Climbing fibers provide essential instructive signals for associative learning.

Supervised learning depends on instructive signals that shape the output of neural circuits to support learned changes in behavior. Climbing fiber (CF) inputs to the cerebellar cortex represent one of the strongest candidates in the vertebrate brain for conveying neural instructive signals. However, recent studies have shown that Purkinje cell stimulation can also drive cerebellar learning and the relative importance of these two neuron types in providing instructive signals for cerebellum-dependent behaviors remains unresolved. In the present study we used cell-type-specific perturbations of various cerebellar circuit elements to systematically evaluate their contributions to delay eyeblink conditioning in mice. Our findings reveal that, although optogenetic stimulation of either CFs or Purkinje cells can drive learning under some conditions, even subtle reductions in CF signaling completely block learning to natural stimuli. We conclude that CFs and corresponding Purkinje cell complex spike events provide essential instructive signals for associative cerebellar learning.

Incidence of typhoid fever in Burkina Faso, Democratic Republic of the Congo, Ethiopia, Ghana, Madagascar, and Nigeria (the Severe Typhoid in Africa programme): a population-based study.

BACKGROUND: Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines. METHODS: A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model. FINDINGS: 27 866 (33·8%) of 82 491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27 544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100 000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility. INTERPRETATION: High disease incidence (ie, >100 per 100 000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices. FUNDING: The Bill & Melinda Gates Foundation.

Structural and Functional Organization of Visual Responses in the Inferior Olive of Larval Zebrafish.

The olivo-cerebellar system plays an important role in vertebrate sensorimotor control. Here, we investigate sensory representations in the inferior olive (IO) of larval zebrafish and their spatial organization. Using single-cell labeling of genetically identified IO neurons, we find that they can be divided into at least two distinct groups based on their spatial location, dendritic morphology, and axonal projection patterns. In the same genetically targeted population, we recorded calcium activity in response to a set of visual stimuli using two-photon imaging. We found that most IO neurons showed direction-selective and binocular responses to visual stimuli and that the functional properties were spatially organized within the IO. Light-sheet functional imaging that allowed for simultaneous activity recordings at the soma and axonal level revealed tight coupling between functional properties, soma location, and axonal projection patterns of IO neurons. Taken together, our results suggest that anatomically defined classes of IO neurons correspond to distinct functional types, and that topographic connections between IO and cerebellum contribute to organization of the cerebellum into distinct functional zones.

The cerebellum.

The cerebellum, that stripey 'little brain', sits at the back of your head, under your visual cortex, and contains more than half of the neurons in your entire nervous system. The cerebellum is highly conserved across vertebrates, and its evolutionary expansion has tended to proceed in concert with expansion of cerebral cortex. The crystalline neuronal architecture of the cerebellar cortex was first described by Cajal a century ago, and its functional connectivity was elucidated in exquisite anatomical and physiological detail by the mid-20th century. The ability to clearly identify molecularly distinct cerebellar cell types that constitute discrete circuit elements is perhaps unparalleled among brain areas, even within the context of modern circuit neuroscience. Although traditionally thought of as primarily a motor structure, the cerebellum is highly interconnected with diverse brain areas and, as I will explain in this Primer, is well-poised to influence a wide range of motor and cognitive functions.

Myomatrix arrays for high-definition muscle recording.

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ('Myomatrix arrays') that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a 'motor unit,' during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.

Synaptic mechanisms for associative learning in the cerebellar nuclei.

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.

Assessing the global risk of typhoid outbreaks caused by extensively drug resistant Salmonella Typhi.

Since its emergence in 2016, extensively drug resistant (XDR) Salmonella enterica serovar Typhi (S. Typhi) has become the dominant cause of typhoid fever in Pakistan. The establishment of sustained XDR S. Typhi transmission in other countries represents a major public health threat. We show that the annual volume of air travel from Pakistan strongly discriminates between countries that have and have not imported XDR S. Typhi in the past, and identify a significant association between air travel volume and the rate of between-country movement of the H58 haplotype of S. Typhi from fitted phylogeographic models. Applying these insights, we analyze flight itinerary data cross-referenced with model-based estimates of typhoid fever incidence to identify the countries at highest risk of importation and sustained onward transmission of XDR S. Typhi. Future outbreaks of XDR typhoid are most likely to occur in countries that can support efficient local S. Typhi transmission and have strong travel links to regions with ongoing XDR typhoid outbreaks (currently Pakistan). Public health activities to track and mitigate the spread of XDR S. Typhi should be prioritized in these countries.

The Challenge Non-Typhoidal Salmonella (CHANTS) Consortium: Development of a non-typhoidal Salmonella controlled human infection model: Report from a consultation group workshop, 05 July 2022, London, UK.

