SARS-CoV-2 Transmission Potential and Policy Changes in South Carolina, February 2020 - January 2021.

INTRODUCTION: We aimed to examine how public health policies influenced the dynamics of coronavirus disease 2019 (COVID-19) time-varying reproductive number (R t ) in South Carolina from February 26, 2020, to January 1, 2021. METHODS: COVID-19 case series (March 6, 2020, to January 10, 2021) were shifted by 9 d to approximate the infection date. We analyzed the effects of state and county policies on R t using EpiEstim. We performed linear regression to evaluate if per-capita cumulative case count varies across counties with different population size. RESULTS: R t shifted from 2-3 in March to <1 during April and May. R t rose over the summer and stayed between 1.4 and 0.7. The introduction of statewide mask mandates was associated with a decline in R t (-15.3%; 95% CrI, -13.6%, -16.8%), and school re-opening, an increase by 12.3% (95% CrI, 10.1%, 14.4%). Less densely populated counties had higher attack rates (P < 0.0001). CONCLUSIONS: The R t dynamics over time indicated that public health interventions substantially slowed COVID-19 transmission in South Carolina, while their relaxation may have promoted further transmission. Policies encouraging people to stay home, such as closing nonessential businesses, were associated with R t reduction, while policies that encouraged more movement, such as re-opening schools, were associated with R t increase.

Spatially refined time-varying reproduction numbers of SARS-CoV-2 in Arkansas and Kentucky and their relationship to population size and public health policy, March - November 2020.

PURPOSE: To examine the time-varying reproduction number, Rt, for COVID-19 in Arkansas and Kentucky and investigate the impact of policies and preventative measures on the variability in Rt. METHODS: Arkansas and Kentucky county-level COVID-19 cumulative case count data (March 6-November 7, 2020) were obtained. Rt was estimated using the R package 'EpiEstim', by county, region (Delta, non-Delta, Appalachian, non-Appalachian), and policy measures. RESULTS: The Rt was initially high, falling below 1 in May or June depending on the region, before stabilizing around 1 in the later months. The median Rt for Arkansas and Kentucky at the end of the study were 1.15 (95% credible interval [CrI], 1.13, 1.18) and 1.10 (95% CrI, 1.08, 1.12), respectively, and remained above 1 for the non-Appalachian region. Rt decreased when facial coverings were mandated, changing by -10.64% (95% CrI, -10.60%, -10.70%) in Arkansas and -5.93% (95% CrI, -4.31%, -7.65%) in Kentucky. The trends in Rt estimates were mostly associated with the implementation and relaxation of social distancing measures. CONCLUSIONS: Arkansas and Kentucky maintained a median Rt above 1 during the entire study period. Changes in Rt estimates allow quantitative estimates of potential impact of policies such as facemask mandate.

Time-varying Reproduction Numbers of COVID-19 in Georgia, USA, March 2, 2020 to November 20, 2020.

BACKGROUND: In 2020, Severe Acute Respiratory Syndrome Coronavirus 2 impacted Georgia, USA. Georgia announced a state-wide shelter-in-place on April 2 and partially lifted restrictions on April 27. We estimated the time-varying reproduction numbers (Rt) of COVID-19 in Georgia, Metro Atlanta, and Dougherty County and environs from March 2, 2020, to November 20, 2020. METHODS: We analyzed the daily incidence of confirmed COVID-19 cases in Georgia, Metro Atlanta, and Dougherty County and its surrounding counties, and estimated Rt using the R package EpiEstim. We used a 9-day correction for the date of report to analyze the data by assumed date of infection. RESULTS: The median Rt estimate in Georgia dropped from between 2 and 4 in mid-March to < 2 in late March to around 1 from mid-April to November. Regarding Metro Atlanta, Rt fluctuated above 1.5 in March and around 1 since April. In Dougherty County, the median Rt declined from around 2 in late March to 0.32 on April 26. Then, Rt fluctuated around 1 in May through November. Counties surrounding Dougherty County registered an increase in Rt estimates days after a superspreading event occurred in the area. CONCLUSIONS: In Spring 2020, Severe Acute Respiratory Syndrome Coronavirus 2 transmission in Georgia declined likely because of social distancing measures. However, because restrictions were relaxed in late April and elections were conducted in November, community transmission continued, with Rt fluctuating around 1 across Georgia, Metro Atlanta, and Dougherty County as of November 2020. The superspreading event in Dougherty County affected surrounding areas, indicating the possibility of local transmission in neighboring counties.

Strain-specific differences in the development of neuronal excitability in the mouse ventral nucleus of the trapezoid body.

