Reply to: Letter on the Effect of Fat Grafting on Scars Hyperpigmentation: A Systematic Review and Meta-Analysis.

Our meta-analysis indicated favorable results in improving scar hyperpigmentation through fat grafting, but there remains a need for further investigation using objective measures to validate these clinical findings and elucidate the underlying mechanisms. Current evidence from animal studies showed that fat grafting may exert its beneficial effects on scar hyperpigmentation through complex cellular and molecular pathways involving the regulation of melanin synthesis and skin remodeling. However, interpretation can be influenced by various factors, highlighting the importance of integrating multiple lines of evidence to draw robust conclusions.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Toxoplasma gondii Infection in Humans: A Comprehensive Approach Involving the General Population, HIV-Infected Patients and Intermediate-Duration Fever in the Canary Islands, Spain.

A prior investigation in 1993 identified a high seroprevalence of toxoplasmosis (63%) in the Canary Islands. This study aims to assess the current prevalence of the disease in diverse population groups. The study was based on a population-scale screening involving 273 residents utilizing T. gondii IgG ELISA and a 20 year retrospective study (1998-2018). This included AIDS/HIV outpatients (1357, of which 324 were residents), AIDS/HIV hospitalized patients (741) and patients with fever of intermediate duration (158). The seroprevalence in the resident population was 37%, with significant differences between islands. Among resident outpatients with AIDS/HIV, 14.2% had specific anti-T. gondii IgG, and three had anti-T. gondii IgM; however, IgG avidity testing indicated non-active infection. In patients hospitalized for AIDS/HIV, T. gondii causing encephalitis was detected in 2%. Among patients with fever of intermediate duration, 28.5% were positive for T. gondii IgG, and four also showed IgM positivity, although the infection was non-active. The study reveals a decrease in human toxoplasmosis over the past 30 years. However, the current seroprevalence, which stands at 37%, together with the substantial risk that T. gondii represents for immunocompromised individuals, highlights the need to implement preventive and control strategies to control the threat that this infection can pose to public health in the Canary Islands population.

Risks and Complications Rate in Liposuction: A Systematic Review and Meta-Analysis.

Liposuction is a surgical procedure used to remove localized excess adipose tissue. According to The Aesthetic Society's latest annual report, liposuction is the most commonly performed cosmetic procedure. Despite its popularity, the existing literature lacks a unified understanding of the risks associated with liposuction. The aim of this study was to measure complications of liposuction. A systematic review and meta-analysis was reported according to PRISMA guidelines and registered on the PROSPERO database (CRD42023471626). The primary outcome was overall complication rate. The absolute risk for individual complications was also assessed. From 2957 articles, 39 studies were selected for analysis. In total, 29,368 patients were included, with a mean age of 40.62 years and mean BMI of 26.36 kg/m2. Overall, the rate of any complication was 2.62 (95% CI, 1.78-3.84). The most common complication was contour deformity, with a prevalence of 2.35% (95% CI, 1.05%-5.16%). The prevalence of hyperpigmentation was 1.49% (95% CI, 1.12%-1.99%), seroma 0.65% (95% CI, 0.33%-1.24%), hematoma 0.27% (95% CI, 0.12%-0.60%), superficial burn 0.25% (95% CI, 0.17%-0.36%), allergic reaction 0.16% (95% CI, 0.050%-0.52%), skin necrosis 0.046% (95% CI, 0.013%-0.16%), generalized edema 0.041% (95% CI, 0.0051%-0.32%), infection 0.020% (95% CI, 0.010%-0.050%), venous thromboembolism 0.017% (95% CI, 0.0060%-0.053%), and local anesthesia toxicity 0.016% (95% CI, 0.0040%-0.064%). Liposuction is a safe procedure with low complications, of which contour deformity is the most common. Raising awareness of specific risks can enhance surgical outcomes and improve patient-physician understanding.

The Effect of Fat Grafting on Scars Hyperpigmentation: A Systematic Review and Meta-Analysis.