Invasive non-typhoidal Salmonella disease (iNTS) is a major cause of morbidity and mortality globally, particularly as a cause of bloodstream infection in children and immunocompromised adults in sub-Saharan Africa. Vaccines to prevent non-typhoidal Salmonella (NTS) would represent a valuable public health tool in this setting to avert cases and prevent expansion of antimicrobial resistance. Several NTS and combination typhoidal-NTS vaccine candidates are in early-stage development, although the pathway to licensure is unclear due to challenges in conducting large phase III field trials. Controlled human infection models (CHIM) present an opportunity to accelerate vaccine development for a range of enteric pathogens. Several recent typhoidal Salmonella CHIMs have been conducted safely and have played pivotal roles in progressing vaccine candidates to pre-qualification and licensure. The Challenge Non-Typhoidal Salmonella (CHANTS) consortium has been formed with funding from the Wellcome Trust, to deliver the first NTS CHIM, which can act as a platform for future vaccine evaluation. This paper reports the conclusions of a consultation group workshop convened with key stakeholders. The aims of this meeting were to: (1) define the rationale for an NTS CHIM (2) map the NTS vaccine pipeline (3) refine study design and (4) establish potential future use cases.

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. Funding: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

Salmonella Typhi (Typhi) is a type of bacteria that causes typhoid fever. More than 110,000 people die from this disease each year, predominantly in areas of sub-Saharan Africa and South Asia with limited access to safe water and sanitation. Clinicians use antibiotics to treat typhoid fever, but scientists worry that the spread of antimicrobial-resistant Typhi could render the drugs ineffective, leading to increased typhoid fever mortality. The World Health Organization has prequalified two vaccines that are highly effective in preventing typhoid fever and may also help limit the emergence and spread of resistant Typhi. In low resource settings, public health officials must make difficult trade-off decisions about which new vaccines to introduce into already crowded immunization schedules. Understanding the local burden of antimicrobial-resistant Typhi and how it is spreading could help inform their actions. The Global Typhoid Genomics Consortium analyzed 13,000 Typhi genomes from 110 countries to provide a global overview of genetic diversity and antimicrobial-resistant patterns. The analysis showed great genetic diversity of the different strains between countries and regions. For example, the H58 Typhi variant, which is often drug-resistant, has spread rapidly through Asia and Eastern and Southern Africa, but is less common in other regions. However, distinct strains of other drug-resistant Typhi have emerged in other parts of the world. Resistance to the antibiotic ciprofloxacin was widespread and accounted for over 85% of cases in South Africa. Around 70% of Typhi from Pakistan were extensively drug-resistant in 2020, but these hard-to-treat variants have not yet become established elsewhere. Variants that are resistant to both ciprofloxacin and ceftriaxone have been identified, and azithromycin resistance has also appeared in several different variants across South Asia. The Consortium's analyses provide valuable insights into the global distribution and transmission patterns of drug-resistant Typhi. Limited genetic data were available fromseveral regions, but data from travel-associated cases helped fill some regional gaps. These findings may help serve as a starting point for collective sharing and analyses of genetic data to inform local public health action. Funders need to provide ongoing supportto help fill global surveillance data gaps.

What Came First: Malnutrition or Severe Disease?

A 20-year-old female with depression presented to the emergency department with chronic weight loss, weakness, fatigue, hair loss, rash, palpitations, and 2 weeks of cough. Initial history revealed that she had disordered eating habits with dietary restriction, experienced a 50-pound unintentional weight loss over 2 years despite reported adherence to nutritional supplementation, and had a normal gastrointestinal workup. On examination, she was markedly cachectic with a BMI of 10.3kg/m2 and hypotensive (84/69 mmHg). Her cardiovascular examination revealed a regular rate and rhythm without a murmur. Her breath sounds were diminished in the upper lobes bilaterally. A skin examination showed diffuse hair loss, skin breakdown, and peeling with a tender, erythematous, papular rash over the bilateral ankles, and nonpitting edema. A chest radiograph showed a right upper lobe opacity and lucent lesions in the left proximal humerus. A focused assessment with sonography for trauma examination showed a large pericardial effusion. Chest computed tomography revealed a right upper lobe opacity with an associated cavitation. Though she began improving with rifampin, isoniazid, pyrazinamide, ethambutol, levofloxacin, azithromycin, and nutritional rehabilitation, her clinical course was complicated by an acute worsening nearly 1 month into her hospitalization with persistent high fevers, worsening cough, development of a murmur, and worsening consolidation on chest computed tomography. Adolescent Medicine, Infectious Diseases, Gastroenterology, and Allergy and Immunology were consulted to guide the diagnostic evaluation and management of this patient's complex clinical course.