This investigation compared the development of neuronal excitability in the ventral nucleus of the trapezoid body (VNTB) between two strains of mice with differing progression rates for age-related hearing loss. In contrast to CBA/Ca (CBA) mice, the C57BL/6J (C57) strain are subject to hearing loss from a younger age and are more prone to damage from sound over-exposure. Higher firing rates in the medial olivocochlear system (MOC) are associated with protection from loud sounds and these cells are located in the VNTB. We postulated that reduced neuronal firing of the MOC in C57 mice could contribute to hearing loss in this strain by reducing efferent protection. Whole cell patch clamp was used to compare the electrical properties of VNTB neurons from the two strains initially in two age groups: before and after hearing onset at âˆ¼ P9 and ∼P16, respectively. Prior to hearing onset VNTB neurons electrophysiological properties were identical in both strains, but started to diverge after hearing onset. One week after hearing onset VNTB neurons of C57 mice had larger amplitude action potentials but in contrast to CBA mice, their waveform failed to accelerate with increasing age, consistent with the faster inactivation of voltage-gated potassium currents in C57 VNTB neurons. The lower frequency action potential firing of C57 VNTB neurons at P16 was maintained to P28, indicating that this change was not a developmental delay. We conclude that C57 VNTB neurons fire at lower frequencies than in the CBA strain, supporting the hypothesis that reduced MOC firing could contribute to the greater hearing loss of the C57 strain.

Nocturnal intermittent hypoxia is independently associated with pain in subjects suffering from sleep-disordered breathing.

BACKGROUND: On the basis of experimental and clinical evidence, the authors hypothesized that nocturnal hypoxemia would be associated with pain reports in subjects suffering from sleep-disordered breathing, independently of sleep fragmentation and inflammation. METHODS: After obtaining institutional approval and access to the Cleveland Family Study phenotype and genotype data, the authors used proportional odds regression to examine the association between arterial desaturation and four different types of pain, as well as their composite measure, sequentially adjusted for: (1) clinical characteristics and (2) sleep fragmentation and inflammation. The authors also examined the association of selected candidate single-nucleotide polymorphisms with pain reports. RESULTS: Decreased minimum nocturnal arterial saturation increased the odds for morning headache (adjusted odds ratio per SD=1.36; 95% CI [1.08-1.71]; P=0.009), headache disrupting sleep (1.29 [1.10-1.51]; P=0.002), and chest pain while in bed (1.37 [1.10-1.70]; P=0.004). A decrease in the minimum nocturnal saturation from 92 to 75% approximately doubled the odds for pain. One single-nucleotide polymorphism for the α 1 chain of collagen type XI (COL11A1-rs1676486) gene was significantly associated with headache disrupting sleep (odds ratio=1.72 [1.01-2.94]; P=0.038), pain disrupting sleep (odds ratio=1.85 [1.04-3.28]; P=0.018), and pain composite (odds ratio=1.89 [1.14-3.14]; P=0.001). CONCLUSION: Nocturnal arterial desaturation may be associated with an increased pain in subjects with sleep-disordered breathing, independently of sleep fragmentation and inflammation.

Protection from noise-induced hearing loss by Kv2.2 potassium currents in the central medial olivocochlear system.

The central auditory brainstem provides an efferent projection known as the medial olivocochlear (MOC) system, which regulates the cochlear amplifier and mediates protection on exposure to loud sound. It arises from neurons of the ventral nucleus of the trapezoid body (VNTB), so control of neuronal excitability in this pathway has profound effects on hearing. The VNTB and the medial nucleus of the trapezoid body are the only sites of expression for the Kv2.2 voltage-gated potassium channel in the auditory brainstem, consistent with a specialized function of these channels. In the absence of unambiguous antagonists, we used recombinant and transgenic methods to examine how Kv2.2 contributes to MOC efferent function. Viral gene transfer of dominant-negative Kv2.2 in wild-type mice suppressed outward K(+) currents, increasing action potential (AP) half-width and reducing repetitive firing. Similarly, VNTB neurons from Kv2.2 knock-out mice (Kv2.2KO) also showed increased AP duration. Control experiments established that Kv2.2 was not expressed in the cochlea, so any changes in auditory function in the Kv2.2KO mouse must be of central origin. Further, in vivo recordings of auditory brainstem responses revealed that these Kv2.2KO mice were more susceptible to noise-induced hearing loss. We conclude that Kv2.2 regulates neuronal excitability in these brainstem nuclei by maintaining short APs and enhancing high-frequency firing. This safeguards efferent MOC firing during high-intensity sounds and is crucial in the mediation of protection after auditory overexposure.

Lateral olivocochlear (LOC) neurons of the mouse LSO receive excitatory and inhibitory synaptic inputs with slower kinetics than LSO principal neurons.

