Ag(III)···Ag(III) Argentophilic Interaction in a Cofacial Corrole Dyad.

Metallophilic interactions between closed-shell metal centers are exemplified by d10 ions, with Au(I) aurophilic interactions as the archetype. Such an interaction extends to d8 species, and examples involving Au(III) are prevalent. Conversely, Ag(III) argentophilic interactions are uncommon. Here, we identify argentophilic interactions in silver corroles, which are authentic Ag(III) species. The crystal structure of a monomeric silver corrole is a dimer in the solid state, and the macrocycle exhibits an atypical domed conformation. In order to evaluate whether this represents an authentic metallophilic interaction or a crystal-packing artifact, the analogous cofacial or "pacman" corrole was prepared. The conformation of the monomer was recapitulated in the silver pacman corrole, exhibiting a short 3.67 Å distance between metal centers and a significant compression of the xanthene backbone. Theoretical calculations support the presence of a rare Ag(III)···Ag(III) argentophilic interaction in the pacman complex.

Solvent-Induced Spin-State Change in Copper Corroles.

The electronic structure of copper corroles has been a topic of debate and revision since the advent of corrole chemistry. The ground state of these compounds is best described as an antiferromagnetically coupled Cu(II) corrole radical cation. In coordinating solvents, these molecules become paramagnetic, and this is often accompanied by a color change. The underlying chemistry of these solvent-induced properties is currently unknown. Here, we show that a coordinating solvent, such as pyridine, induces a change in the ground spin state from an antiferromagnetically coupled Cu(II) corrole radical cation to a ferromagnetically coupled triplet. Over time, the triplet reacts to produce a species with spectral signatures that are characteristic of the one-electron-reduced Cu(II) corrole. These observations account for the solvent-induced paramagnetism and the associated color changes that have been observed for copper corroles in coordinating solvents.

Syntheses and Properties of Metalated Tetradehydrocorrins.

The monoanionic tetrapyrrolic macrocycle B,C-tetradehydrocorrin (TDC) resides chemically between corroles and corrins. This chemical space remains largely unexplored due to a lack of reliable synthetic strategies. We now report the preparation and characterization of Co(II)- and Ni(II)-metalated TDC derivatives ([Co-TDC]+ and [Ni-TDC]+, respectively) with a combination of crystallographic, electrochemical, computational, and spectroscopic techniques. [Ni-TDC]+ was found to undergo primarily ligand-centered electrochemical reduction, leading to hydrogenation of the macrocycle under cathodic electrolysis in the presence of acid. Transient absorption (TA) spectroscopy reveals that [Ni-TDC]+ and the two-electron-reduced [Ni-TDC]- possess long-lived excited states, whereas the excited state of singly reduced [Ni-TDC] exhibits picosecond dynamics. The Co(I) compound [Co-TDC] is air stable, highlighting the notable property of the TDC ligand to stabilize low-valent metal centers in contradistinction to other tetrapyrroles such as corroles, which typically stabilize metals in higher oxidation states.

Establishment and Evaluation of a Large Contact-Tracing and Case Investigation Virtual Training Academy.

During the COVID-19 pandemic, the Virtual Training Academy (VTA) was established to rapidly develop a contact-tracing workforce for California. Through June 2021, more than 10 000 trainees enrolled in a contact-tracing or case investigation course at the VTA. To evaluate program effectiveness, we analyzed trainee pre- and postassessment results using the Wilcoxon signed-rank test. There was a statistically significant (P < .001) improvement in knowledge and self-perceived skills after course completion, indicating success in training a competent contact-tracing workforce. (Am J Public Health. 2021;111(11):1934-1938. https://doi.org/10.2105/AJPH.2021.306468).

Improving the benefits of HIV testing and referrals in large household surveys through active linkages to care: lessons and recommendations from the Namibia population-based HIV impact assessment (NAMPHIA), 2017.