BACKGROUND: Hyperpigmented scars, particularly in exposed body areas, can be difficult to conceal and may evoke psychological distress. While the precise causes of scar dyschromia are not fully understood, alterations in melanogenic activity appear to hold more significance than changes in melanocyte quantity. Current treatments encompass laser interventions. However, it is essential to consider their costs and potential complications in relation to their limited proven effectiveness. Fat grafting has gained interest as a scar modulation technique due to its regenerative properties, and its efficacy in reducing scar hyperpigmentation is currently under investigation. METHODS: A systematic review and meta-analysis was reported according to PRISMA guidelines. PubMed, Embase, and Cochrane Library databases were accessed. PROSPERO registration number is CRD42023457778. The primary outcome was a change in scar pigmentation after fat grafting. Pigmentation changes after fat grafting were calculated using the standardized mean difference (SMD) between baseline and postoperative scores according to POSAS and VSS scales. Bias assessment was conducted according to the National Institute for Health and Clinical Excellence quality assessment tool. RESULTS: A total of 8 articles meeting inclusion and exclusion criteria were identified, involving 323 patients with hyperpigmented scars treated with fat grafting. A significant difference in scar pigmentation was noted after treatment with fat grafting according to observers' ratings, with a SMD of - 1.09 [95% CI: - 1.32; - 0.85], p<0.01. The SMD for patient-reported scar pigmentation after treatment with fat grafting was - 0.99 [96% CI: - 1.31; - 0.66], p<0.01. Four studies provided objective measurements of melanin changes after fat grafting and revealed inconsistent findings compared to subjective observations. CONCLUSIONS: Fat grafting shows promise in ameliorating hyperpigmented scars based on subjective assessments, but further corroborating evidence from objective measures is required. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Metformin and adipose-derived stem cell combination therapy alleviates radiation-induced skin fibrosis in mice.

BACKGROUND: Radiation therapy often leads to late radiation-induced skin fibrosis (RISF), causing movement impairment and discomfort. We conducted a comprehensive study to assess the effectiveness of metformin and adipose-derived stem cells (ASCs), whether autologous or allogeneic, individually or in combination therapy, in mitigating RISF. METHODS: Using a female C57BL/6J mouse model subjected to hind limb irradiation as a representative RISF model, we evaluated metformin, ASCs, or their combination in two contexts: prophylactic (started on day 1 post-irradiation) and therapeutic (initiated on day 14 post-irradiation, coinciding with fibrosis symptoms). We measured limb movement, examined skin histology, and analyzed gene expression to assess treatment efficacy. RESULTS: Prophylactic metformin and ASCs, whether autologous or allogeneic, effectively prevented late fibrosis, with metformin showing promising results. However, combination therapy did not provide additional benefits when used prophylactically. Autologous ASCs, alone or with metformin, proved most effective against late-stage RISF. Prophylactic intervention outperformed late therapy for mitigating radiation skin damage. Co-culture studies revealed that ASCs and metformin downregulated inflammation and fibrotic gene expression in both mouse and human fibroblasts. CONCLUSIONS: Our study suggests metformin's potential as a prophylactic measure to prevent RISF, and the combination of ASCs and metformin holds promise for late-stage RISF treatment. These findings have clinical implications for improving the quality of life for those affected by radiation-induced skin fibrosis.

Can ChatGPT be the Plastic Surgeon's New Digital Assistant? A Bibliometric Analysis and Scoping Review of ChatGPT in Plastic Surgery Literature.

BACKGROUND: ChatGPT, an artificial intelligence (AI) chatbot that uses natural language processing (NLP) to interact in a humanlike manner, has made significant contributions to various healthcare fields, including plastic surgery. However, its widespread use has raised ethical and security concerns. This study examines the presence of ChatGPT, an artificial intelligence (AI) chatbot, in the literature of plastic surgery. METHODS: A bibliometric analysis and scoping review of the ChatGPT plastic surgery literature were performed. PubMed was queried using the search term "ChatGPT" to identify all biomedical literature on ChatGPT, with only studies related to plastic, reconstructive, or aesthetic surgery topics being considered eligible for inclusion. RESULTS: The analysis included 30 out of 724 articles retrieved from PubMed, focusing on publications from December 2022 to July 2023. Four key areas of research emerged: applications in research/creation of original work, clinical application, surgical education, and ethics/commentary on previous studies. The versatility of ChatGPT in research, its potential in surgical education, and its role in enhancing patient education were explored. Ethical concerns regarding patient privacy, plagiarism, and the accuracy of information obtained from ChatGPT-generated sources were also highlighted. CONCLUSION: While ethical concerns persist, the study underscores the potential of ChatGPT in plastic surgery research and practice, emphasizing the need for careful utilization and collaboration to optimize its benefits while minimizing risks. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Human adipose ECM alleviates radiation-induced skin fibrosis via endothelial cell-mediated M2 macrophage polarization.

