Fernández et al. report on the safety and efficacy of implanting an intracortical microelectrode array in a blind person, suggesting the potential for this approach to restore functional vision. Image credit: Anita Ponne/Shutterstock.
Justin B. Echouffo-Tcheugui, Sabra C. Lewsey, Robert G. Weiss
In this issue of the JCI, the dream of restoring useful vision to blind individuals with neurotechnology moves one step closer to realization. Fernández et al. implanted an electrode array with 96 penetrating electrodes in the visual cortex of a blind patient who had been without light perception for 16 years due to optic neuropathy. Remarkably, the patient was able to perceive visual patterns created by passing current through array electrodes. The use of a penetrating electrode array meant that action potentials from single neurons could be recorded to study the neural response to stimulation. Compared with electrodes resting on the cortical surface, penetrating electrodes require one-tenth the current to create a visual percept. However, patterned electrical stimulation often fails to produce the expected percept for penetrating and surface electrode arrays, highlighting the need for further research to untangle the relationship between stimulus and perception.
Michael S. Beauchamp, William H. Bosking, Denise Oswalt, Daniel Yoshor
GWAS involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases, including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multicenter consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this Commentary, we evaluate the advantages and limitations of this approach.
Vito Luigi Colona, Michela Biancolella, Antonio Novelli, Giuseppe Novelli
Epilepsy is the neurological disorder defined by spontaneous recurrent seizures, which are abnormal patterns of electrical discharge in the brain. A major advance in neurology over the last 20 years is the identification of genetic variation as an important cause of epilepsy, and in particular as a cause of the epileptic encephalopathies, defined by childhood-onset, treatment-resistant epilepsy accompanied by developmental delay leading to intellectual disability. Unfortunately, this progress in genetic diagnosis has yet to translate to effective precision or targeted therapeutics. However, in this issue of the JCI, Li and Jancovski et al. use antisense oligonucleotides (ASO) to treat or prevent epilepsy and epilepsy-associated cognitive and behavioral comorbidities in a mouse model of SCN2A encephalopathy, paralogous to the recurrent human variant SCN2A c.5645G>A (p.R1882Q) associated with epileptic encephalopathy. These findings may inform the development of targeted or personalized therapies for what is currently an incurable and largely untreatable disorder.
Ethan M. Goldberg
Excessive inflammation drives the progression from sepsis to septic shock. Macrophage migration inhibitory factor (MIF) is of interest because MIF promoter polymorphisms predict mortality in different infections, and anti-MIF antibody improves survival in experimental models when administered 8 hours after infectious insult. The recent description of a second MIF superfamily member, D-dopachrome tautomerase (D-DT/MIF-2), prompted closer investigation of MIF-dependent responses. We subjected Mif–/– and Mif-2–/– mice to polymicrobial sepsis and observed a survival benefit with Mif but not Mif-2 deficiency. Survival was associated with reduced numbers of small peritoneal macrophages (SPMs) that, in contrast to large peritoneal macrophages (LPMs), were recruited into the peritoneal cavity. LPMs produced higher quantities of MIF than SPMs, but SPMs expressed higher levels of inflammatory cytokines and the MIF receptors CD74 and CXCR2. Adoptive transfer of WT SPMs into Mif–/– hosts reduced the protective effect of Mif deficiency in polymicrobial sepsis. Notably, MIF-2 lacks the pseudo-(E)LR motif present in MIF that mediates CXCR2 engagement and SPM migration, supporting a specific role for MIF in the recruitment and accumulation of inflammatory SPMs.
Pathricia Veronica Tilstam, Wibke Schulte, Thomas Holowka, Bong-Sung Kim, Jessica Nouws, Maor Sauler, Marta Piecychna, Georgios Pantouris, Elias Lolis, Lin Leng, Jürgen Bernhagen, Günter Fingerle-Rowson, Richard Bucala
To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB–specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.
Mengyan Li, Scott J. Garforth, Kaitlyn E. O’Connor, Hang Su, Danica M. Lee, Alev Celikgil, Rodolfo J. Chaparro, Ronald D. Seidel, R. Brad Jones, Ravit Arav-Boger, Steven C. Almo, Harris Goldstein
Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.
