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We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R. [ABSTRACT FROM AUTHOR]

Aims: Salmonella enterica is a leading cause of acute enteritis in people, and dairy cattle are an important reservoir of this pathogen. The objective of this study was to analyse serotype and anti‐microbial resistance trends of Salmonella isolated from dairy cattle in the United States between 2007 and 2021. Methods and Results: We collected data for bovine Salmonella isolates obtained from samples submitted to Cornell University's Animal Health Diagnostic Center (AHDC). We analysed 5114 isolates for serotype trends, and a subset of 2521 isolates tested for anti‐microbial susceptibility were analysed for resistance trends. The most frequently identified serotypes were Salmonella Cerro, Dublin, Typhimurium, Montevideo, 4,[5],12:i:‐, and Newport. Among these serotypes, a Cochran–Armitage trend test determined there was a significant increase in the proportion of isolates serotyped as Salmonella Dublin (p < 0.0001) and Montevideo (p < 0.0001) over time. There was a significant decrease in the proportion of isolates serotyped as Salmonella Cerro (p < 0.0001), Typhimurium (p < 0.0001), and Newport (p < 0.0001). For the anti‐microbial resistance (AMR) analysis, we found an overall increase in the proportion of multi‐drug‐resistant isolates over time (p = 0.009). There was a significant increase in the proportion of isolates resistant to ampicillin (p = 0.007), florfenicol (p = 0.0002), and ceftiofur (p < 0.0001) and a marginal increase in resistance to enrofloxacin (p = 0.05). There was a significant decrease in the proportion of isolates resistant to spectinomycin (p = 0.0002), trimethoprim/sulphamethoxazole (p = 0.01), sulphadimethoxine (p = 0.003), neomycin (p < 0.0001), and gentamicin (p = 0.0002). Conclusions: Our results provide evidence of an increase in resistance to key anti‐microbial agents, although the observed trends were driven by the sharp increase in the proportion of Salmonella Dublin isolates over time. [ABSTRACT FROM AUTHOR]

Global emergence of ciprofloxacin‐resistant ST198 Salmonella Kentucky poses an important public health threat. While conducting Salmonella surveillance among wildlife patients admitted to our veterinary medical teaching hospital in central New York, we isolated multidrug‐resistant (MDR) ST198 Salmonella Kentucky from an American black bear (Ursus americanus) in September 2020. The isolate was phenotypically resistant to numerous antimicrobial agents, including ceftriaxone and ciprofloxacin, and several antimicrobial resistance genes and mutational resistance determinants were detected. Between April and July 2021, the same strain of MDR ST198 Salmonella Kentucky was also isolated from seven other wildlife patients and multiple hospital environmental locations, suggesting nosocomial transmission. Ciprofloxacin resistance is conferred by triple point mutations in the quinolone resistance‐determining regions (QRDRs), a genotypic profile indicative of Clade ST198.2. To our knowledge, this is the first report of this ciprofloxacin‐resistant clade being identified in animals or animal products in the United States. Timely resolution of the outbreak was achieved following efforts to further enhance environmental disinfection protocols and biosecurity measures at the hospital, with no known cases or positive environmental samples after July 2021. [ABSTRACT FROM AUTHOR]

The hypothalamic paraventricular nucleus (PVN) is essential to peripheral chemoreflex neurocircuitry, but the specific efferent pathways utilized are not well defined. The PVN sends dense projections to the nucleus tractus solitarii (nTS), which exhibits neuronal activation following a hypoxic challenge. We hypothesized that nTS‐projecting PVN (PVN‐nTS) neurons contribute to hypoxia‐induced nTS neuronal activation and cardiorespiratory responses. To selectively target PVN‐nTS neurons, rats underwent bilateral nTS nanoinjection of retrogradely transported adeno‐associated virus (AAV) driving Cre recombinase expression. We then nanoinjected into PVN AAVs driving Cre‐dependent expression of Gq or Gi designer receptors exclusively activated by designer drugs (DREADDs) to test the degree that selective activation or inhibition, respectively, of the PVN‐nTS pathway affects the hypoxic ventilatory response (HVR) of conscious rats. We used immunohistochemistry for Fos and extracellular recordings to examine how DREADD activation influences PVN‐nTS neuronal activation by hypoxia. Pathway activation enhanced the HVR at moderate hypoxic intensities and increased PVN and nTS Fos immunoreactivity in normoxia and hypoxia. In contrast, PVN‐nTS inhibition reduced both the HVR and PVN and nTS neuronal activation following hypoxia. To further confirm selective pathway effects on central cardiorespiratory output, rats underwent hypoxia before and after bilateral nTS nanoinjections of C21 to activate or inhibit PVN‐nTS terminals. PVN terminal activation within the nTS enhanced tachycardic, sympathetic and phrenic (PhrNA) nerve activity responses to hypoxia whereas inhibition attenuated hypoxia‐induced increases in nTS neuronal action potential discharge and PhrNA. The results demonstrate the PVN‐nTS pathway enhances nTS neuronal activation and is necessary for full cardiorespiratory responses to hypoxia. Key points: The hypothalamic paraventricular nucleus (PVN) contributes to peripheral chemoreflex cardiorespiratory responses, but specific PVN efferent pathways are not known.The nucleus tractus solitarii (nTS) is the first integration site of the peripheral chemoreflex, and the nTS receives dense projections from the PVN.Selective GqDREADD activation of the PVN‐nTS pathway was shown to enhance ventilatory responses to hypoxia and activation (Fos immunoreactivity (IR)) of nTS neurons in conscious rats, augmenting the sympathetic and phrenic nerve activity (SSNA and PhrNA) responses to hypoxia in anaesthetized rats.Selective GiDREADD inhibition of PVN‐nTS neurons attenuates ventilatory responses, nTS neuronal Fos‐IR, action potential discharge and PhrNA responses to hypoxia.These results demonstrate that a projection from the PVN to the nTS is critical for full chemoreflex responses to hypoxia. [ABSTRACT FROM AUTHOR]