In household-based surveys that include rapid HIV testing services (HTS), passive referral systems that give HIV-positive participants information about how and where to access ART but minimal follow-up support from survey staff may result in suboptimal linkage. In the 2017 Namibia Population-based HIV Impact Assessment (NAMPHIA), we piloted a system of active linkage to care and ART (ALCART) that utilized the infrastructure of existing community-based partner organizations (CBPOs). All HIV-positive participants age 15-64 years not on ART were given standard passive referrals to ART plus the option to participate in ALCART. Cases were assigned to CBPOs in participants' localities. Healthcare workers from the CBPO's contacted cases and facilitated their linkage to facility-based ART. A total of 510 participants were eligible and consented to ALCART. The majority were new diagnoses (80.8%), while the remainder were previously diagnosed but not on ART (19.2%). Of the 510, 473 (92.7%) were successfully linked into care. Of these, all but one initiated ART. Our ALCART system used existing CBPOs and contributed to >90% linkage-to-care and >99% ART-initiation among linked participants in a large, nationally-representative survey. This approach can be used to improve the potential benefits of HTS in other large population-based surveys.

Ligand Noninnocence in Nickel Porphyrins: Nickel Isobacteriochlorin Formation under Hydrogen Evolution Conditions.

An electron-deficient nickel porphyrin complex undergoes facile ring reduction to form a nickel isobacteriochlorin complex under hydrogen evolution conditions. Spectroscopic experiments indicate that the reduced nickel porphyrin undergoes subsequent reduction and protonation to form a phlorin anion rather than a metal hydride, demonstrating that the key initial proton-coupled electron transfer step is directed toward the ligand versus the metal. The phlorin anion facilely converts to the isobacteriochlorin in the presence of two-electron and three-proton equivalents. Cyclic voltammetry (CV) and spectroscopic experiments reveal that the four-electron, four-proton electrochemical reduction of nickel porphyrin to isobacteriochlorin occurs promptly in the presence of the strong proton donor tosic acid, followed by hydrogen evolution reaction (HER) catalysis at slightly more negative potentials. CVs of independently synthesized Ni isobacteriochlorin show a catalytic HER at the same potentials as those observed for the HER in CVs of the Ni porphyrin. We find that, under strongly acidic conditions, the HER catalysis arises from conversion of the Ni isobacteriochlorin into a nickel-containing, catalytically active electrode-adsorbed species. These results show that Ni porphyrin converts to Ni isobacteriochlorin under HER catalysis conditions via a ligand-based PCET process and that it is the isobacteriochlorin complex which gives rise to an active HER catalysis.

Nickel phlorin intermediate formed by proton-coupled electron transfer in hydrogen evolution mechanism.

The development of more effective energy conversion processes is critical for global energy sustainability. The design of molecular electrocatalysts for the hydrogen evolution reaction is an important component of these efforts. Proton-coupled electron transfer (PCET) reactions, in which electron transfer is coupled to proton transfer, play an important role in these processes and can be enhanced by incorporating proton relays into the molecular electrocatalysts. Herein nickel porphyrin electrocatalysts with and without an internal proton relay are investigated to elucidate the hydrogen evolution mechanisms and thereby enable the design of more effective catalysts. Density functional theory calculations indicate that electrochemical reduction leads to dearomatization of the porphyrin conjugated system, thereby favoring protonation at the meso carbon of the porphyrin ring to produce a phlorin intermediate. A key step in the proposed mechanisms is a thermodynamically favorable PCET reaction composed of intramolecular electron transfer from the nickel to the porphyrin and proton transfer from a carboxylic acid hanging group or an external acid to the meso carbon of the porphyrin. The C-H bond of the active phlorin acts similarly to the more traditional metal-hydride by reacting with acid to produce H2. Support for the theoretically predicted mechanism is provided by the agreement between simulated and experimental cyclic voltammograms in weak and strong acid and by the detection of a phlorin intermediate through spectroelectrochemical measurements. These results suggest that phlorin species have the potential to perform unique chemistry that could prove useful in designing more effective electrocatalysts.

Observation of a Photogenerated Rh2 Nitrenoid Intermediate in C-H Amination.

Rh2-catalyzed C-H amination is a powerful method for nitrogenating organic molecules. While Rh2 nitrenoids are often invoked as reactive intermediates in these reactions, the exquisite reactivity and fleeting lifetime of these species has precluded their observation. Here, we report the photogeneration of a transient Rh2 nitrenoid that participates in C-H amination. The developed approach to Rh2 nitrenoids, based on photochemical cleavage of N-Cl bonds in N-chloroamido ligands, has enabled characterization of a reactive Rh2 nitrenoid by mass spectrometry and transient absorption spectroscopy. We anticipate that photogeneration of metal nitrenoids will contribute to the development of C-H amination catalysis by providing tools to directly study the structures of these critical intermediates.

Halogen Photoelimination from SbV Dihalide Corroles.