Radiation therapy can lead to late radiation-induced skin fibrosis (RISF), causing movement restriction, pain, and organ dysfunction. This study evaluated adipose-derived extracellular matrix (Ad-ECM) as a mitigator of RISF. Female C57BL/6J mice that were irradiated developed fibrosis, which was mitigated by a single local Ad-ECM injection, improving limb movement and reducing epithelium thickness and collagen deposition. Ad-ECM treatment resulted in decreased expression of pro-inflammatory and fibrotic genes, and upregulation of anti-inflammatory cytokines, promoting M2 macrophage polarization. Co-culture of irradiated human fibroblasts with Ad-ECM down-modulated fibrotic gene expression and enhanced bone marrow cell migration. Ad-ECM treatment also increased interleukin (IL)-4, IL-5, and IL-15 expression in endothelial cells, stimulating M2 macrophage polarization and alleviating RISF. Prophylactic use of Ad-ECM showed effectiveness in mitigation. This study suggests Ad-ECM's potential in treating chronic-stage fibrosis.

Application of Adipose-Tissue Derived Products for Burn Wound Healing.

Burn injuries are a significant global health concern, leading to high morbidity and mortality. Deep burn injuries often result in delayed healing and scar formation, necessitating effective treatment options. Regenerative medicine, particularly cell therapy using adipose-derived stem cells (ASCs), has emerged as a promising approach to improving burn wound healing and reducing scarring. Both in vitro and preclinical studies have demonstrated the efficacy of ASCs and the stromal vascular fraction (SVF) in addressing burn wounds. The application of ASCs for burn healing has been studied in various forms, including autologous or allogeneic cells delivered in suspension or within scaffolds in animal burn models. Additionally, ASC-derived non-cellular components, such as conditioned media or exosomes have shown promise. Injection of ASCs and SVF at burn sites have been demonstrated to enhance wound healing by reducing inflammation and promoting angiogenesis, epithelialization, and granulation tissue formation through their paracrine secretome. This review discusses the applications of adipose tissue derivatives in burn injury treatment, encompassing ASC transplantation, as well as the utilization of non-cellular components utilization for therapeutic benefits. The application of ASCs in burn healing in the future will require addressing donor variability, safety, and efficacy for successful clinical application.

Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation.

Adipose tissue plays a crucial role in maintaining metabolic homeostasis by serving as a storage site for excess fat and protecting other organs from the detrimental effects of lipotoxicity. However, the aging process is accompanied by a redistribution of fat, characterized by a decrease in insulin-sensitive subcutaneous adipose depot and an increase in insulin-resistant visceral adipose depot. This age-related alteration in adipose tissue distribution has implications for metabolic health. Adipose-derived stem cells (ASCs) play a vital role in the regeneration of adipose tissue. However, aging negatively impacts the stemness and regenerative potential of ASCs. The accumulation of oxidative stress and mitochondrial dysfunction-associated cellular damage contributes to the decline in stemness observed in aged ASCs. Nicotinamide adenine dinucleotide (NAD+) is a crucial metabolite that is involved in maintaining cellular homeostasis and stemness. The dysregulation of NAD+ levels with age has been associated with metabolic disorders and the loss of stemness. In this study, we aimed to investigate the effects of nicotinamide riboside (NR), a precursor of NAD+, on the stemness of human ASCs in cell culture. Our findings reveal that adipogenesis is accompanied by an increase in mitochondrial activity and the production of reactive oxygen species (ROS). However, treatment with NR leads to a reduction in mitochondrial activity and ROS production in ASCs. Furthermore, NR administration improves the stemness-related genes expression in ASCs and mitigates their propensity for adipocyte differentiation. These results suggest that NR treatment holds promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using animal models and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established drug for enhancing the stemness of aged stem cells.