Won Gun Choi, Wonsuk Choi, Tae Jung Oh, Hye-Na Cha, Inseon Hwang, Yun Kyung Lee, Seung Yeon Lee, Hyemi Shin, Ajin Lim, Dongryeol Ryu, Jae Myoung Suh, So-Young Park, Sung Hee Choi, Hail Kim
Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.
Cyril Djari, Isabelle Sahut-Barnola, Amandine Septier, Ingrid Plotton, Nathanaëlle Montanier, Damien Dufour, Adrien Levasseur, James Wilmouth Jr., Jean-Christophe Pointud, Fabio R. Faucz, Crystal Kamilaris, Antoine-Guy Lopez, Florian Guillou, Amanda Swain, Seppo J. Vainio, Igor Tauveron, Pierre Val, Hervé Lefebvre, Constantine A. Stratakis, Antoine Martinez, Anne-Marie Lefrançois-Martinez
The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN’s receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.
Alexander L. Greninger, Ksenia Rybkina, Michelle J. Lin, Jennifer Drew-Bear, Tara C. Marcink, Ryan C. Shean, Negar Makhsous, Michael Boeckh, Olivia Harder, Francesca Bovier, Shana R. Burstein, Stefan Niewiesk, Bert K. Rima, Matteo Porotto, Anne Moscona
Naive and memory CD4+ T cells reactive with human immunodeficiency virus type 1 (HIV-1) are detectable in unexposed, unimmunized individuals. The contribution of preexisting CD4+ T cells to a primary immune response was investigated in 20 HIV-1–seronegative volunteers vaccinated with an HIV-1 envelope (Env) plasmid DNA prime and recombinant modified vaccinia virus Ankara (MVA) boost in the HVTN 106 vaccine trial (clinicaltrials.gov NCT02296541). Prevaccination naive or memory CD4+ T cell responses directed against peptide epitopes in Env were identified in 14 individuals. After priming with DNA, 40% (8/20) of the elicited responses matched epitopes detected in the corresponding preimmunization memory repertoires, and clonotypes were shared before and after vaccination in 2 representative volunteers. In contrast, there were no shared epitope specificities between the preimmunization memory compartment and responses detected after boosting with recombinant MVA expressing a heterologous Env. Preexisting memory CD4+ T cells therefore shape the early immune response to vaccination with a previously unencountered HIV-1 antigen.
Suzanne L. Campion, Elena Brenna, Elaine Thomson, Will Fischer, Kristin Ladell, James E. McLaren, David A. Price, Nicole Frahm, Juliana M. McElrath, Kristen W. Cohen, Janine R. Maenza, Stephen R. Walsh, Lindsey R. Baden, Barton F. Haynes, Bette Korber, Persephone Borrow, Andrew J. McMichael
BACKGROUND A long-held goal of vision therapy is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists.METHODS We implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a 6-month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation.RESULTS Implantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 μA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes was associated with a significant reduction in thresholds (P < 0.001, ANOVA) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries.CONCLUSIONS Our results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind.TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02983370.FUNDING The Spanish Ministerio de Ciencia Innovación y Universidades, the Generalitat Valenciana (Spain), the Europan Union’s Horizon 2020 programme, the Bidons Egara Research Chair of the University Miguel Hernández (Spain), and the John Moran Eye Center of the University of Utah.