Review of Toxocariasis at a Children's Hospital Prompting Need for Public Health Interventions.

BACKGROUND: Toxocariasis, caused the by dog and cat roundworm, is one of the most common zoonotic helminth infections in the United States and can lead to severe lifelong morbidity in children. Although historical seroprevalence studies have identified a high frequency of toxocariasis regionally in the United States, there are few studies linking epidemiology and clinical disease in children. The study objective was to examine the contemporary epidemiology of pediatric toxocariasis within an endemic US region. METHODS: We conducted an epidemiologic study analyzing children diagnosed with toxocariasis presenting to a tertiary pediatric hospital in Texas from 2010 to 2021. We examined risk factors and performed a geospatial analysis, including a comparative analysis of human cases and locations of surrendered infected stray animals in the same region. RESULTS: Children diagnosed with toxocariasis were most commonly of Hispanic/Latino ethnicity (30/46; 65%), white race (41/45; 91%) and receiving Medicaid (34/44, 77%). Many infected children had contact with dogs or cats. Ocular toxocariasis was associated with a lack of peripheral eosinophilia ( P < 0.001). No other Toxocara syndromes were associated with defined absolute eosinophil count levels. Post-treatment resolution of eosinophilia was variable, ranging from 1 to 172 weeks. A Toxocara hotspot was identified in northeast Houston, comprising one of the lowest median household incomes in the region. CONCLUSIONS: Toxocariasis is a devastating zoonotic infection in children living in the US. As it is not a reportable disease, the true burden remains unknown. It is critical to increase awareness of toxocariasis to direct public health interventions and ultimately reduce Toxocara -induced morbidity in US children.

Using Typhoid Conjugate Vaccines to Prevent Disease, Promote Health Equity, and Counter Drug-Resistant Typhoid Fever.

Typhoid fever is a serious disease that disproportionately impacts children in low-resource settings in sub-Saharan Africa, South and Southeast Asia, and the Western Pacific. The prevalence of antimicrobial-resistant strains of S. Typhi continue to increase worldwide. Two safe, effective, and cost-effective typhoid conjugate vaccines (TCVs) are World Health Organization-prequalified for the prevention of typhoid fever in children as young as 6 months. Typhoid conjugate vaccines have proven effectiveness in preventing drug-resistant S. Typhi and have been deployed successfully in outbreak response and routine immunization scenarios. Broad and equitable distribution of TCVs is essential to combat the spread and potentially devastating consequences of typhoid fever. It is vital to empower decision-makers in typhoid-endemic countries to introduce TCVs and for leaders to embrace this critical tool to prevent typhoid fever, slow the spread of drug-resistant S. Typhi strains, promote health equity, and save lives.

Unlocking the Potential of Genomic Data to Inform Typhoid Fever Control Policy: Supportive Resources for Genomic Data Generation, Analysis, and Visualization.

The global response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic demonstrated the value of timely and open sharing of genomic data with standardized metadata to facilitate monitoring of the emergence and spread of new variants. Here, we make the case for the value of Salmonella Typhi (S. Typhi) genomic data and demonstrate the utility of freely available platforms and services that support the generation, analysis, and visualization of S. Typhi genomic data on the African continent and more broadly by introducing the Africa Centres for Disease Control and Prevention's Pathogen Genomics Initiative, SEQAFRICA, Typhi Pathogenwatch, TyphiNET, and the Global Typhoid Genomics Consortium.

Myomatrix arrays for high-definition muscle recording.

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

Multifactor dimensionality reduction method identifies novel SNP interactions in the WNT protein interaction networks that are associated with recurrence risk in colorectal cancer.

Background: Interactions among genetic variants are rarely studied but may explain a part of the variability in patient outcomes. Objectives: In this study, we aimed to identify 1 to 3 way interactions among SNPs from five Wnt protein interaction networks that predict the 5-year recurrence risk in a cohort of stage I-III colorectal cancer patients. Methods: 423 patients recruited to the Newfoundland Familial Colorectal Cancer Registry were included. Five Wnt family member proteins (Wnt1, Wnt2, Wnt5a, Wnt5b, and Wnt11) were selected. The BioGRID database was used to identify the proteins interacting with each of these proteins. Genotypes of the SNPs located in the interaction network genes were retrieved from a genome-wide SNP genotype data previously obtained in the patient cohort. The GMDR 0.9 program was utilized to examine 1-, 2-, and 3-SNP interactions using a 5-fold cross validation step. Top GMDR 0.9 models were assessed by permutation testing and, if significant, prognostic associations were verified by multivariable logistic regression models. Results: GMDR 0.9 has identified novel 1, 2, and 3-way SNP interactions associated with 5-year recurrence risk in colorectal cancer. Nine of these interactions were multi loci interactions (2-way or 3-way). Identified interaction models were able to distinguish patients based on their 5-year recurrence-free status in multivariable regression models. The significance of interactions was the highest in the 3-SNP models. Several of the identified SNPs were eQTLs, indicating potential biological roles of the genes they were associated with in colorectal cancer recurrence. Conclusions: We identified novel interacting genetic variants that associate with 5-year recurrence risk in colorectal cancer. A significant portion of the genes identified were previously linked to colorectal cancer pathogenesis or progression. These variants and genes are of interest for future functional and prognostic studies. Our results provide further evidence for the utility of GMDR models in identifying novel prognostic biomarkers and the biological importance of the Wnt pathways in colorectal cancer.