Background: There is little information on the epidemiology of enteric pathogens in Lebanon, a low- and middle-income country that suffers from a myriad of public health challenges. To address this knowledge gap, we aimed to assess the prevalence of enteric pathogens, identify risk factors and seasonal variations, and describe associations between pathogens among diarrheic patients in the Lebanese community. Methodology and principal findings: A multicenter cross-sectional community-based study was conducted in the north of Lebanon. Stool samples were collected from 360 outpatients suffering from acute diarrhea. Based on fecal examination using the BioFire® FilmArray® Gastrointestinal Panel assay, the overall prevalence of enteric infections was 86.1%. Enteroaggregative Escherichia coli (EAEC) was the most frequently identified (41.7%), followed by enteropathogenic E. coli (EPEC) (40.8%) and rotavirus A (27.5%). Notably, two cases of Vibrio cholerae were identified, while Cryptosporidium spp. (6.9%) was the most common parasitic agent. Overall, 27.7% (86/310) of the cases were single infections, and the majority, 73.3% (224/310), were mixed infections. Multivariable logistic regression models showed that enterotoxigenic E. coli (ETEC) and rotavirus A infections were significantly more likely to occur in the fall and winter compared to the summer. Rotavirus A infections significantly decreased with age but increased in patients living in rural areas or suffering from vomiting. We identified strong associations in the co-occurrence of EAEC, EPEC, and ETEC infections and a higher percentage of rotavirus A and norovirus GI/GII infections among EAEC-positive cases. Conclusions: Several of the enteric pathogens reported in this study are not routinely tested in Lebanese clinical laboratories. However, anecdotal evidence suggests that diarrheal diseases are on the rise due to widespread pollution and the deterioration of the economy. Therefore, this study is of paramount importance to identify circulating etiologic agents and prioritize dwindling resources to control them and limit outbreaks in the future. [ABSTRACT FROM AUTHOR]

We recently showed that in male rats, orexin contributes to the hypoxic ventilatory response (HVR), with a stronger effect in the active phase. The effect of orexin on the HVR in females has not been investigated. As estrogen can inhibit orexin neurons, here we hypothesized that orexin neurons are activated by hypoxia and facilitate the HVR only in diestrus, when estrogen is low. We exposed female rats (n = 10) to near-isocapnic hypoxia (FIO2 from 0.21 to 0.09) over _5 min, after vehicle and again after suvorexant (a dual OxR antagonist; 20 mg/kg ip), with ventilation measured using whole body plethysmography. Each rat was tested in proestrus or estrus (p/estrus), and again in diestrus, during both inactive and active phases. We also performed immunohistochemistry (IHC) to determine the proportion of orexin neurons activated by acute hypoxia during diestrus (n = 6) or proestrus/estrus (n = 6) in the active phase. In the inactive phase, the HVR was unaffected by OxR blockade, irrespective of estrus stage. In the active phase, the effect of OxR blockade depended on stage: the slope of the HVR was significantly reduced by OxR blockade only during diestrus. IHC revealed that hypoxia activated more orexin neurons during diestrus compared with p/estrus. We conclude that in females, orexin neurons are activated by hypoxia and contribute to the HVR only in diestrus when estrogen levels are low. Stage of the estrus cycle should be considered when examining the physiological function of orexin neurons in females. NEW & NOTEWORTHY We previously showed that orexin facilitates the hypoxic ventilatory response (HVR) of adult male rats during the active phase. Others have shown that estrogen inhibits orexin neurons. Here we show that orexin neurons are activated by hypoxia and facilitate the HVR of adult female rats during the active phase, but only in diestrus. These data suggest that orexin neurons facilitate the HVR in females when they are free from the inhibitory effects of estrogen. [ABSTRACT FROM AUTHOR]

Mycobacterium bovis is the etiologic agent of bovine tuberculosis (BTB), a serious infectious disease in both humans and animals. BTB is a zoonotic disease primarily affecting cattle and occasionally humans infected through close contact with infected hosts or the consumption of unpasteurized dairy products. Zoonotic tuberculosis is strongly associated with poverty and poor hygiene, and low- and middle-income countries bear the brunt of the disease. BTB has been increasingly recognized as a growing public health threat in developing countries. However, the lack of effective surveillance programs in many of these countries poses a barrier to accurately determining the true burden of this disease. Additionally, the control of BTB is threatened by the emergence of drug-resistant strains that affect the effectiveness of current treatment regimens. Here, we analyzed current trends in the epidemiology of the disease as well as the antimicrobial susceptibility patterns of M. bovis in the Middle East and North Africa (MENA) region, a region that includes several developing countries. Following PRISMA guidelines, a total of 90 studies conducted in the MENA region were selected. Our findings revealed that the prevalence of BTB among humans and cattle varied significantly according to the population size and country in the MENA region. Most of the available studies were based on culture and/or PCR strategies and were published without including data on antimicrobial resistance and molecular typing. Our findings highlighted the paramount need for the use of appropriate diagnostic tools and the implementation of sustainable control measures, especially at the human/animal interface, in the MENA region. [ABSTRACT FROM AUTHOR]