Eduardo Fernández, Arantxa Alfaro, Cristina Soto-Sánchez, Pablo Gonzalez-Lopez, Antonio M. Lozano, Sebastian Peña, Maria Dolores Grima, Alfonso Rodil, Bernardeta Gómez, Xing Chen, Pieter R. Roelfsema, John D. Rolston, Tyler S. Davis, Richard A. Normann
Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
Binita Chakraborty, Jovita Byemerwa, Jonathan Shepherd, Corinne N. Haines, Robert Baldi, Weida Gong, Wen Liu, Debarati Mukherjee, Sandeep Artham, Felicia Lim, Yeeun Bae, Olivia Brueckner, Kendall Tavares, Suzanne E. Wardell, Brent A. Hanks, Charles M. Perou, Ching-Yi Chang, Donald P. McDonnell
De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function in SCN2A is seen in some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction in SCN2A expression could substantially improve clinical outcomes. We tested this theory by central administration of a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA in a mouse model of Scn2a early seizure onset DEE (Q/+ mice). Untreated Q/+ mice presented with spontaneous seizures at P1 and did not survive beyond P30. Administration of the ASO to Q/+ mice reduced spontaneous seizures and significantly extended life span. Across a range of behavioral tests, Scn2a ASO-treated Q/+ mice were largely indistinguishable from WT mice, suggesting treatment is well tolerated. A human SCN2A gapmer ASO could likewise impact the lives of patients with SCN2A gain-of-function DEE.
Melody Li, Nikola Jancovski, Paymaan Jafar-Nejad, Lisseth E. Burbano, Ben Rollo, Kay Richards, Lisa Drew, Alicia Sedo, Jacqueline Heighway, Svenja Pachernegg, Armand Soriano, Linghan Jia, Todd Blackburn, Blaine Roberts, Alex Nemiroff, Kelley Dalby, Snezana Maljevic, Christopher A. Reid, Frank Rigo, Steven Petrou
Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic, latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins, with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing-antibody titers were higher at 1 month and declined far less by 8 months in mRNA- compared with protein-immunized animals. Both vaccines protected against death and genital lesions when infected 1 month after immunization; however, protection was more durable in the mRNA group compared with the protein group when infected after 8 months, an interval representing greater than 15% of the animal’s lifespan. Serum and vaginal neutralizing-antibody titers correlated with protection against infection, as measured by genital lesions and vaginal virus titers 2 days after infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times after immunization that persisted for up to 1 year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.
Sita Awasthi, James J. Knox, Angela Desmond, Mohamad-Gabriel Alameh, Brian T. Gaudette, John M. Lubinski, Alexis Naughton, Lauren M. Hook, Kevin P. Egan, Ying K. Tam, Norbert Pardi, David Allman, Eline T. Luning Prak, Michael P. Cancro, Drew Weissman, Gary H. Cohen, Harvey M. Friedman
Background There is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.Methods We combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.Results We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2–1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6–2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2–2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2–2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8–3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2–1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.Conclusions The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.
Tomoko Nakanishi, Sara Pigazzini, Frauke Degenhardt, Mattia Cordioli, Guillaume Butler-Laporte, Douglas Maya-Miles, Luis Bujanda, Youssef Bouysran, Mari E.K. Niemi, Adriana Palom, David Ellinghaus, Atlas Khan, Manuel Martínez-Bueno, Selina Rolker, Sara Amitrano, Luisa Roade Tato, Francesca Fava, FinnGen, The COVID-19 Host Genetics Initiative (HGI), Christoph D. Spinner, Daniele Prati, David Bernardo, Federico Garcia, Gilles Darcis, Israel Fernández-Cadenas, Jan Cato Holter, Jesus M. Banales, Robert Frithiof, Krzysztof Kiryluk, Stefano Duga, Rosanna Asselta, Alexandre C. Pereira, Manuel Romero-Gómez, Beatriz Nafría-Jiménez, Johannes R. Hov, Isabelle Migeotte, Alessandra Renieri, Anna M. Planas, Kerstin U. Ludwig, Maria Buti, Souad Rahmouni, Marta E. Alarcón-Riquelme, Eva C. Schulte, Andre Franke, Tom H. Karlsen, Luca Valenti, Hugo Zeberg, J. Brent Richards, Andrea Ganna