Main-group p-block metals are ideally suited for mediating two-electron reactions because they cycle between M n and M n+2 redox states, as the one-electron state is thermodynamically unstable. Here, we report the synthesis and structure of an SbIII corrole and its SbVX2 (X = Cl, Br) congeners. SbIII sits above the corrole ring, whereas SbV resides in the corrole centroid. Electrochemistry suggests interconversion between the SbIII and SbVX2 species. TD-DFT calculations indicate a HOMO → LUMO+2 parentage for excited states in the Soret spectral region that have significant antibonding character with respect to the Sb-X fragment. The photochemistry of 2 and 3 in THF is consistent with the computational results, as steady-state photolysis at wavelengths coincident with the Soret absorption of SbVX2 corrole lead to its clean conversion to the SbIII corrole. This ability to photoactivate the Sb-X bond reflects the proclivity of the pnictogens to rely on the PnIII/V couple to drive the two-electron photochemistry of M-X bond activation, an essential transformation needed to develop HX-splitting cycles.

Role of pendant proton relays and proton-coupled electron transfer on the hydrogen evolution reaction by nickel hangman porphyrins.

The hangman motif provides mechanistic insights into the role of pendant proton relays in governing proton-coupled electron transfer (PCET) involved in the hydrogen evolution reaction (HER). We now show improved HER activity of Ni compared with Co hangman porphyrins. Cyclic voltammogram data and simulations, together with computational studies using density functional theory, implicate a shift in electrokinetic zone between Co and Ni hangman porphyrins due to a change in the PCET mechanism. Unlike the Co hangman porphyrin, the Ni hangman porphyrin does not require reduction to the formally metal(0) species before protonation by weak acids in acetonitrile. We conclude that protonation likely occurs at the Ni(I) state followed by reduction, in a stepwise proton transfer-electron transfer pathway. Spectroelectrochemical and computational studies reveal that upon reduction of the Ni(II) compound, the first electron is transferred to a metal-based orbital, whereas the second electron is transferred to a molecular orbital on the porphyrin ring.

Label-free Raman spectroscopic imaging to extract morphological and chemical information from a formalin-fixed, paraffin-embedded rat colon tissue section.

Animal models and archived human biobank tissues are useful resources for research in disease development, diagnostics and therapeutics. For the preservation of microscopic anatomical features and to facilitate long-term storage, a majority of tissue samples are denatured by the chemical treatments required for fixation, paraffin embedding and subsequent deparaffinization. These aggressive chemical processes are thought to modify the biochemical composition of the sample and potentially compromise reliable spectroscopic examination useful for the diagnosis or biomarking. As a result, spectroscopy is often conducted on fresh/frozen samples. In this study, we provide an extensive characterization of the biochemical signals remaining in processed samples (formalin fixation and paraffin embedding, FFPE) and especially those originating from the anatomical layers of a healthy rat colon. The application of chemometric analytical methods (unsupervised and supervised) was shown to eliminate the need for tissue staining and easily revealed microscopic features consistent with goblet cells and the dense populations of cells within the mucosa, principally via strong nucleic acid signals. We were also able to identify the collagenous submucosa- and serosa- as well as the muscle-associated signals from the muscular regions and blood vessels. Applying linear regression analysis to the data, we were able to corroborate this initial assignment of cell and tissue types by confirming the biological origin of each layer by reference to a subset of authentic biomolecular standards. Our results demonstrate the potential of using label-free Raman microspectroscopy to obtain superior imaging contrast in FFPE sections when compared directly to conventional haematoxylin and eosin (H&E) staining.

Electronic Structure of Copper Corroles.

The ground state electronic structure of copper corroles has been a topic of debate and revision since the advent of corrole chemistry. Computational studies formulate neutral Cu corroles with an antiferromagnetically coupled Cu(II) corrole radical cation ground state. X-ray photoelectron spectroscopy, EPR, and magnetometry support this assignment. For comparison, Cu(II) isocorrole and [TBA][Cu(CF3)4] were studied as authentic Cu(II) and Cu(III) samples, respectively. In addition, the one-electron reduction and one-electron oxidation processes are both ligand-based, demonstrating that the Cu(II) centre is retained in these derivatives. These observations underscore ligand non-innocence in copper corrole complexes.

Trap-Free Halogen Photoelimination from Mononuclear Ni(III) Complexes.