Previously we showed that a loss of central nervous system (CNS) 5-hydroxytryptamine (5-HT) (tryptophan hydroxylase 2 knockout; TPH2-/-) leads to hypertension in male rats during wakefulness and REM sleep. Here, we tested the hypotheses that hypertension is also revealed in female TPH2-/- when sex hormones are controlled, and that the especially high arterial blood pressure (ABP) of male TPH2-/- rats is due to increased sympathetic vascular tone. The ABP of females was measured specifically during proestrus or estrus and again following ovariectomy. The ABP of males was measured before and after a-adrenergic blockade. Prior to ovariectomy, the ABP of female TPH2-/- rats was -3 mmHg higher than TPH2+/+ during REM sleep while in proestrus/estrus. This difference increased to -9 mmHg following ovariectomy (P = 0.047). Hypertension of female TPH2-/- was most obvious upon the transition to rapid eye movement (REM) sleep from the previous state (P < 0.0001). Mean arterial pressure (MAP) of male TPH2-/- rats was -14 mmHg higher than male TPH2+/+ (P = 0.02), a difference that was eliminated by a-adrenergic blockade. Male TPH2-/- had normal plasma levels of 5-HT, norepinephrine, and epinephrine, whereas plasma dopamine was reduced by 50% compared with TPH2+/+ (P < 0.0001). From these data, we conclude that: 1) a deficiency of CNS 5-HT leads to hypertension in males and females alike, although in females the effect is mild and possibly obscured by ovarian hormones; 2) hypertension in females, like males, is most apparent in REM sleep, indicating a neural origin, and 3) increased sympathetic vascular tone underlies the elevated ABP of TPH2-/- rats. [ABSTRACT FROM AUTHOR]

Salmonella enterica remains a formidable public health challenge, resulting in [approximately equals] 1.2 million illnesses and 400 deaths annually in the United States alone (1). Disease manifestations include diarrhea, fever, [...]

Neonatal rodents deficient in medullary serotonin neurons have respiratory instability and enhanced spontaneous bradycardias. This study asks if, in [Pet-1.sup.-/-] mice over development: 1) the respiratory instability leads to hypoxia; 2) greater bradycardia is related to the degree of hypoxia or concomitant hypopnea; and 3) hyperthermia exacerbates bradycardias. Pet-1+/+, [Pet-1.sup.+/-], and [Pet-1.sup.-/-] mice [postnatal days (P) 4-5, P11-12, P14-15] were held at normal body temperature ([T.sub.b]) and were then made 2[degrees]C hypo-and byperthermic. Using a pneumotach-mask system with ECG, we measured heart rate, metabolic rate ([[??]o.sub.2]), and ventilation. We also calculated indexes for apnea-induced hypoxia (total hypoxia: apnea incidence x [O.sub.2] consumed during apnea = [micro]l x [g.sup.-1] x [min.sup.-1]) and bradycardia (total bradycardia: bradycardia incidence x magnitude = beats missed/min). Resting heart rate was significantly lower in all [Pet-1.sup.-/-] animals, irrespective of [T.sub.b]. At P4-5, [Pet-1.sup.-/-] animals had approximately four- to eightfold greater total bradycardia (P < 0.001), owing to an approximately two- to threefold increase in bradycardia magnitude and a near doubling in bradycardia incidence. [Pet-1.sup.-/-] animals had a significantly reduced [[??]o.sub.2] at all [T.sub.b]; thus there was no genotype effect on total hypoxia. At P 11-12, total bradycardia was nearly threefold greater in hyperthermic Pet-l-/- animals compared with controls (P < 0.01). In both genotypes, bradycardia magnitude was positively related to the degree of hypopnea (P = 0.02), but there was no genotype effect on degree of hypopnea or total hypoxia. At P14-15, genotype had no effect on total bradycardia, but Pet-1-/- animals had up to seven times more total hypoxia (P < 0.001), owing to longer and more frequent apneas and a normalized [[??]o.sub.2]. We infer from these data that 1) [Pet-1.sup.-/-] neonates are probably not hypoxic from respiratory dysfunction until P14-15; 2) neither apnea-related hypoxia nor greater hypopnea contribute to the enhanced bradycardias of Pet-l-/- neonates from approximately P4 to approximately P 12; and 3) an enhancement of a temperature-sensitive reflex may contribute to the greater bradycardia in hyperthermic [Pet-1.sup.-/-] animals at approximately P12. heart rate; apnea; body temperature; breathing; sudden infant death syndrome doi: 10.1152/ajpregu.00110.2010.

The breathing of newborns is destabilized by warm temperatures. We hypothesized that in unanesthetized, intact newborn rats, body temperature ([T.sub.B]) influences the peripheral chemoreflex response (PCR response) to hypercapnia. To test this, we delivered square-wave challenges of 8% C[O.sub.2] in air to postnatal day 4-5 (P4-P5) rats held at a [T.sub.B] of 30[degrees]C (Cold group, n = 11), 33[degrees]C (Cool group, n = 10), and 35[degrees]C thermoneutral zone group [thermoneutral zone (TNZ) group, n = 11], while measuring ventilation ([??]) directly with a pneumotach and mask. Cool animals were challenged with 8% C[O.sub.2] balanced in either air or hyperoxia (n = 10) to identify the PCR response. Breath-to-breath analysis was performed on 30 room air breaths and every breath of the 1-min C[O.sub.2] challenge. As expected, warmer [T.sub.B] was associated with an unstable breathing pattern in room air: TNZ animals had a coefficient of variation in [??] ([??] CV%) that was double that of animals held at cooler [T.sub.B] (P < 0.001). Hyperoxia markedly suppressed the hypercapnic ventilatory response over the first 10 breaths (or ~4 s), suggesting that this domain is dominated by the PCR response. The PCR response (P = 0.03) and total response (P = 0.04) were significantly greater in TNZ animals compared with hypothermic animals. The total response had a significant, negative relationship with [??]C[O.sub.2] ([R.sup.2] = 0.53; P < 0.001). Breathing stability was positively related to the total response ([R.sup.2] = 0.36; P < 0.001) and to a lesser extent, the PCR response ([R.sup.2] = 0.19; P - 0.01) and was negatively related to [??]C[O.sub.2] ([R.sup.2] = 0.34; P < 0.001). ANCOVA confirmed a significant effect of [T.sub.B] alone on breathing stability (P < 0.01), with no independent effects of [??]C[O.sub.2] (P = 0.41), the PCR response (P = 0.82), or the total VE response (P = 0.08). Our data suggest that in early postnatal life, the chemoreflex responses to C[O.sub.2] are highly influenced by [T.sub.B], and while related to breathing stability, are not predictors of stability after accounting for the independent effect of [T.sub.B]. ventilation; carotid body; newborn; apnea; C[O.sub.2] response

