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Effective infectious disease surveillance in high-risk regions is critical for clinical care and pandemic preemption; however, few clinical diagnostics are available for the wide range of potential human pathogens. Here, we conduct unbiased metagenomic sequencing of 593 samples from febrile Nigerian patients collected in three settings: i) population-level surveillance of individuals presenting with symptoms consistent with Lassa Fever (LF); ii) real-time investigations of outbreaks with suspected infectious etiologies; and iii) undiagnosed clinically challenging cases. We identify 13 distinct viruses, including the second and third documented cases of human blood-associated dicistrovirus, and a highly divergent, unclassified dicistrovirus that we name human blood-associated dicistrovirus 2. We show that pegivirus C is a common co-infection in individuals with LF and is associated with lower Lassa viral loads and favorable outcomes. We help uncover the causes of three outbreaks as yellow fever virus, monkeypox virus, and a noninfectious cause, the latter ultimately determined to be pesticide poisoning. We demonstrate that a local, Nigerian-driven metagenomics response to complex public health scenarios generates accurate, real-time differential diagnoses, yielding insights that inform policy. Applying metagenomics, the authors identify 13 viruses in febrile Nigerians, including a new dicistrovirus. Real-time phylogenetics spurred national vaccination campaigns, while retrospective analysis linked pegivirus C co-infections to favorable Lassa Fever outcomes.

Haptic perception is an active process that provides an awareness of objects that are encountered as an organism scans its environment. In contrast to the sensation of touch produced by contact with an object, the perception of object location arises from the interpretation of tactile signals in the context of the changing configuration of the body. A discrete sensory representation and a low number of degrees of freedom in the motor plant make the ethologically prominent rat vibrissa system an ideal model for the study of the neuronal computations that underlie this perception. We found that rats with only a single vibrissa can combine touch and movement to distinguish the location of objects that vary in angle along the sweep of vibrissa motion. The patterns of this motion and of the corresponding behavioral responses show that rats can scan potential locations and decide which location contains a stimulus within 150 ms. This interval is consistent with just one to two whisk cycles and provides constraints on the underlying perceptual computation. Our data argue against strategies that do not require the integration of sensory and motor modalities. The ability to judge angular position with a single vibrissa thus connects previously described, motion-sensitive neurophysiological signals to perception in the behaving animal.

The discovery of a postsynaptically expressed form of cerebellar parallel fiber-Purkinje cell long-term potentiation (LTP) raises the question whether this is the long-sought resetting mechanism for long-term depression (LTD). Extracellular monitoring of PC spikes enables stable prolonged recordings of parallel fiber-Purkinje cell synaptic efficacy. LTD, saturated by repeated induction protocols, can be reversed by a single round of postsynaptic LTP or nitric oxide (NO), enabling LTD to be reinduced. Conversely, after postsynaptic LTP has been saturated, one round of LTD permits fresh postsynaptic LTP. By contrast, after saturation of LTD, induction of presynaptic LTP or application of forskolin leaves LTD still saturated. Likewise, presynaptic LTP cannot be reversed by LTD. Therefore postsynaptic LTP mediated by NO without postsynaptic Ca2+elevation, unlike presynaptic LTP mediated by cAMP, is a true counterbalance to LTD mediated by coincidence of NO plus postsynaptic Ca2+.

Fifty patients with unexplained fever and poor outcomes presented at Irrua Specialist Teaching Hospital (ISTH) in Edo State, Nigeria, an area endemic for Lassa fever, between September 2018 - January 2019. After ruling out Lassa fever, plasma samples from these epidemiologically-linked cases were sent to the African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Ede, Osun State, Nigeria, where we carried out metagenomic sequencing which implicated yellow fever virus (YFV) as the etiology of this outbreak. Twenty-nine of the 50 samples were confirmed positive for YFV by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), 14 of which resulted in genome assembly. Maximum likelihood phylogenetic analysis revealed that these YFV sequences formed a tightly clustered clade more closely related to sequences from Senegal than sequences from earlier Nigerian isolates, suggesting that the YFV clade responsible for this outbreak in Edo State does not descend directly from the Nigerian YFV outbreaks of the last century, but instead reflects a broader diversity and dynamics of YFV in West Africa. Here we demonstrate the power of metagenomic sequencing for identifying ongoing outbreaks and their etiologies and informing real-time public health responses, resulting in accurate and prompt disease management and control.