We examined membrane properties and synaptic responses of neurons in the mouse lateral superior olivary nucleus (LSO). Two clear populations were identified consistent with: principal neurons which are involved in detecting interaural intensity differences (IIDs) and efferent neurons of the lateral olivocochlear (LOC) system which project to the cochlea. Principal neurons fired a short latency action potential (AP) often followed by an AP train during maintained depolarization. They possessed sustained outward K(+) currents, with little or no transient K(+) current (I(A)) and a prominent hyperpolarization-activated non-specific cation conductance, I(H). On depolarization, LOC neurons exhibited a characteristic delay to the first AP. These neurons possessed a prominent transient outward current I(A), but had no I(H). Both LOC and principal neurons received glutamatergic and glycinergic synaptic inputs. LOC synaptic responses decayed more slowly than those of principal neurons; the mean decay time constant of AMPA receptor-mediated EPSCs was around 1 ms in principal neurons and 4 ms in LOC neurons. Decay time constants for glycinergic IPSCs were around 5 ms in principal neurons and 10 ms in LOC neurons. We conclude that principal cells receive fast synaptic responses appropriate for integration of IID inputs, while the LOC cells possess excitatory and inhibitory receptors with much slower kinetics.

TRPML3 mutations cause impaired mechano-electrical transduction and depolarization by an inward-rectifier cation current in auditory hair cells of varitint-waddler mice.

TRPML3 (mucolipin-3) belongs to one of the transient-receptor-potential (TRP) ion channel families. Mutations in the Trpml3 gene cause disorganization of the stereociliary hair bundle, structural aberrations in outer and inner hair cells and stria vascularis defects, leading to deafness in the varitint-waddler (Va) mouse. Here we refined the stereociliary localization of TRPML3 and investigated cochlear hair cell function in varitint-waddler (Va(J)) mice carrying the TRPML3 mutations. Using a TRPML3-specific antibody we detected a approximately 68 kDa protein with near-equal expression levels in cochlea and vestibule of wild-type and Va(J) mutants. At postnatal days 3 and 5, we observed abundant localization of TRPML3 at the base of stereocilia near the position of the ankle links. This stereociliary localization domain was absent in Va(J) heterozygotes and homozygotes. Electrophysiological recordings revealed reduced mechano-electrical transducer currents in hair cells from Va(J)/+ and Va(J)/Va(J) mice. Furthermore, FM1-43 uptake and [(3)H]gentamicin accumulation were decreased in hair cells in cultured organs of Corti from Va(J)/+ and Va(J)/Va(J) mice. We propose that TRPML3 plays a critical role at the ankle-link region during hair-bundle growth and that an adverse effect of mutant TRPML3 on bundle development and mechano-electrical transduction is the main cause of hearing loss in Va(J)/+ mutant mice. Outer hair cells of Va(J)/Va(J) mice additionally had depolarized resting potentials due to an inwardly rectifying leak conductance formed by the mutant channels, leading over time to hair-cell degeneration and contributing to their deafness. Our findings argue against TRPML3 being a component of the hair-cell transducer channel.

TRPML3 and hearing loss in the varitint-waddler mouse.

TRPML3 (also known as mucolipin-3, MCOLN3) belongs to the small family of TRPML ion channel proteins. The mammalian Trpml3 gene encodes a protein of 553 amino acids with short amino and carboxy termini and a transient receptor potential motif spanning from the third to the sixth trans membrane domain. Dominant mutant alleles of Trpml3 cause hearing loss, circling behaviour, pigmentation defects and embryonic lethality in the varitint-waddler (Va) mouse. In the inner ear these mutations cause a reduction or loss of endocochlear potentials, compound action potentials, and auditory-evoked brain stem responses. The hearing phenotype is associated with defects in the cochlea that include disorganization and fusion of stereocilia, distortions at the apical and distal regions of inner and outer hair cells, and loss of pigmented intermediate cells in the stria vascularis. In hair cells the TRPML3 protein is targeted to cytoplasmic vesicles and to the plasma membrane of stereocilia. Both the sub-cellular localization of TRPML3 and the mutant phenotype suggest that TRPML3 is critical for stereocilia bundle formation during development and may function during endocytosis or exocytosis.

Acoustic environment determines phosphorylation state of the Kv3.1 potassium channel in auditory neurons.