The medullary 5-HT system has potent effects on heart rate and breathing in adults. We asked whether this system mitigates the respiratory instability and bradycardias frequently occurring during the neonatal period. 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was administered to rat pups at postnatal day 2 (P2), and we then compared the magnitude of bradycardias occurring with disruptions to eupnea in treated and vehicle control littermates at P5-6 and P10-12. We then used a novel method that would allow accurate assessment of the ventilatory and heart rate responses to near square-wave challenges of hypoxia (10% [O.sub.2]), hypercapnia (5 and 8% C[O.sub.2] in normoxia and hyperoxia), and asphyxia (8% C[O.sub.2]-10% [O.sub.2]), and to the induction of the Hering-Breuer inflation reflex (HBR), a potent, apnea-inducing reflex in newborns. The number of 5-HT-positive neurons was reduced ~80% by drug treatment. At both ages, lesioned animals had considerably larger bradycardias during brief apnea; at P5-6, average and severe events were ~50% and 70% greater, respectively, in lesioned animals (P = 0.002), whereas at P10-12, events were ~ 23% and 50% greater (P = 0.018). However, lesioning had no effect on the HR responses to sudden gas challenge or the HBR. At P5-6, lesioned animals had reduced breathing frequency and ventilation ([V.sub.E]), but normal [V.sub.E] relative to metabolic rate (VE/[Vo.sub.2]). At P10-12, lesioned animals had a more unstable breathing pattern (P = 0.04) and an enhanced VE response to moderate hypercapnia (P = 0.007). Within the first two postnatal weeks, the medullary 5-HT system plays an important role in cardiorespiratory control, mitigating spontaneous bradycardia, stabilizing the breathing pattern, and dampening the hypercapnic VE response. neonate; C[O.sub.2]; breathing; SIDS; Hering-Breuer; chemoreflex

Curbing the coronavirus disease 2019 (COVID‐19) pandemic requires a thorough understanding of risk factors for transmission of SARS‐CoV‐2, the etiologic agent. Institutions of higher education present unique challenges for controlling disease spread because of features inherent to these settings. Our objective was to determine risk factors for SARS‐CoV‐2 infection among a university student population in the northeastern USA during the spring and fall 2021 semesters, using the case–control study design. Cases were defined as students with a newly diagnosed SARS‐CoV‐2 infection detected either through the robust PCR‐based surveillance testing program on campus or through healthcare testing if symptoms compatible with COVID‐19 were present. Controls were defined as students with negative SARS‐CoV‐2 status, based on consistently negative PCR results at the time of selection. A comprehensive questionnaire was administered to each student enrolled in the study, covering a broad range of campus life activities. A total of 446 cases and 1,185 controls were included in this study. Multivariable logistic regression analysis showed that recent party attendance (adjusted OR = 2.3, p <.0001), recently visiting a bar (aOR = 1.6, p =.007), living in a campus residence hall (aOR = 1.6, p =.001), fraternity/sorority membership (aOR = 1.8, p =.002), and recent travel (aOR = 1.3, p =.04) were associated with being a COVID‐19 case. Having an on‐campus job was negatively associated with being a COVID‐19 case (aOR = 0.6, p =.0003). Among cases, the most commonly reported symptoms were cough (43.9%), fatigue (38.1%) and sore throat (30.3%). These findings can be used to inform the development of COVID‐19 mitigation strategies and public health outreach efforts in university settings, thus reducing SARS‐CoV‐2 transmission among students and helping to preserve the vital education and research missions of these institutions. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?We investigated the interaction between central and peripheral respiratory chemoreceptors in healthy, awake human participants by using a background of step increases in steady‐state normoxic fraction of inspired carbon dioxide to alter central chemoreceptor activation and by using the transient hypoxia test to target the peripheral chemoreceptors.What is the main finding and its importance?Our data suggest that the interaction between central and peripheral respiratory chemoreceptors is additive in minute ventilation and respiratory rate, but hypo‐additive in tidal volume. Our study adds important new data in reconciling chemoreceptor interaction in awake healthy humans and is consistent with previous reports of simple addition in intact rodents and humans. Arterial blood gas levels are maintained through respiratory chemoreflexes, mediated by central chemoreceptors in the CNS and peripheral chemoreceptors located in the carotid bodies. The interaction between central and peripheral chemoreceptors is controversial, and few studies have investigated this interaction in awake, healthy humans, owing, in part, to methodological challenges. We investigated the interaction between the central and peripheral chemoreceptors in healthy humans using a transient hypoxia test (three consecutive breaths of 100% N2; TT‐HVR), which targets the temporal domain and stimulus specificity of the peripheral chemoreceptors. The TT‐HVRs were superimposed upon three randomized background levels of steady‐state inspired fraction of normoxic CO2(FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$; 0, 0.02 and 0.04). Chemostimuli [calculated oxygen saturation (ScO2${S}_{{\rm{cO}}_{\rm{2}}}$)] and respiratory variable responses [respiratory rate (RR), inspired tidal volume (VTI) and ventilation (V̇I${{{\dot{V}}}_{\rm{I}}}$)] were averaged from all three TT‐HVR trials at each FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ level. Responses were assessed as: (1) a change (∆) from baseline; and (2) indexed against ΔScO2$\Delta {S}_{{\rm{cO}}_{\rm{2}}}$. Aside from a significantly lower ∆VTI response in 0.04 FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ (P = 0.01), the hypoxic rate responses (∆RR or ∆RR/ΔScO2$\Delta {S}_{{\rm{cO}}_{\rm{2}}}$; P = 0.46 and P = 0.81), hypoxic tidal volume response (ΔVTI/ΔVTIΔScO2ΔScO2${{\Delta {V}_{{\rm{TI}}}} \mathord{/ {\vphantom {{\Delta {V}_{{\rm{TI}}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$; P = 0.08) and the hypoxic ventilatory responses (ΔV̇I${{\Delta {{\dot{V}}}_{\rm{I}}}}$ and ΔV̇I/ΔV̇IΔScO2ΔScO2${{\Delta {{\dot{V}}}_{\rm{I}}} \mathord{/ {\vphantom {{\Delta {{\dot{V}}}_{\rm{I}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$; P = 0.09 and P = 0.31) were not significantly different across FI,CO2${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ trials. Our data suggest simple addition between central and peripheral chemoreceptors in V̇I${{{\dot{V}}}_{\rm{I}}}$, which is mediated through simple addition in RR responses, but hypo‐addition in VTI responses. Our study adds important new data in reconciling chemoreceptor interaction in awake, healthy humans and is consistent with previous reports of simple addition in intact rodents and humans. [ABSTRACT FROM AUTHOR]

