Stationary distribution of the linkage disequilibrium coefficient r2.

The linkage disequilibrium coefficient r2 is a measure of statistical dependence of the alleles possessed by an individual at different genetic loci. It is widely used in association studies to search for the locations of disease-causing genes on chromosomes. Most studies to date treat r2 as a fixed property of two loci in a finite population, and investigate the sampling distribution of estimators due to the statistical sampling of individuals from the population. Here, we instead consider the distribution of r2 itself under a process of genetic sampling through the generations. Using a classical two-locus model for genetic drift, mutation, and recombination, we investigate the probability density function of r2 at stationarity. This density function provides a tool for inference on evolutionary parameters such as mutation and recombination rates. We reconstruct the approximate stationary density of r2 by calculating a finite sequence of the distribution's moments and applying the maximum entropy principle. Our approach is based on the diffusion approximation, under which we demonstrate that for certain models in population genetics, moments of the stationary distribution can be obtained without knowing the probability distribution itself. To illustrate our approach, we show how the stationary probability density of r2 can be used in a maximum likelihood framework to estimate mutation and recombination rates from sample data of r2.

Investing in Immunity: Prepandemic Immunization to Combat Future Influenza Pandemics.

We are unlikely, with current technologies, to have sufficient pandemic influenza vaccine ready in time to impact the first wave of the next pandemic. Emerging data show that prior immunization with an immunologically distinct hemagglutinin of the same subtype offers the potential to "prime" recipients for rapid protection with a booster dose, years later, of a vaccine then manufactured to match the pandemic strain. This article proposes making prepandemic priming vaccine(s) available for voluntary use, particularly to those at high risk of early occupational exposure, such as first responders and healthcare workers, and to others maintaining critical infrastructure. In addition to providing faster protection and potentially reducing social disruption, being able, early in a pandemic, to immunize those who had received prepandemic vaccine with one dose of the pandemic vaccine, rather than the 2 doses typically required, would reduce the total doses of pandemic vaccine then needed, extending vaccine supplies.

Review and analysis of the overlapping threats of carbapenem and polymyxin resistant E. coli and Klebsiella in Africa.

BACKGROUND: Carbapenem-resistant Enterobacterales are among the most serious antimicrobial resistance (AMR) threats. Emerging resistance to polymyxins raises the specter of untreatable infections. These resistant organisms have spread globally but, as indicated in WHO reports, the surveillance needed to identify and track them is insufficient, particularly in less resourced countries. This study employs comprehensive search strategies with data extraction, meta-analysis and mapping to help address gaps in the understanding of the risks of carbapenem and polymyxin resistance in the nations of Africa. METHODS: Three comprehensive Boolean searches were constructed and utilized to query scientific and medical databases as well as grey literature sources through the end of 2019. Search results were screened to exclude irrelevant results and remaining studies were examined for relevant information regarding carbapenem and/or polymyxin(s) susceptibility and/or resistance amongst E. coli and Klebsiella isolates from humans. Such data and study characteristics were extracted and coded, and the resulting data was analyzed and geographically mapped. RESULTS: Our analysis yielded 1341 reports documenting carbapenem resistance in 40 of 54 nations. Resistance among E. coli was estimated as high (> 5%) in 3, moderate (1-5%) in 8 and low (< 1%) in 14 nations with at least 100 representative isolates from 2010 to 2019, while present in 9 others with insufficient isolates to support estimates. Carbapenem resistance was generally higher among Klebsiella: high in 10 nations, moderate in 6, low in 6, and present in 11 with insufficient isolates for estimates. While much less information was available concerning polymyxins, we found 341 reports from 33 of 54 nations, documenting resistance in 23. Resistance among E. coli was high in 2 nations, moderate in 1 and low in 6, while present in 10 with insufficient isolates for estimates. Among Klebsiella, resistance was low in 8 nations and present in 8 with insufficient isolates for estimates. The most widespread associated genotypes were, for carbapenems, blaOXA-48, blaNDM-1 and blaOXA-181 and, for polymyxins, mcr-1, mgrB, and phoPQ/pmrAB. Overlapping carbapenem and polymyxin resistance was documented in 23 nations. CONCLUSIONS: While numerous data gaps remain, these data show that significant carbapenem resistance is widespread in Africa and polymyxin resistance is also widely distributed, indicating the need to support robust AMR surveillance, antimicrobial stewardship and infection control in a manner that also addresses broader animal and environmental health dimensions.

Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus.

BACKGROUND: On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA. METHODS: An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases. RESULTS: The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports. CONCLUSIONS: Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information.

Vaccine Preparedness for the Next Influenza Pandemic: A Regulatory Perspective.