Sound localization by auditory brainstem nuclei relies on the detection of microsecond interaural differences in action potentials that encode sound volume and timing. Neurons in these nuclei express high amounts of the Kv3.1 potassium channel, which allows them to fire at high frequencies with short-duration action potentials. Using computational modeling, we show that high amounts of Kv3.1 current decrease the timing accuracy of action potentials but enable neurons to follow high-frequency stimuli. The Kv3.1b channel is regulated by protein kinase C (PKC), which decreases current amplitude. Here we show that in a quiet environment, Kv3.1b is basally phosphorylated in rat brainstem neurons but is rapidly dephosphorylated in response to high-frequency auditory or synaptic stimulation. Dephosphorylation of the channel produced an increase in Kv3.1 current, facilitating high-frequency spiking. Our results indicate that the intrinsic electrical properties of auditory neurons are rapidly modified to adjust to the ambient acoustic environment.

Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults.

BACKGROUND: Little information is currently available on the role of the gut microflora in modulating isoflavone bioavailability or on sex differences in isoflavone metabolism and bioavailability. OBJECTIVE: We sought to determine whether chronic soy consumption influences isoflavone bioavailability as judged by plasma isoflavone concentrations and modified gut microflora activities [beta-glucoside hydrolysis and equol and O-desmethylangolensin (O-DMA) production]. We also examined whether sex differences in isoflavone metabolism exist. DESIGN: A randomized, parallel, controlled study design was used to compare a high-soy diet (104 +/- 24 mg total isoflavones/d) with a low-soy diet (0.54 +/- 0.58 mg total isoflavones/d) in 76 healthy young adults for 10 wk. RESULTS: Concentrations of isoflavones and their gut microflora metabolites in the plasma, urine, and feces were significantly higher in the subjects who consumed the high-soy diet than in those who consumed the low-soy diet. Concentrations of O-DMA in plasma and urine were higher in the men than in the women. Fecal bacteria from subjects consuming both diets could convert daidzein to equol ex vivo. Fecal beta-glucosidase activity was significantly higher in the subjects who consumed the high-soy diet than in those who consumed the low-soy diet. CONCLUSIONS: Although interindividual variation in isoflavone metabolism was high, intraindividual variation was low. Only concentrations of O-DMA in plasma and urine appeared to be influenced by sex. Chronic soy consumption does not appear to induce many significant changes to the gut metabolism of isoflavones other than higher beta-glucosidase activity.

Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive.

Principal neurons of the lateral superior olive (LSO) detect interaural intensity differences by integration of excitatory projections from ipsilateral bushy cells and inhibitory inputs from the medial nucleus of the trapezoid body. The intrinsic membrane currents active around firing threshold will form an important component of this binaural computation. Whole cell patch recording in an in vitro brain slice preparation was employed to study conductances regulating action potential (AP) firing in principal neurons. Current-clamp recordings from different neurons showed two types of firing pattern on depolarization, one group fired only a single initial AP and had low input resistance while the second group fired multiple APs and had a high input resistance. Under voltage-clamp, single-spiking neurons showed significantly higher levels of a dendrotoxin-sensitive, low threshold potassium current (ILT). Block of ILT by dendrotoxin-I allowed single-spiking cells to fire multiple APs and indicated that this current was mediated by Kv1 channels. Both neuronal types were morphologically similar and possessed similar amounts of the hyperpolarization-activated nonspecific cation conductance (Ih). However, single-spiking cells predominated in the lateral limb of the LSO (receiving low frequency sound inputs) while multiple-firing cells dominated the medial limb. This functional gradient was mirrored by a medio-lateral distribution of Kv1.1 immunolabelling. We conclude that Kv1 channels underlie the gradient of LSO principal neuron firing properties. The properties of single-spiking neurons would render them particularly suited to preserving timing information.

A hospital care pathway for alcohol.

Inappropriate placing of alcohol misusers on gastroenterology wards spurred the two ward managers into leading a campaign for better diagnosis, placement and treatment of these patients.

Ontogeny of bone and the role of heterochrony in the myobatrachine genera Uperoleia, Crinia, and Pseudophryne (anura: Leptodactylidae: Myobatrachinae).

Descriptive data are provided for ontogeny of bone to metamorphosis in the myobatrachine species Uperoleia trachyderma; in pre- and postmetamorphic specimens of U. lithomoda, Crinia signifera, and Pseudophryne bibroni; and in postmetamorphic specimens of U. laevigata. Data derived from postmetamorphic U. laevigata indicate that dermal and endochondral elements ossify independently of each other in Uperoleia. Crinia signifera does not show the same degree of independence of ossification of dermal and endochondral elements as Uperoleia, whereas dermal and endochondral elements are not independent in P. bibroni. Ten (or possibly eleven) features are identified as being influenced by heterochrony within Uperoleia, confirming that the genus represents a highly pedomorphic lineage, four elements are influenced by heterochrony in Crinia, but only two in Pseudophryne.