Developing and deploying new diagnostic tests are difficult, but the need to do so in response to a rapidly emerging pandemic such as COVID-19 is crucially important. During a pandemic, laboratories play a key role in helping healthcare providers and public health authorities detect active infection, a task most commonly achieved using nucleic acid-based assays. While the landscape of diagnostics is rapidly evolving, PCR remains the gold-standard of nucleic acid-based diagnostic assays, in part due to its reliability, flexibility and wide deployment. To address a critical local shortage of testing capacity persisting during the COVID-19 outbreak, our hospital set up a molecular-based laboratory developed test (LDT) to accurately and safely diagnose SARS-CoV-2. We describe here the process of developing an emergency-use LDT, in the hope that our experience will be useful to other laboratories in future outbreaks and will help to lower barriers to establishing fast and accurate diagnostic testing in crisis conditions.

We report here the use of metagenomic sequencing to identify and characterize yellow fever virus (YFV) in a cluster of undiagnosed febrile patients from Edo State, Nigeria. Yellow fever, an acute mosquito-borne viral haemorrhagic fever, re-emerged in Nigeria in 2017 after decades of relative control. Once a major public health concern in the region, the prolonged absence of yellow fever has left a gap in knowledge about circulating virus and lowered clinical suspicion for a disease whose spectrum overlaps with endemic infections (e.g., malaria and Lassa fever). In this context, metagenomic sequencing can be a powerful tool for identifying and tracking pathogens causing infectious disease. Footnotes * Author affiliations updated

Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (KATP) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the KATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the KATP channel blocker glibenclamide. These results suggest that activation of hypothalamic KATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.

An increase in Lassa fever cases was identified in Nigeria this year. In this analysis of the infecting viruses, the predominant mode of transmission appeared to be multiple insertions from local rodent populations rather than sustained person-to-person spread.

Lassa virus (LASV) is the causative agent of Lassa fever (LF), an often-fatal hemorrhagic disease. LF is endemic in Nigeria, Sierra Leone and other West African countries. Diagnosis of LASV infection is challenged by the genetic diversity of the virus, which is greatest in Nigeria. The ReLASV Pan-Lassa Antigen Rapid Test (Pan-Lassa RDT) is a point-of-care, in vitro diagnostic test that utilizes a mixture of polyclonal antibodies raised against recombinant nucleoproteins of representative strains from the three most prevalent LASV lineages (II, III and IV). We compared the performance of the Pan-LASV RDT to available quantitative PCR (qPCR) assays during the 2018 LF outbreak in Nigeria. For patients with acute LF (RDT positive, IgG/IgM negative) during initial screening, RDT performance was 83.3% sensitivity and 92.8% specificity when compared to composite results of two qPCR assays. 100% of samples that gave Ct values below 22 on both qPCR assays were positive on the Pan-Lassa RDT. There were significantly elevated case fatality rates and elevated liver transaminase levels in subjects whose samples were RDT positive compared to RDT negative.

Atologous transplantation with peripheral blood stem cells (PBSC) results in faster haematopoietic-cell repopulation than with bone marrow. We prospectively compared bone marrow and PBSC for allogeneic transplantation. Adult HLA-identical sibling donors provided bone marrow and lenograstim-mobilised PBSC. 39 patients with malignant haematological disorders were infused with either bone marrow (n=19) or PBSC (n=20) after standard conditioning regimens in a double-blind, randomised fashion. The identity of the infused products for all patients remained masked until 1 year after the last patient had received transplantation. The PBSC group had significantly faster neutrophil recovery to 0·5 × 109/L (median 17·5 vs 23 days, p=0·002), and platelet recovery to 20 × 109/L (median 11 vs 18 days, p<0·0001) and to 50 × 109/L (median 20·5 vs 27 days, p=0·02) than the bone-marrow group. PBSC patients were discharged from hospital earlier than were bone-marrow patients (median 26 vs 31 days, p=0·01). At 4 weeks after transplantation, absolute lymphocytes (0·48 vs 0·63, p=0·08) and CD25 cells (0·04 vs 0·08, p=0·007) were higher in the PBSC group, and the proportion of patients with absolute lymphopenia (74% vs 33%, p=0·03) and CD4 lymphopenia (59% vs 24%, p=0·05) was significantly higher in the bone-marrow group. There was no significant difference in the occurrence of acute or chronic graft-versus-host disease and overall survival. The probability of relapse was significantly higher in the bone-marrow group than in the PBSC group (p=0·01); all five relapses occurred among bone-marrow recipients. Our small study indicates that PBSCs are better than bone marrow for allogeneic transplantation from HLA-identical siblings in terms of faster haematopoietic and immune recovery, and have the potential to reduce disease recurrence.