The response to SARS-CoV-2 demonstrated the tremendous potential of investments in vaccine research and development to impact a global pandemic, resulting in the rapid development and deployment of lifesaving vaccines. However, this unprecedented speed was insufficient to either effectively combat initial waves of the pandemic or adapt in real time to new variants. This review focuses on opportunities from a public health oriented regulatory perspective for enhancing research, development, evaluation, production, and monitoring of safety and effectiveness to facilitate more rapid availability of pandemic influenza vaccines. We briefly review regulatory pathways and processes relevant to pandemic influenza, including how they can be strengthened and globally coordinated. We then focus on what we believe are critical opportunities to provide better approaches, tools, and methods to accelerate and improve vaccine development and evaluation and thus greatly enhance pandemic preparedness. In particular, for the improved vaccines needed to respond to a future influenza pandemic better and more rapidly, moving as much of the development and evaluation process as possible into the pre-pandemic period is critical, including through approval and use of analogous seasonal influenza vaccines with defined immune correlates of protection.

Long Paths in First Passage Percolation on the Complete Graph II. Global Branching Dynamics.

We study the random geometry of first passage percolation on the complete graph equipped with independent and identically distributed positive edge weights. We consider the case where the lower extreme values of the edge weights are highly separated. This model exhibits strong disorder and a crossover between local and global scales. Local neighborhoods are related to invasion percolation that display self-organised criticality. Globally, the edges with relevant edge weights form a barely supercritical Erdos-Rényi random graph that can be described by branching processes. This near-critical behaviour gives rise to optimal paths that are considerably longer than logarithmic in the number of vertices, interpolating between random graph and minimal spanning tree path lengths. Crucial to our approach is the quantification of the extreme-value behavior of small edge weights in terms of a sequence of parameters ( s n ) n ≥ 1 that characterises the different universality classes for first passage percolation on the complete graph. We investigate the case where s n → ∞ with s n = o ( n 1 / 3 ) , which corresponds to the barely supercritical setting. We identify the scaling limit of the weight of the optimal path between two vertices, and we prove that the number of edges in this path obeys a central limit theorem with mean approximately s n log ( n / s n 3 ) and variance s n 2 log ( n / s n 3 ) . Remarkably, our proof also applies to n-dependent edge weights of the form E s n , where E is an exponential random variable with mean 1, thus settling a conjecture of Bhamidi et al. (Weak disorder asymptotics in the stochastic meanfield model of distance. Ann Appl Probab 22(1):29-69, 2012). The proof relies on a decomposition of the smallest-weight tree into an initial part following invasion percolation dynamics, and a main part following branching process dynamics. The initial part has been studied in Eckhoff et al. (Long paths in first passage percolation on the complete graph I. Local PWIT dynamics. Electron. J. Probab. 25:1-45, 2020. 10.1214/20-EJP484); the current paper focuses on the global branching dynamics.

Anaplasma phagocytophilum-induced gene expression in both human neutrophils and HL-60 cells.

Anaplasma phagocytophilum (Ap), the etiologic agent of the tick-borne disease human granulocytic anaplasmosis, is an obligate intracellular pathogen unique in its ability to target and replicate within neutrophils. We define and compare the spectra of host gene expression in response to Ap infection of human neutrophils and of HL-60 cells using long (70-mer)-oligonucleotide array technology. In addition to apoptosis-related genes, genes involved in signaling pathways, transcriptional regulation, immune response, host defense, cell adhesion, and cytoskeleton were modulated in neutrophils infected with Ap. Ap infection affected the same pathways in HL-60 cells but transcriptional changes occurred more slowly and in a reduced spectrum of genes. Gene expression changes detected by microarray were confirmed for randomly selected genes by QRT-PCR and Western blot studies. These studies demonstrate for the first time that the ERK pathway is activated in Ap-infected neutrophils and also define multiple pathways that are activated during intracellular Ap infection, which together serve to prolong the cell survival that is needed to allow bacterial replication and survival in neutrophils, which otherwise would rapidly apoptose.

Carbapenem and colistin resistance in Enterobacteriaceae in Southeast Asia: Review and mapping of emerging and overlapping challenges.

Carbapenem-resistant Enterobacteriaceae infections have spread globally, leaving polymyxins, including colistin, as 'last-resort treatments'. Emerging colistin resistance raises the spectre of untreatable infections. Despite this threat, data remain limited for much of the world, including Southeast Asia where only 3 of 11 nations submitted data on carbapenem and colistin resistance for recent World Health Organization (WHO) reports. To improve our understanding of the challenge, we utilised broad strategies to search for and analyse data on carbapenem and colistin resistance among Escherichia coli and Klebsiella in Southeast Asia. We found 258 studies containing 526 unique reports and document carbapenem-resistant E. coli and Klebsiella in 8 and 9 of 11 nations, respectively. We estimated carbapenem resistance proportions through meta-analysis of extracted data for nations with ≥100 representative isolates. Estimated resistance among Klebsiella was high (>5%) in four nations (Indonesia, Philippines, Thailand and Vietnam), moderate (1-5%) in two nations (Malaysia and Singapore) and low (<1%) in two nations (Cambodia and Brunei). For E. coli, resistance was generally lower but was high in two of seven nations with ≥100 isolates (Indonesia and Myanmar). The most common carbapenemases were NDM metallo-ß-lactamases and OXA ß-lactamases. Despite sparse data, polymyxin resistance was documented in 8 of 11 nations, with mcr-1 being the predominant genotype. Widespread presence of carbapenem and polymyxin resistance, including their overlap in eight nations, represents a continuing risk and increases the threat of infections resistant to both classes. These findings, and remaining data gaps, highlight the urgent need for sufficiently-resourced robust antimicrobial resistance surveillance.

