fill the alveolar cleft. The advent of techniques such as minimally invasive trephine drill harvest and placement of continuous-infusion pain pumps at the donor site has made outpatient ABG an increasingly feasible and cost-effective procedure. However, enhanced recovery after surgery protocols to maximize pain control and recovery times for this patient population have not been well established. METHODS: A retrospective single-institution review was conducted of pediatric patients with cleft palate who underwent iliac crest bone graft ABG at a large urban academic children's hospital from 2017 to 2022. Patient age, alveolar cleft repair laterality, pain scores, surgery duration, hospital LOS, readmissions, and re-operations within 30 days were examined. RESULTS: Fifty-four patients met our inclusion criteria. Fifty patients (92.6%) received a pain pump during the operation. The median duration of surgery and LOS in the post-anesthesia care unit were 1.28 and 1.75 hours, respectively. Fifty-two patients (96.3%) were discharged on the same day as their surgery whereas 2 patients (3.7%) stayed in the hospital overnight. The median pain score at the time of discharge was 0 (interquartile range 0, 0). There were 6 (11.1%) minor complications including 5 pain pump malfunctions and 1 recipient site wound breakdown. There was 1 readmission (1.9%) for development of a surgical site infection at the hip and no re-operations within 30 days of surgery. CONCLUSION: The described outpatient ABG protocol demonstrates effective postoperative pain control, short hospital LOS, and few complications requiring hospital readmission or reoperation.

Promoting rural residents' participation in clinical trials: clinical trials basics programming and training for rural public librarians.

Background: Having diverse representation in clinical trial participation is important. Historically, rural residents have been underrepresented in clinical trial research. Public librarians have an opportunity to promote clinical trial participation among rural residents by offering consumer health information services that help patrons to understand what clinical trials are and how they can find relevant clinical trials. Case Presentation: A consumer health library and a clinical trial center located at a large academic medical center collaborated to provide clinical trial information programming to rural public libraries. The group was awarded a Network of the National Library of Medicine (NNLM) Community Outreach Grant and was able to plan, develop, promote, and implement programs including training workshops, a speaker event, and a book discussion to rural public librarians. Discussion: Marketing the programs to rural public libraries was difficult and many barriers were encountered. Though registration and subsequent participation were low, participants expressed interest and gratitude for the programs. For any future programs targeting this population, further strategies will need to be implemented to ensure increased registrations and attendees.

Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Barriers to initiating and maintaining participation in parkrun.

Interventions that increase population physical activity are required to promote health and wellbeing. parkrun delivers community-based, 5 km events worldwide yet 43% who register never participate in a parkrun event. This research had two objectives; i) explore the demographics of people who register for parkrun in United Kingdom, Australia, Ireland, and don't initiate or maintain participation ii) understand the barriers to participating in parkrun amongst these people. Mandatory data at parkrun registration provided demographic characteristics of parkrun registrants. A bespoke online survey distributed across the three countries captured the reasons for not participating or only participating once. Of 680,255 parkrun registrants between 2017 and 19, 293,542 (43%) did not participate in any parkrun events and 147,148 (22%) only participated in one parkrun event. Females, 16-34 years and physically inactive were more likely to not participate or not return to parkrun. Inconvenient start time was the most frequently reported barrier to participating, with females more likely than males to report the psychological barrier of feeling too unfit to participate. Co-creating strategies with and for people living with a chronic disease, women, young adults, and physically inactive people, could increase physical activity participation within parkrun.

Water Capture Mechanisms at Zeolitic Imidazolate Framework Interfaces.

Water capture mechanisms of zeolitic imidazolate framework ZIF-90 are revealed by differentiating the water clustering and the center pore filling step, using vibrational sum-frequency generation spectroscopy (VSFG) at a one-micron spatial resolution and state-of-the-art molecular dynamics (MD) simulations. Through spectral line shape comparison between VSFG and IR spectra, the relative humidity dependence of VSFG intensity, and MD simulations, based on MB-pol, we found water clustering and center pore filling happen nearly simultaneously within each pore, with water filling the other pores sequentially. The integration of nonlinear optics with MD simulations provides critical mechanistic insights into the pore filling mechanism and suggests that the relative strength of the hydrogen bonds governs the water uptake mechanisms. This molecular-level detailed mechanism can inform the rational optimization of metal-organic frameworks for water harvesting.

A prospective study of type 2 diabetes, metformin use, and risk of breast cancer.

BACKGROUND: Type 2 diabetes (T2D) has been associated with increased breast cancer risk, but commonly prescribed antidiabetic medications such as metformin may reduce risk. Few studies have investigated T2D and medications together in relation to breast cancer. PATIENTS AND METHODS: Data came from 44 541 Sister Study participants aged 35 to 74 years at enrollment (2003-2009) who satisfied eligibility criteria, followed through 15 September 2017. Information on time-varying, self-reported, physician-diagnosed, prevalent and incident T2D, use of antidiabetic medications, and covariates was obtained from baseline and follow-up questionnaires. Incident breast cancers were confirmed with medical records. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. RESULTS: During follow-up (median, 8.6 years), 2678 breast cancers were diagnosed at least 1 year after enrollment. There were 3227 women (7.2%) with prevalent and 2389 (5.3%) with incident T2D, among whom 61% (n = 3386) were ever treated with metformin. There was no overall association between T2D and breast cancer risk (HR 0.99; 95% CI, 0.87-1.13). However, T2D was associated with increased risk of triple-negative breast cancer (HR 1.40; 95% CI, 0.90-2.16). Compared with not having T2D, T2D with metformin use was not associated with overall breast cancer risk (HR 0.98; 95% CI, 0.83-1.15), but it was associated with decreased risk of estrogen receptor (ER)-positive breast cancer (HR 0.86; 95% CI 0.70-1.05) and increased risk of ER-negative (HR 1.25; 95% CI, 0.84-1.88) and triple-negative breast cancer (HR 1.74; 95% CI, 1.06-2.83). The inverse association with ER-positive cancer was stronger for longer duration (≥10 year) metformin use (HR 0.62; 95% CI, 0.38-1.01; P for trend = 0.09). Results were supported by sensitivity analyses. CONCLUSION: Our findings suggest that associations between T2D and breast cancer may differ by hormone receptor status and that associations between T2D and ER-positive breast cancer may be reduced by long-term metformin use.

Informing the public health response to COVID-19: a systematic review of risk factors for disease, severity, and mortality.

BACKGROUND: Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics. METHODS: Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised. RESULTS: One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity. CONCLUSIONS: The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected. REGISTRATION: This review was registered on PROSPERO as CRD42020177714 .