Mild reductions in ambient temperature dramatically increase the mortality of neonatal mice deficient in pituitary adenylate cyclase-activating polypeptide (PACAP), with the majority of animals succumbing in the second postnatal week. During anesthesia-induced hypothermia, [PACAP.sup.-/-] mice at this age are also vulnerable to prolonged apneas and sudden death. From these observations, we hypothesized that before the onset of genotype-specific mortality and in the absence of anesthetic, the breathing of PACAP-deficient mice is more susceptible to mild reductions in ambient temperature than wild-type littermates. To test this hypothesis, we recorded breathing in one group of postnatal day 4 [PACAP.sup.+/+, +/], and [sup.-/-] neonates (using unrestrained, flow-through plethysmography) and metabolic rate in a separate group (using indirect calorimetry), both of which were exposed acutely to ambient temperatures slightly below (29[degrees]C), slightly above (36[degrees]C), or at thermoneutrality (32[degrees]C). At 32[degrees]C, the breathing frequency of [PACAP.sup.-/-] neonates was significantly less than [PACAP.sup.+/+] littermates. Reducing the ambient temperature to 29[degrees]C caused a significant suppression of tidal volume and ventilation in both [PACAP.sup.+/-] and [sup.-/-] animals, while the tidal volume and ventilation of [PACAP.sup.+/+] animals remained unchanged. Genotype had no effect on the ventilatory responses to ambient warming. At all three ambient temperatures, genotype had no influence on oxygen consumption or body temperature. These results suggest that during mild reductions in ambient temperature, PACAP is vital for the preservation of neonatal tidal volume and ventilation, but not for metabolic rate or body temperature. neonatal apnea; temperature; metabolism; hypoxia; neonatal apnea; sudden infant death syndrome

The ventilatory response to several minutes of hypoxia consists of various time-dependent phenomena, some of which occur during hypoxia (e.g., short-term depression), whereas others appear on return to normoxia (e.g., posthypoxic frequency decline). Additional phenomena can be elicited by acute, intermittent hypoxia (e.g., progressive augmentation, long-term facilitation). Current data suggest that these phenomena originate centrally. We tested the hypothesis that carotid body afferent activity undergoes time-dependent modulation, consistent with a direct role in these ventilatory phenomena. Using an in vitro rat carotid body preparation, we found that 1) afferent activity declined during the first 5 min of severe (40 Torr [Po.sub.2]), moderate (60 Torr [Po.sub.2]), or mild (80 Torr [Po.sub.2]) hypoxia; 2) after return to normoxia (100 Torr [Po.sub.2]) and after several minutes of moderate or severe hypoxia, afferent activity was transiently reduced compared with prehypoxic levels; and 3) with successive 5-min bouts of mild, moderate, or severe hypoxia, afferent activity during bouts increased progressively. We call these phenomena sensory hypoxic decline, sensory posthypoxic decline, and sensory progressive augmentation, respectively. These phenomena were stimulus specific: similar phenomena were not seen with 5-min bouts of normoxic hypercapnia (100 Torr [Po.sub.2] and 50-60 Torr PC[O.sub.2]) or hypoxic hypocapnia (60 Torr [Po.sub.2] and 30 Torr PC[O.sub.2]). However, bouts of either normoxic hypercapnia or hypocapnic hypoxia resulted in sensory long-term facilitation. We suggest time-dependent carotid body activity acts in parallel with central mechanisms to shape the dynamics of ventilatory responses to respiratory chemostimuli. control of breathing; blood gases; peripheral chemoreceptor; response; dynamics