Evaluation of the Relationship Between Diabetic Macular Edema and Renal Function in a Latino Population.

INTRODUCTION: Diabetic macular edema (DME) is one of the leading causes of vision impairment. The relationship between DME and estimated glomerular filtration rate (eGFR) has not been clearly evaluated in Hispanic or Latino populations. The objective of this study was to evaluate the eGFR in a Latino population with DME. METHODS: A cross-sectional, observational, and descriptive study was carried out on the basis of a multicenter phase III clinical trial. RESULTS: A total of 82 subjects diagnosed with DME (36 women and 46 men) were included in the study. The mean age was 61.93 ± 6.71 years. Mean values of the blood chemistry parameters glycated hemoglobin and eGFR were 7.20 ± 0.95% and 74.42 ± 26.82 mL/min/1.73 m2, respectively. The time elapsed since diagnosis of diabetes mellitus was 15.30 ± 7.35 years, while the duration of DME was 1.41 ± 1.75 years. Mean values for central macular thickness (CMT) and total macular volume (TMV) were 440.99 ± 132.22 µm and 11.97 ± 2.11 mm3, respectively. DME duration had a negative correlation with TMV (Rho - 0.26, p < 0.05) and a positive correlation with mean arterial pressure (Rho 0.26, p < 0.05). CMT was correlated with TMV (Rho 0.43, p < 0.0001) and visual acuity (Rho 0.26, p < 0.05). No significant correlations were observed between eGFR and CMT, TMV, or any demographic variable (p > 0.05). Chronic kidney disease (CKD) was associated with hypertension (OR 9.32, p = 0.035), elevated intraocular pressure (IOP) (OR 0.03, p = 0.011), and advanced age (OR 0.45, p = 0.011). CMT was significantly associated with TMV (ß = 27.69, p < 0.0001). CONCLUSIONS: We did not find a correlation between eGFR and DME. Our findings suggest that the presence of hypertension is associated with a decrease in the GFR < 60 mL/min/1.73 m2, and CKD may be associated with advanced age and elevated IOP which may increase the risk for the development of glaucoma. TRIAL REGISTRATION: NCT05217680 (clinicaltrials.gov).

Adsorption and Photodegradation of Lanasol Yellow 4G in Aqueous Solution by Natural Zeolite Treated by CO2-Laser Radiation.

Natural zeolite is a widely used material with excellent environmental cleaning performance, especially in water and wastewater treatment. Natural zeolite (Zini) calcined by CO2-laser radiation (ZL) was tested as a catalyst for the photodegradation and the adsorption of industrial azo dye Lanasol Yellow 4G (LY4G) in water. Morphology, chemical structure, and surface composition of Zini and ZL were analyzed by XRD, SEM, EDS, and XPS. UV/Visible spectrophotometry was used to evaluate the photocatalytic activity of Zini and ZL. The photocatalytic activity of the studied zeolites was associated with the presence of Fe oxides in their composition. Laser-treated natural zeolite showed higher efficiency as a photocatalyst compared to untreated natural zeolite.

Bibliometric and systemic analysis of the relationship between quality of work life and productivity during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic brought with it changes in the way of working and the well-being of workers. OBJECTIVE: To identify research trends on work life quality and its impact on productivity in the context of the COVID-19 pandemic. METHOD: The Proknow-C constructivist methodology was used, with which a bibliographic portfolio of 49 articles obtained from the Web of Science was prepared, resulting from four stages of search between 2012 and 2022; a bibliometric analysis was performed on that database and bibliometric networks were created with the software VOSviewer; the systemic analysis of the articles was carried out, thus showing theories, definitions and indicators; and areas of opportunity of research were identified. RESULTS: The most important high-impact specialized journals and authors, articles considered central, most used keywords such as job satisfaction, quality of work life and COVID-19, as well as the most representative countries such as European and Asian, are presented. CONCLUSION: It was found that the health sector is one of the most studied, allowing researchers from other sectors the opportunity to delve into the issue of the affectations of the quality of work life reflected in productivity and common variables were synthesized such as job satisfaction, well-being, motivation and security, among others.