Pilot Study of the Effects of Paced Breathing on Measures of Convergent and Divergent Thinking.

BACKGROUND: The ability of the autonomic nervous system's stress response to impair aspects of cognitive flexibility is known. However, the ability to modulate the sympathetic response and improve these cognitive impairments via nonpharmacological intervention, such as paced breathing (PB), requires further investigation. OBJECTIVE: To better elucidate the effects of PB on cognition. METHOD: We employed a PB protocol in a total of 52 healthy men and women and measured performance on convergent and divergent cognitive tasks, perceived stress, and physiological measures (eg, blood pressure, heart rate). Participants attended two experimental sessions consisting of either PB or normal breathing followed by cognitive assessments including convergent (compound remote associate, anagram) and divergent (alternate use, fluency) tasks. Experiment 2 consisted of more difficult versions of cognitive tasks compared with Experiment 1. RESULTS: In Experiment 1, PB significantly reduced the female participants' systolic and diastolic blood pressure immediately after the breathing protocol without affecting their cognition. In Experiment 2, PB significantly reduced perceived stress immediately after the breathing protocol, regardless of sex. There was no effect on cognition in Experiment 2, but a correlation was observed between perceived stress change and anagram number solved change. CONCLUSION: While PB modulates sympathetic activity in females, there was a lack of improvement in cognitive flexibility performance. At least for a single trial of PB, cognitive flexibility did not improve.

Examining SNP-SNP interactions and risk of clinical outcomes in colorectal cancer using multifactor dimensionality reduction based methods.

Background: SNP interactions may explain the variable outcome risk among colorectal cancer patients. Examining SNP interactions is challenging, especially with large datasets. Multifactor Dimensionality Reduction (MDR)-based programs may address this problem. Objectives: 1) To compare two MDR-based programs for their utility; and 2) to apply these programs to sets of MMP and VEGF-family gene SNPs in order to examine their interactions in relation to colorectal cancer survival outcomes. Methods: This study applied two data reduction methods, Cox-MDR and GMDR 0.9, to study one to three way SNP interactions. Both programs were run using a 5-fold cross validation step and the top models were verified by permutation testing. Prognostic associations of the SNP interactions were verified using multivariable regression methods. Eight datasets, including SNPs from MMP family genes (n = 201) and seven sets of VEGF-family interaction networks (n = 1,517 SNPs) were examined. Results: ∼90 million potential interactions were examined. Analyses in the MMP and VEGF gene family datasets found several novel 1- to 3-way SNP interactions. These interactions were able to distinguish between the patients with different outcome risks (regression p-values 0.03-2.2E-09). The strongest association was detected for a 3-way interaction including CHRM3.rs665159_EPN1.rs6509955_PTGER3.rs1327460 variants. Conclusion: Our work demonstrates the utility of data reduction methods while identifying potential prognostic markers in colorectal cancer.

Typhoid fever control in the 21st century: where are we now?

PURPOSE OF REVIEW: Momentum for achieving widespread control of typhoid fever has been growing over the past decade. Typhoid conjugate vaccines represent a potentially effective tool to reduce the burden of disease in the foreseeable future and new data have recently emerged to better frame their use-case. RECENT FINDINGS: We describe how antibiotic resistance continues to pose a major challenge in the treatment of typhoid fever, as exemplified by the emergence of azithromycin resistance and the spread of Salmonella Typhi strains resistant to third-generation cephalosporins. We review efficacy and effectiveness data for TCVs, which have been shown to have high-level efficacy (≥80%) against typhoid fever in diverse field settings. Data from randomized controlled trials and observational studies of TCVs are reviewed herein. Finally, we review data from multicountry blood culture surveillance studies that have provided granular insights into typhoid fever epidemiology. These data are becoming increasingly important as countries decide how best to introduce TCVs into routine immunization schedules and determine the optimal delivery strategy. SUMMARY: Continued advocacy is needed to address the ongoing challenge of typhoid fever to improve child health and tackle the rising challenge of antimicrobial resistance.