To minimize the impacts of COVID-19 and to keep campus open, Cornell University's Ithaca, NY, campus implemented a comprehensive process to monitor COVID-19 spread, support prevention practices, and assess early warning indicators linked to knowledge, behaviors, and attitudes of campus community members. The integrated surveillance approach informed leadership and allowed for prompt adjustments to university policies and practices through evidence-based decisions. This approach enhanced healthy behaviors and promoted the well-being and safety of all community members. (Am J Public Health. 2022;112(7):980–984. https://doi.org/10.2105/AJPH.2022.306838) [ABSTRACT FROM AUTHOR]

Orexin neurons are sensitive to CO2 and contribute to cardiorespiratory homeostasis as well as sensorimotor control. Whether orexin facilitates respiratory and behavioral responses to acute hypoxia is unclear. We hypothesized that orexin neurons are activated by acute hypoxia and that orexin facilitates the hypoxic ventilatory response (HVR), as well as the arterial blood pressure (ABP) and behavioral (movement) responses to acute hypoxia. We further hypothesized that orexin has greater effects in the active phase of the rat circadian cycle, when orexin neurons have high activity. Using whole body plethysmography with EEG, EMG, and the dual-orexin receptor (OxR) antagonist suvorexant (20 mg/kg ip), we determined the effect of OxR blockade on the respiratory, ABP, and behavioral responses of adult rats to acute, graded hypoxia (FIO2= 0.15, 0.13, 0.11, and 0.09) and hyperoxic hypercapnia (FICO2= 0.05; FIO2= 0.95). OxR blockade had no effect on eupnea. OxR blockade significantly reduced the HVR in both inactive and active phases, with a stronger effect in the active phase. OxR blockade reduced the behavioral response to acute hypoxia in the active phase. The central component of the ventilatory and the ABP responses to hypercapnia were reduced by OxR blockade solely in the inactive phase. In the inactive phase, hypoxia activated ~10% of orexin neurons in the perifornical hypothalamus. These data suggest that orexin neurons participate in the peripheral chemoreflex to facilitate the ventilatory and behavioral responses to acute hypoxia in rats, particularly in the active phase. Orexin also facilitates central chemoreflex responses to CO2 in the inactive phase. [ABSTRACT FROM AUTHOR]

Background: Listeria monocytogenes (Lm) present in farming soil and food‐processing facilities threatens food safety, but little is known about the carriage of Lm by wildlife. Objectives: We estimated the prevalence of faecal Lm shedding among wildlife admitted to a veterinary medical teaching hospital in central New York and characterized a subset of the Lm isolates. Methods: Wildlife samples were collected between May 2018 and December 2019. We characterized the Lm isolates by assessing the growth at three temperatures approximating the body temperatures of reptiles (25°C), mammals (37°C), and birds (42°C) and identifying genotypic characteristics related to transmission and virulence. Results: The apparent prevalence of faecal Lm shedding was 5.6% [18/324; 95% confidence interval (CI), 3.3%–8.6%]. Among 13 isolates that represented two lineages and 11 clonal complexes, three and five isolates were grouped into the same SNP clusters with human clinical isolates and environmental isolates, respectively. However, specific SNP difference data showed that Lm from wildlife was generally not closely related (>22 SNP differences) to Lm from human clinical sources and the food‐processing environment. While the stress response locus SSI‐2 was absent, SSI‐1 was found in four isolates. Virulence genes prfA, plcA, hly, mpl, actA, plcB, inlA, inlB, inlC, inlE, inlH, inlJ, and inlK were present, without any premature stop codons, in all isolates. Virulence loci Listeria pathogenicity island 3 (LIPI‐3) and LIPI‐4, which have been linked to hypervirulence, and inlG were found in four, three, and seven isolates, respectively. Conclusions: Wildlife represents a potential reservoir for genetically diverse and putatively hypervirulent Lm strains. No statistically significant association between growth parameters and hosts was observed. However, compared to lineage I isolates, lineage II isolates showed significantly (p < 0.05) faster growth at 25°C and significantly slower growth at 42°C, suggesting that wildlife Lm isolates that belong to lineages I and II differ in their ability to grow at 25°C and 42°C. [ABSTRACT FROM AUTHOR]

Livestock represent a possible reservoir for facilitating the transmission of the zoonotic foodborne pathogen Salmonella enterica to humans; there is also concern that strains can acquire resistance to antimicrobials in the farm environment. Here, whole-genome sequencing (WGS) was used to characterize Salmonella strains (n = 128) isolated from healthy dairy cattle and their associated environments on 13 New York State farms to assess the diversity and microevolution of this important pathogen at the level of the individual herd. Additionally, the accuracy and concordance of multiple in silico tools are assessed, including: (i) two in silico serotyping tools, (ii) combinations of five antimicrobial resistance (AMR) determinant detection tools and one to five AMR determinant databases, and (iii) one antimicrobial minimum inhibitory concentration (MIC) prediction tool. For the isolates sequenced here, in silico serotyping methods outperformed traditional serotyping and resolved all un-typable and/or ambiguous serotype assignments. Serotypes assigned in silico showed greater congruency with the Salmonella whole-genome phylogeny than traditional serotype assignments, and in silico methods showed high concordance (99% agreement). In silico AMR determinant detection methods additionally showed a high degree of concordance, regardless of the pipeline or database used (≥98% agreement among susceptible/resistant assignments for all pipeline/database combinations). For AMR detection methods that relied exclusively on nucleotide BLAST, accuracy could be maximized by using a range of minimum nucleotide identity and coverage thresholds, with thresholds of 75% nucleotide identity and 50–60% coverage adequate for most pipeline/database combinations. In silico characterization of the microevolution and AMR dynamics of each of six serotype groups (S. Anatum, Cerro, Kentucky, Meleagridis, Newport, Typhimurium/Typhimurium variant Copenhagen) revealed that some lineages were strongly associated with individual farms, while others were distributed across multiple farms. Numerous AMR determinant acquisition and loss events were identified, including the recent acquisition of cephalosporin resistance-conferring bla CMY- and bla CTX–M-type beta-lactamases. The results presented here provide high-resolution insight into the temporal dynamics of AMR Salmonella at the scale of the individual farm and highlight both the strengths and limitations of WGS in tracking zoonotic pathogens and their associated AMR determinants at the livestock-human interface. [ABSTRACT FROM AUTHOR]