Increased peripartum mortality associated with maternal subclinical malaria in Mozambique.

BACKGROUND: Plasmodium falciparum infection in pregnant women in sub-Saharan Africa is often asymptomatic. As these forms of malaria are often submicroscopic and difficult to diagnose by conventional methods (microscopy and/or rapid diagnostic test), diagnosis requires the use of molecular techniques such as polymerase chain reaction (PCR). This study analyses the prevalence of subclinical malaria and its association with adverse maternal and neonatal outcomes, a topic that has been scarcely evaluated in the literature. METHODS: A cross-sectional study was conducted using semi-nested multiplex PCR to assess the presence of P. falciparum in placental and peripheral blood of 232 parturient pregnant women at the Hospital Provincial de Tete, Mozambique between March 2017 and May 2019. Multivariate regressions were performed to assess the associations of maternal subclinical malaria with several maternal and neonatal outcomes after controlling for the presence of preeclampsia/eclampsia (PE/E) and HIV infection, as well as for other maternal and pregnancy characteristics. RESULTS: In total, 17.2% (n = 40) of the women studied had positive PCR for P. falciparum (7 in placental blood only, 3 in peripheral blood only). We found a significant association between subclinical malaria and a higher peripartum mortality risk, which persisted after controlling for maternal comorbidity and maternal and pregnancy characteristics (adjusted odds ratio: 3.50 [1.11-10.97]). In addition, PE/E and HIV infections were also significantly associated with several adverse maternal and neonatal outcomes. CONCLUSION: This study demonstrated the association of subclinical malaria, as well as of PE/E and HIV, in pregnant women with adverse maternal and neonatal outcomes. Therefore, molecular methods may be sensitive tools to identify asymptomatic infections that can reduce the impact on peripartum mortality and their contribution to sustained transmission of the parasite in endemic countries.

Increased peripartum mortality associated with maternal subclinical malaria in Mozambique

Background: Plasmodium falciparum infection in pregnant women in sub-Saharan Africa is often asymptomatic. As these forms of malaria are often submicroscopic and difficult to diagnose by conventional methods (microscopy and/or rapid diagnostic test), diagnosis requires the use of molecular techniques such as polymerase chain reaction (PCR). This study analyses the prevalence of subclinical malaria and its association with adverse maternal and neonatal outcomes, a topic that has been scarcely evaluated in the literature. Methods: A cross-sectional study was conducted using semi-nested multiplex PCR to assess the presence of P. falciparum in placental and peripheral blood of 232 parturient pregnant women at the Hospital Provincial de Tete, Mozambique between March 2017 and May 2019. Multivariate regressions were performed to assess the associations of maternal subclinical malaria with several maternal and neonatal outcomes after controlling for the presence of preeclampsia/eclampsia (PE/E) and HIV infection, as well as for other maternal and pregnancy characteristics. Results: In total, 17.2% (n = 40) of the women studied had positive PCR for P. falciparum (7 in placental blood only, 3 in peripheral blood only). We found a significant association between subclinical malaria and a higher peripartum mortality risk, which persisted after controlling for maternal comorbidity and maternal and pregnancy characteristics (adjusted odds ratio: 3.50 [1.11-10.97]). In addition, PE/E and HIV infections were also significantly associated with several adverse maternal and neonatal outcomes. Conclusion: This study demonstrated the association of subclinical malaria, as well as of PE/E and HIV, in pregnant women with adverse maternal and neonatal outcomes. Therefore, molecular methods may be sensitive tools to identify asymptomatic infections that can reduce the impact on peripartum mortality and their contribution to sustained transmission of the parasite in endemic countries.