Background Gingivitis and periodontitis are prevalent inflammatory diseases of the periodontal tissues. Current treatments are often ineffective or do not prevent disease recurrence. Uncontrolled complement activation and the resulting chronic gingival inflammation are hallmarks of periodontal diseases. We determined the efficacy and safety of a complement 3–targeted therapeutic, AMY-101, which was locally administered to adult patients with periodontal inflammation.Methods Thirty-two patients with gingival inflammation were enrolled in a randomized, placebo-controlled, double-blind, split-mouth phase IIa trial that followed a dose escalation study to select a safe and effective dose in an additional 8 patients. Half of the patient’s mouth was randomly assigned to AMY-101 (0.1 mg/site) or placebo injections at sites of inflammation, administered on days 0, 7, and 14, and then evaluated for safety and efficacy outcomes on days 28, 60, and 90. The primary efficacy outcome was a change in gingival inflammation, measured by a modified gingival index (MGI), and secondary outcomes included changes in bleeding on probing (BOP), the amount of plaque, pocket depth, clinical attachment level, and gingival crevicular fluid levels of matrix metalloproteinases (MMPs) over 90 days.Results A once-weekly intragingival injection of AMY-101 for 3 weeks was safe and well tolerated in all participants and resulted in significant (P < 0.001) reductions in clinical indices measuring gingival inflammation (MGI and BOP). AMY-101 significantly (P < 0.05) reduced MMP-8 and MMP-9 levels, indicators of inflammatory tissue destruction. These therapeutic effects persisted for at least 3 months after treatment.Conclusion AMY-101 treatment resulted in a significant and sustainable reduction in gingival inflammation without adverse events and, we believe, merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions.Trial registration ClinicalTrials.gov identifier NCT03694444.Funding Amyndas Pharmaceuticals.
Hatice Hasturk, George Hajishengallis, The Forsyth Institute Center for Clinical and Translational Research staff, John D. Lambris, Dimitrios C. Mastellos, Despina Yancopoulou
Background SARS-CoV-2 infection in pregnancy is associated with a higher risk of pregnancy-related complications and neonatal respiratory distress and hospitalization. Effectiveness of SARS-CoV-2 vaccines in pregnant women is not known.Methods All women with confirmed pregnancy who presented to the national referral hospital in Qatar between December 20, 2020, and May 30, 2021, with at least 1 SARS-CoV-2 test and not testing prior to pregnancy were included. We determined the vaccine effectiveness of mRNA vaccines in preventing confirmed SARS-CoV-2 infection during pregnancy using both cohort and test-negative case-control designs. Analyses were adjusted for age group, nationality, and gestational age.Results Among 4534 pregnant women, there were 407 vaccinated and 407 unvaccinated women in the matched cohort analysis. Vaccine effectiveness was 87.6% (95%CI 44.1%–97.2%) at least 14 days after the second dose. There were 386 test-positive and 834 matched women in the test-negative case control analysis. Vaccine effectiveness was 86.8% (95%CI 47.5%–98.5%) at least 14 days after the second dose. Adjustment for age, nationality, and gestational age yielded similar results for both designs. In the test-negative analysis, vaccine effectiveness at least 14 days after the first dose but before the second dose was 40.8% (95% CI 0.0%–80.4%). Of the 386 test-positive pregnant women, 74 cases were Alpha variant, 163 cases were Beta variant, and 156 cases were variants of unknown status. There were 9 severe or critical disease cases and no deaths in the test-positive pregnant women, all of whom were unvaccinated.Conclusion The mRNA vaccines provide a high level of protection against documented SARS-CoV-2 infection, which supports the inclusion of pregnant women in vaccination campaigns.FUNDING Hamad Medical Corporation, Weill Cornell Medicine Qatar, and the Ministry of Public Health Qatar.
Adeel A. Butt, Hiam Chemaitelly, Abdullatif Al Khal, Peter V. Coyle, Huda Saleh, Anvar H. Kaleeckal, Ali Nizar Latif, Roberto Bertollini, Abdul-Badi Abou-Samra, Laith J. Abu-Raddad
Marton Keszei, Julien Record, Joanna S. Kritikou, Hannah Wurzer, Chiara Geyer, Meike Thiemann, Paul Drescher, Hanna Brauner, Laura Köcher, Jaime James, Minghui He, Marisa A.P. Baptista, Carin I.M. Dahlberg, Amlan Biswas, Sonia Lain, David P. Lane, Wenxia Song, Katrin Pütsep, Peter Vandenberghe, Scott B. Snapper, Lisa S. Westerberg