The role of wildlife as a source of zoonotic Salmonella transmission is poorly understood, as are the clinical implications of this pathogen among wildlife species. Wildlife hospitals represent an important location to conduct Salmonella surveillance, given the wide variety of species admitted for medical and surgical care. Our objectives were to estimate the prevalence of fecal Salmonella shedding among wildlife admitted to a veterinary medical teaching hospital, to identify risk factors for infection, and to fully characterize the isolates. Voided fecal samples (birds and mammals) and cloacal swab samples (reptiles and amphibians) were collected between May 2018 and March 2020. Standard bacteriologic culture methods were used to detect Salmonella, and isolates were characterized via serotyping, antimicrobial susceptibility testing, and whole-genome sequencing. Samples were collected from 348 wildlife patients representing 74 wildlife species, and the apparent prevalence of fecal Salmonella shedding was 1.4% (5/348; 95% confidence interval, 0.5–3.3%). Four serotypes were identified, and isolates were phenotypically susceptible to all antimicrobial agents tested. Two isolates were closely related to human clinical isolates, demonstrating the overlap between wildlife and human pathogens. Fecal Salmonella shedding among hospitalized wildlife appears to be uncommon, and the risk of either nosocomial or zoonotic Salmonella transmission is presumably low. Nevertheless, the occurrence of Salmonella in wildlife, particularly among common species found in a wide array of habitats, poses a potential threat to public health and may result in transmission to more-vulnerable wildlife populations. [ABSTRACT FROM AUTHOR]

Orexin neurons are active in wakefulness and mostly silent in sleep. In adult rats and humans, orexin facilitates the hypercapnic ventilatory response but has little effect on resting ventilation. The influence of orexin on breathing in the early postnatal period, and across states of vigilance, have not been investigated. This is relevant as the orexin system may be impaired in Sudden Infant Death Syndrome (SIDS) cases. We addressed three hypotheses: 1) orexin provides a drive to breathe in infancy; 2) the effect of orexin depends on stage of postnatal development; and 3) orexin has a greater influence on breathing in wakefulness compared with sleep. Whole body plethysmography was used to monitor breathing of infant rats at three ages: postnatal days (P) 7–8, 12–14, and 17–19. Respiratory variables were analyzed in wakefulness (W), quiet sleep (QS), and active sleep (AS), following suvorexant (5 mg/kg ip), a dual orexin receptor antagonist, or vehicle (DMSO). Effects of suvorexant on ventilatory responses to graded hypercapnia (FICO2 = 0.02, 0.04, 0.06), hypoxia (FIO2 = 0.10), and hyperoxia (FIO2 = 1.0) at P12–14 were also tested. At P12–14, but not at other ages, suvorexant significantly reduced respiratory frequency in all states, reduced the ventilatory equivalent in QW and QS, and increased PaCO2 to ˜5 mmHg. Suvorexant had no effect on ventilatory responses to graded hypercapnia or hypoxia. Hyperoxia eliminated the effects of suvorexant on respiratory frequency at P12–14. Our data suggest that orexin preserves eupneic frequency and ventilation in rats, specifically at ˜2 wk of age, perhaps by facilitating tonic peripheral chemoreflex activity [ABSTRACT FROM AUTHOR]

Eupnea and gasping in infancy depend on central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT). Although previous in vitro preparations have provided some evidence that 5-HT acts through type 2A receptors (5-HT2A) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT2A receptor activation is necessary for eupnea and the proper generation of gasping in vivo. To test this, we administered 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25 mg/kg i.p.), a 5-HT2A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT1A agonist, or vehicle (saline) to 7-9-day-old tryptophan hydroxylase 2 knockout (TPH2-/-) mice. A second experiment assessed the effect of MDL-11,939 (MDL; 10 mg/kg i.p.), the specific 5-HT2A antagonist, or vehicle (DMSO) on the gasping of wild-type (TPH2þ/þ) animals. Drugs were given 15 min prior to five episodes of severe hypoxia that elicited gasping. TPH2-/- breathed more slowly but had the same VE and VE/VO2 compared with TPH2þ/þ. As previously reported, the gasping of TPH2-/- was significantly delayed (P < 0.001) and occurred at a significantly lower frequency compared with TPH2þ/þ (P = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on VE or VE/VO2. The gasping of TPH2-/-, although unaffected by 8-OH-DPAT, was indistinguishable from the gasping of TPH2þ/þ following DOI. In TPH2þ/þ, application of MDL led to hypoventilation (P = 0.01), a delay in the appearance of gasping (P = 0.005), and reduced gasp frequency (P = 0.05). These data show that, in vivo, 5-HT2A receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT2A probably promotes gasping by exciting hypoxia-resistant pacemaker neurons. [ABSTRACT FROM AUTHOR]