Review and mapping of carbapenem-resistant Enterobacteriaceae in Africa: Using diverse data to inform surveillance gaps.

Carbapenem-resistant Enterobacteriaceae (CRE) are among the most difficult to treat emerging multidrug-resistant organisms. Major limitations exist in surveillance needed to address CRE, particularly in areas with inadequate resources. We utilised optimised strategies to search for data on carbapenem susceptibility of Klebsiella spp. and Escherichia coli from the World Health Organization (WHO) Africa Region. Core data elements were extracted for meta-analysis and mapping. Despite sparse data in existing reviews, 180 documents including 314 reports on susceptibility of E. coli and/or Klebsiella were located, providing information on 31 (66%) of 47 nations. Carbapenem-resistant E. coli or Klebsiella were identified in 22 (71%) of these 31 countries. Crude resistance proportions were estimated for nations with >100 representative isolates. Median resistance among E. coli was <1% in 11 (61%) of 18 nations meeting criteria, 1-5% in 6 nations (33%) and >5% in 1 nation (6%). For Klebsiella spp., corresponding figures were <1% in 10 (67%) of 15 nations, 1-5% in 3 nations (20%) and >5% in 2 nations (13%). Comprehensive, customised search strategies with analysis and mapping of defined data elements provide an enhanced view of carbapenem-resistant E. coli and Klebsiella in Africa. These CRE are widely distributed and are generally present at low to moderate levels. Whilst use of diverse and largely clinically derived data has limitations and cannot substitute for surveillance, it can enhance situational awareness. The approaches utilised can support improved risk understanding and prioritisation and may be applied to other micro-organisms and areas where surveillance remains inadequate.

Transmission of West Nile virus through blood transfusion in the United States in 2002.

BACKGROUND: During the 2002 West Nile virus epidemic in the United States, patients were identified whose West Nile virus illness was temporally associated with the receipt of transfused blood and blood components. METHODS: Patients with laboratory evidence of recent West Nile virus infection within four weeks after receipt of a blood component from a donor with viremia were considered to have a confirmed transfusion-related infection. We interviewed the donors of these components, asking them whether they had had symptoms compatible with the presence of a viral illness before or after their donation; blood specimens retained from the time of donation and collected at follow-up were tested for West Nile virus. RESULTS: Twenty-three patients were confirmed to have acquired West Nile virus through transfused leukoreduced and nonleukoreduced red cells, platelets, or fresh-frozen plasma. Of the 23 recipients, 10 (43 percent) were immunocompromised owing to transplantation or cancer and 8 (35 percent) were at least 70 years of age. Immunocompromised recipients tended to have longer incubation periods than nonimmunocompromised recipients and infected persons in mosquito-borne community outbreaks. Sixteen donors with evidence of viremia at donation were linked to the 23 infected recipients; of these donors, 9 reported viral symptoms before or after donation, 5 were asymptomatic, and 2 were lost to follow-up. Fever, new rash, and painful eyes were independently associated with being an implicated donor with viremia rather than a donor without viremia. All 16 donors were negative for West Nile virus-specific IgM antibody at donation. CONCLUSIONS: Transfused red cells, platelets, and fresh-frozen plasma can transmit West Nile virus. Screening of potential donors with the use of nucleic acid-based assays for West Nile virus may reduce this risk.

Transmission of West Nile virus from an organ donor to four transplant recipients.

BACKGROUND: In August 2002, fever and mental-status changes developed in recipients of organs from a common donor. Transmission of West Nile virus through organ transplantation was suspected. METHODS: We reviewed medical records, conducted interviews, and collected blood and tissue samples for testing with a variety of assays. Persons who donated blood to the organ donor and associated blood components were identified and tested for West Nile virus. RESULTS: We identified West Nile virus infection in the organ donor and in all four organ recipients. Encephalitis developed in three of the organ recipients, and febrile illness developed in one. Three recipients became seropositive for West Nile virus IgM antibody; the fourth recipient had brain tissue that was positive for West Nile virus by isolation and nucleic acid and antigen assays. Serum specimens obtained from the organ donor before and immediately after blood transfusions showed no evidence of West Nile virus; however, serum and plasma samples obtained at the time of organ recovery were positive on viral nucleic acid testing and viral culture. The organ donor had received blood transfusions from 63 donors. A review of blood donors and follow-up testing identified one donor who had viremia at the time of donation and who became seropositive for West Nile virus IgM antibodies during the next two months. CONCLUSIONS: Our investigation of this cluster documents the transmission of West Nile virus by organ transplantation. Organ recipients receiving immunosuppressive drugs may be at high risk for severe disease after West Nile virus infection. Blood transfusion was the probable source of the West Nile virus viremia in the organ donor.

A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.