Halogen photoelimination reactions constitute the oxidative half-reaction of closed HX-splitting energy storage cycles. Here, we report high-yielding, endothermic Cl2 photoelimination chemistry from mononuclear Ni(III) complexes. On the basis of time-resolved spectroscopy and steady-state photocrystallography experiments, a mechanism involving ligand-assisted halogen elimination is proposed. Employing ancillary ligands to promote elimination offers a strategy to circumvent the inherently short-lived excited states of 3d metal complexes for the activation of thermodynamically challenging bonds.

Limited utility of dried-blood- and plasma spot-based screening for antiretroviral treatment failure with Cobas Ampliprep/TaqMan HIV-1 version 2.0.

The 2013 WHO antiretroviral therapy (ART) guidelines recommend dried blood spots (DBS) as an alternative specimen type for viral load (VL) monitoring. We assessed the programmatic utility of screening for antiretroviral (ARV) treatment failure (TF) at 5,000 and 1,000 copies/ml using DBS and dried plasma spots (DPS) with a commonly used VL assay, the Roche Cobas Ampliprep/Cobas TaqMan V.2.0 (CAP/CTM). Plasma, DBS, and DPS were prepared from 839 whole-blood specimens collected from patients on ART for ≥ 6 months at three public facilities in Namibia. Using the CAP/CTM test, VL were measured in plasma, DBS, and DPS, and the results were compared using the plasma VL as the reference standard. The clinical sensitivities, specificities, and positive (PPV) and negative predictive values (NPV) of DBS at ARV TF diagnostic thresholds of 5,000 copies/ml and 1,000 copies/ml were 0.99, 0.55, 0.33, and 0.99 and 0.99, 0.26, 0.29, and 0.99, respectively, and for DPS at TF diagnostic thresholds of 5,000 copies/ml and 1,000 copies/ml, they were 0.88, 0.98, 0.92, and 0.97 and 0.91, 0.96, 0.89, and 0.97, respectively. The prevalences of TF were overestimated in DBS by 33% and 57% at these two thresholds, respectively. A high rate of false-positive results would occur if the CAP/CTM with DBS were to be used to screen for ARV TF. WHO recommendations for DBS-based VL monitoring should be specific to the VL assay version and type. Despite the better performance of DPS, the programmatic utility for TF screening may be limited by requirements for processing the whole blood at the collection site.

Targeting STAT6-mediated synovial macrophage activation improves pain in experimental knee osteoarthritis.

BACKGROUND: Pain from osteoarthritis (OA) is one of the top causes of disability worldwide, but effective treatment is lacking. Nociceptive factors are released by activated synovial macrophages in OA, but depletion of synovial macrophages paradoxically worsens inflammation and tissue damage in previous studies. Rather than depleting macrophages, we hypothesized that inhibiting macrophage activation may improve pain without increasing tissue damage. We aimed to identify key mechanisms mediating synovial macrophage activation and test the role of STAT signaling in macrophages on pain outcomes in experimental knee OA. METHODS: We induced experimental knee OA in rats via knee destabilization surgery, and performed RNA sequencing analysis on sorted synovial tissue macrophages to identify macrophage activation mechanisms. Liposomes laden with STAT1 or STAT6 inhibitors, vehicle (control), or clodronate (depletion control) were delivered selectively to synovial macrophages via serial intra-articular injections up to 12 weeks after OA induction. Treatment effects on knee and hindpaw mechanical pain sensitivity were measured during OA development, along with synovitis, cartilage damage, and synovial macrophage infiltration using histopathology and immunofluorescence. Lastly, crosstalk between drug-treated synovial tissue and articular chondrocytes was assessed in co-culture. RESULTS: The majority of pathways identified by transcriptomic analyses in OA synovial macrophages involve STAT signaling. As expected, macrophage depletion reduced pain, but increased synovial tissue fibrosis and vascularization. In contrast, STAT6 inhibition in macrophages led to marked, sustained improvements in mechanical pain sensitivity and synovial inflammation without worsening synovial or cartilage pathology. During co-culture, STAT6 inhibitor-treated synovial tissue had minimal effects on healthy chondrocyte gene expression, whereas STAT1 inhibitor-treated synovium induced changes in numerous cartilage turnover-related genes. CONCLUSION: These results suggest that STAT signaling is a major mediator of synovial macrophage activation in experimental knee OA. STAT6 may be a key mechanism mediating the release of nociceptive factors from macrophages and the development of mechanical pain sensitivity. Whereas therapeutic depletion of macrophages paradoxically increases inflammation and fibrosis, blocking STAT6-mediated synovial macrophage activation may be a novel strategy for OA-pain management without accelerating tissue damage.

Rapid and sustained contact tracing training for COVID-19 in San Francisco: a training model for developing an emergency public health workforce.

The City and County of San Francisco was the first municipality in the United States to institute a COVID-19 contact tracing program. The San Francisco Department of Public Health (SFDPH) and the University of California, San Francisco (UCSF) created an outcome-based fully remote contact tracing curriculum using participatory learning methods to train non-public health emergency workers as contact tracers. Between April and December 2020, we trained over 300 individuals in contact tracing skills and procedures over three training phases. Using iterative curriculum design and Kirkpatrick's evaluation methodology, we aimed to ensure high quality and successful person-centered contact tracing. The resulting curriculum consisted of 24 learning outcomes taught with six participatory skills development activities, asynchronous materials, and one-on-one contact tracer support. We collected more than 700 responses from trainees using various evaluation tools across the training phases, and contact tracers interviewed more than 24,000 contacts after training in our program. Our evaluations showed that knowledge and skills improved for most trainees and demonstrated the utility of the training program in preparing trainees to perform person-centered contact tracing in San Francisco. Local health jurisdictions and state health agencies can use this model of curriculum development and evaluation to rapidly train a non-public health workforce to respond to future public health emergencies.

Use of HIV Recency Assays for HIV Incidence Estimation and Other Surveillance Use Cases: Systematic Review.

BACKGROUND: HIV assays designed to detect recent infection, also known as "recency assays," are often used to estimate HIV incidence in a specific country, region, or subpopulation, alone or as part of recent infection testing algorithms (RITAs). Recently, many countries and organizations have become interested in using recency assays within case surveillance systems and routine HIV testing services to measure other indicators beyond incidence, generally referred to as "non-incidence surveillance use cases." OBJECTIVE: This review aims to identify published evidence that can be used to validate methodological approaches to recency-based incidence estimation and non-incidence use cases. The evidence identified through this review will be used in the forthcoming technical guidance by the World Health Organization (WHO) and United Nations Programme on HIV/AIDS (UNAIDS) on the use of HIV recency assays for identification of epidemic trends, whether for HIV incidence estimation or non-incidence indicators of recency. METHODS: To identify the best methodological and field implementation practices for the use of recency assays to estimate HIV incidence and trends in recent infections for specific populations or geographic areas, we conducted a systematic review of the literature to (1) understand the use of recency testing for surveillance in programmatic and laboratory settings, (2) review methodologies for implementing recency testing for both incidence estimation and non-incidence use cases, and (3) assess the field performance characteristics of commercially available recency assays. RESULTS: Among the 167 documents included in the final review, 91 (54.5%) focused on assay or algorithm performance or methodological descriptions, with high-quality evidence of accurate age- and sex-disaggregated HIV incidence estimation at national or regional levels in general population settings, but not at finer geographic levels for prevention prioritization. The remaining 76 (45.5%) described the field use of incidence assays including field-derived incidence (n=45), non-incidence (n=25), and both incidence and non-incidence use cases (n=6). The field use of incidence assays included integrating RITAs into routine surveillance and assisting with molecular genetic analyses, but evidence was generally weaker or only reported on what was done, without validation data or findings related to effectiveness of using non-incidence indicators calculated through the use of recency assays as a proxy for HIV incidence. CONCLUSIONS: HIV recency assays have been widely validated for estimating HIV incidence in age- and sex-specific populations at national and subnational regional levels; however, there is a lack of evidence validating the accuracy and effectiveness of using recency assays to identify epidemic trends in non-incidence surveillance use cases. More research is needed to validate the use of recency assays within HIV testing services, to ensure findings can be accurately interpreted to guide prioritization of public health programming.

Performance of a novel rapid test for recent HIV infection among newly-diagnosed pregnant adolescent girls and young women in four high-HIV-prevalence districts-Malawi, 2017-2018.

Tests for recent HIV infection (TRI) distinguish recent from long-term HIV infections using markers of antibody maturation. The limiting antigen avidity enzyme immunoassay (LAg EIA) is widely used with HIV viral load (VL) in a recent infection testing algorithm (RITA) to improve classification of recent infection status, estimate population-level HIV incidence, and monitor trends in HIV transmission. A novel rapid test for recent HIV infection (RTRI), Asanté™, can determine HIV serostatus and HIV recency within minutes on a lateral flow device through visual assessment of test strip or reader device. We conducted a field-based laboratory evaluation of the RTRI among pregnant adolescent girls and young women (AGYW) attending antenatal clinics (ANC) in Malawi.We enrolled pregnant AGYW aged <25 years testing HIV-positive for the first time at their first ANC visit from 121 ANCs in four high-HIV burden districts. Consenting participants provided blood for recency testing using LAg EIA and RTRI, which were tested in central laboratories. Specimens with LAg EIA normalized optical density values ≤2.0 were classified as probable recent infections. RTRI results were based on: (1) visual assessment: presence of a long-term line (LT) indicating non-recent infection and absence of the line indicating recent infection; or (2) a reader; specimens with LT line intensity units <3.0 were classified as probable recent infections. VL was measured for specimens classified as a probable recent infections by either assay; those with HIV-1 RNA ≥1,000 copies/mL were classified as confirmed recent infections. We evaluated the performance of the RTRI by calculating correlation between RTRI and LAg EIA results, and percent agreement and kappa between RTRI and LAg EIA RITA results.Between November 2017 to June 2018, 380 specimens were available for RTRI evaluation; 376 (98.9%) were confirmed HIV-positive on RTRI. Spearman's rho between RTRI and LAg EIA was 0.72 indicating strong correlation. Percent agreement and kappa between RTRI- and LAg EIA-based RITAs were >90% and >0.65 respectively indicating substantial agreement between the RITAs.This was the first field evaluation of an RTRI in sub-Saharan Africa, which demonstrated good performance of the assay and feasibility of integrating RTRI into routine HIV testing services for real-time surveillance of recent HIV infection.

MERS-CoV Confirmation among 6,873 suspected persons and relevant Epidemiologic and Clinical Features, Saudi Arabia - 2014 to 2019.

BACKGROUND: Of the three lethal coronaviruses, in addition to the ongoing pandemic-causing SARS-CoV 2, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) remains in circulation. Information on MERS-CoV has relied on small sample of patients. We updated the epidemiology, laboratory and clinical characteristics, and survival patterns of MERS-CoV retrospectively with the largest sample of followed patients. METHODS: We conducted a retrospective review of line-listed records of non-random, continuously admitted patients who were suspected (6,873) or confirmed with MERS-CoV (501) admitted to one of the four MERS-CoV referral hospitals in Saudi Arabia, 2014-2019. FINDINGS: Of the 6,873 MERS-CoV suspected persons, the majority were male (56%) and Saudi nationals (83%) and 95% had no known history that increased their risk of exposure to MERS-CoV patients or vectors (95%). More confirmed cases reported history that increased their risk of MERS-CoV infection (41%). Among the suspected, MERS-CoV confirmation (7.4% overall) was independently associated with being male, known transmission link to MERS-CoV patients or vectors, fever, symptoms for 7 days, admission through intensive care unit, and diabetes. Among persons with confirmed MERS-CoV, single symptoms were reported by 20%, 3-symptom combinations (fever, cough and dyspnea) reported by 21% and 2-symptom combinations (fever, cough) reported by 16%. Of the two-thirds (62%) of MERS-CoV confirmed patients who presented with co-morbidity, 32% had 2-"comorbidities (diabetes, hypertension). More than half of the MERS-CoV patents showed abnormal chest X-ray, elevated aspartate aminotransferase, and creatinine kinase. About a quarter of MERS-CoV patients had positive cultures on blood, urine, or respiratory secretions. During an average hospital stay of 18 days (range 11 to 30), 64% developed complications involving liver, lungs, or kidneys. Ventilation requirement (29% of MERS-CoV cases) was independently associated with abnormal chest X-ray, viremia (Ct value <30), elevated creatinine, and prothrombin time. Death (21% overall) was independently associated with older age, dyspnea and abnormal chest X-ray on admission, and low hemoglobulin levels. INTERPRETATIONS: With two-thirds of the symptomatic persons developing multiorgan complications MERS-CoV remains the coronavirus with the highest severity (29%) and case fatality rate (21%) among the three lethal coronaviruses. Metabolic abnormalities appear to be an independent risk factor for sustained MERS-CoV transmission. The poorly understood transmission dynamics and non-specific clinical and laboratory features call for high index of suspicion among respiratory disease experts to help early detection of outbreaks. We reiterate the need for case control studies on transmission. FUNDING: No special funding to declare.