Background: Combatting antimicrobial resistance requires a One Health approach to antimicrobial stewardship including antimicrobial drug (AMD) use evaluation. Current veterinary AMD prescribing data are limited. Objectives: To quantify companion animal AMD prescribing in primary care and specialty practice across 3 academic veterinary hospitals with particular focus on third‐generation cephalosporins, fluoroquinolones, and carbapenems. Animals Dogs and cats presented to 3 academic veterinary hospitals from 2012 to 2017. Methods: In this retrospective study, AMD prescribing data from 2012 to 2017 were extracted from electronic medical records at each hospital and prescriptions classified by service type: primary care, specialty practice or Emergency/Critical Care (ECC). Hospital‐level AMD prescribing data were summarized by species, service type, AMD class, and drug. Multivariable logistic full‐factorial regression models were used to estimate hospital, year, species, and service‐type effects on AMD prescribing. Estimated marginal means and confidence intervals were plotted over time. Results: The probability of systemic AMD prescribing for any indication ranged between 0.15 and 0.28 and was higher for dogs than cats (P <.05) apart from 2017 at hospital 1. Animals presented to primary care were least likely to receive AMDs (dogs 0.03‐0.15, cats 0.03‐0.18). The most commonly prescribed AMD classes were aminopenicillins/β‐lactamase inhibitors (0.02‐0.15), first‐generation cephalosporins (0.00‐0.09), fluoroquinolones (0.00‐0.04), nitroimidazoles (0.01‐0.06), and tetracyclines (0.00‐0.03). Among the highest priority classes, fluoroquinolones (dogs 0.00‐0.09, cats 0.00‐0.08) and third‐generation cephalosporins (dogs 0.00‐0.04, cats 0.00‐0.05) were most frequently prescribed. Conclusions and Clinical Importance: Antimicrobial drug prescribing frequencies were comparable to previous studies. Additional stewardship efforts might focus on fluoroquinolones and third‐generation cephalosporins. [ABSTRACT FROM AUTHOR]

Medullary serotonin (5-hydroxytryptamine; 5-HT) neurons project to multiple autonomic nuclei in the central nervous system (CNS). Infant rats lacking 5-HT have low arterial blood pressure (ABP) in quiet sleep, but the role of 5-HT in ABP regulation across vigilance states in adults has not been studied. We hypothesized that in adults, CNS 5-HT deficiency leads to hypotension mainly in quiet wakefulness (QW) and non-rapid eye movement (NREM) sleep, when 5-HT neurons are active. We tested male and female tryptophan hydroxylase 2 knockout rats (TPH2−/−), specifically deficient in CNS 5-HT, and wild-type (TPH2+/+) controls at 2–3, 5–8, and 12–13 mo of age. Compared with TPH2+/+, mean arterial pressure of 5–8- and 12–13-mo-old (middle-aged) male TPH2−/− rats was significantly elevated (∼10 mmHg) in QW and rapid eye movement (REM) sleep. Middle-aged male TPH2−/− rats also had more frequent extreme hypertensive events during prolonged episodes of REM sleep. Female TPH2−/− had normal ABP. The low- and very-low-frequency components of systolic ABP variability were significantly higher in middle-aged male, but not female, TPH2−/− rats compared with in TPH2+/+ rats, suggesting elevated sympathetic vascular tone in male TPH2−/− rats. However, the hypertension of male TPH2−/− rats was not ameliorated by ganglionic blockade. Hearts and lungs of middle-aged male TPH2−/− rats were significantly heavier than those of TPH2+/+ rats. We show that a loss of CNS 5-HT leads to high ABP only in middle-aged males during wakefulness and REM sleep, possibly due to increased vascular tone. It should be investigated whether elevated ventricular afterload associated with CNS 5-HT deficiency initiates cardiac remodeling or alters pulmonary hemodynamics. NEW & NOTEWORTHY The role of serotonin in arterial blood pressure (ABP) regulation across states of vigilance is unknown. We hypothesized that adult rats devoid of CNS serotonin (TPH2−/−) have low ABP in wakefulness and NREM sleep, when serotonin neurons are active. However, TPH2−/− rats experience higher ABP than TPH2+/+ rats in wakefulness and REM only, a phenotype present only in older males and not females. CNS serotonin may be critical for preventing high ABP in males with aging. [ABSTRACT FROM AUTHOR]

Dogs are a potential source of zoonotic Salmonella transmission. We had previously estimated the prevalence of Salmonella shedding among shelter dogs throughout Texas using a repeated cross‐sectional study design. Our current objectives were to fully characterize the Salmonella isolates and to assess their relatedness, using whole‐genome sequencing. Antimicrobial resistance (AMR) genes were detected in 4/27 (15%) of the isolates. The fosfomycin resistance gene fosA7 was identified in two isolates; to our knowledge, there are no published reports of this gene in canine Salmonella isolates. The biocide resistance gene qacEdelta1, conferring resistance to quaternary ammonium compounds, was detected in an isolate that had four additional AMR genes. The most frequently identified serotypes were Newport (6/27, 22%) and Javiana (4/27, 15%), both of which were widespread among animal shelters. For these serotypes, there was evidence of both transmission of Salmonella within the shelter environment and separate introductions of Salmonella into a shelter. Several canine Salmonella isolates were closely related to human clinical isolates (four canine isolates within 10 SNPs and six more within 20 SNPs), suggesting a shared pathogen population. Educational outreach programmes targeting animal shelter workers would be useful for optimizing knowledge of Salmonella and other canine‐associated zoonotic pathogens. [ABSTRACT FROM AUTHOR]