Executive summary consensus statement of imported diseases group (GEPI) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Tropical Medicine and International Health (SETMSI), on the diagnostic and treatment of imported schistosomiasis.

Schistosomiasis is a highly prevalent disease, especially in immigrant populations, and is associated with significant morbidity and diagnostic delays outside endemic areas. For these reasons, the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Tropical Medicine and International Health (SEMTSI) have developed a joint consensus document to serve as a guide for the screening, diagnosis and treatment of this disease outside endemic areas. A panel of experts from both societies identified the main questions to be answered and developed recommendations based on the scientific evidence available at the time. The document was reviewed by the members from both societies for final approval.

Seroprevalence of Strongyloides stercolaris in Patients about to Receive Immunosuppressive Treatment in Gran Canaria (Spain).

Strongyloides stercoralis infection is generally asymptomatic or mildly symptomatic, but in the immunosuppressed host, it is associated with more severe and complicated forms with a worse prognosis. S. stercoralis seroprevalence was studied in 256 patients before receiving immunosuppressive treatment (before kidney transplantation or starting biological treatments). As a control group, serum bank data of 642 individuals representative of the population of the Canary Islands were retrospectively analyzed. To avoid false positives due to cross-reactivity with other similar helminth antigens present in the study area, IgG antibodies to Toxocara spp. and Echinococcus spp. were evaluated in cases positive for Strongyloides. The data show this is a prevalent infection: 1.1% of the Canarian population, 2.38% of Canarian individuals awaiting organ transplants and 4.8% of individuals about to start biological agents. On the other hand, strongyloidiasis can remain asymptomatic (as observed in our study population). There are no indirect data, such as country of origin or eosinophilia, to help raise suspicion of the disease. In summary, our study suggests that screening for S. stercoralis infection should be performed in patients who receive immunosuppressive treatment for solid organ transplantation or biological agents, in line with previous publications.

Effects of HIV infection and/or malaria on maternal and neonatal health in a high-prevalence setting.

OBJECTIVE: HIV infection and malaria have been associated with different complications during pregnancy and delivery. HIV-positive pregnant women are at increased risk for all adverse outcomes of malaria during pregnancy. The main objective was to analyse the obstetric and perinatal consequences of malaria, HIV infection and HIV/malaria co-infection in pregnant women and newborns, which has been less well evaluated. METHODS: A cross-sectional study was carried out in the Maternity Service of the Provincial Hospital of Tete Mozambique, involving completion of a structured questionnaire that included demographic data, and information on the current pregnancy, delivery and the newborn. In total, 819 women (13-45 years old) in the immediate postpartum period were enrolled between 1 March and 31 October 2016. RESULTS: The overall prevalence of HIV and malaria, considered separately, in pregnant women was ~12% (103 women with HIV and 101 with malaria). Only one-fifth of HIV-infected women knew their HIV status before pregnancy. A significantly higher proportion of women with HIV attended four or more antenatal care visits than women without HIV. Caesarean section was less frequent in HIV patients, and peripartum urinary infection was more frequent than in seronegative women (13/103 [12.6%] vs. 34/716 [4.7%]). HIV/malaria co-infection were 17/819 (2%) and was significantly associated with the development of pre-eclampsia when HIV-infected patients received anti-retroviral treatment, and with an increase in urinary tract infections around delivery. With respect to the newborn, co-infection increased the frequency of early neonatal death, as well as neonatal asphyxia and jaundice. CONCLUSIONS: In Mozambique, the prevalence of malaria and HIV infection in women of childbearing age continues to be high and contributes additively to complications during pregnancy and childbirth, and in the newborn. Therefore, integrating HIV, malaria and reproductive health services is essential if maternal and foetal outcomes are to improve.

Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers.

OBJECTIVES: To assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk. METHODS: EPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs. RESULTS: Of 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00-1.98) for TDF + HCQ, 0.34 (0.00-2.06) for TDF, and 0.49 (0.00-2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21-1.00) for TDF + HCQ, 0.81 (0.44-1.49) for TDF, and 0.73 (0.41-1.38) for HCQ. Adverse events were generally mild. DISCUSSION: The target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo.