Emergence of SARS-CoV-2 Delta Variant and Effect of Nonpharmaceutical Interventions, British Columbia, Canada.

In British Columbia, Canada, initial growth of the SARS-CoV-2 Delta variant was slower than that reported in other jurisdictions. Delta became the dominant variant (>50% prevalence) within ≈7-13 weeks of first detection in regions within the United Kingdom and United States. In British Columbia, it remained at <10% of weekly incident COVID-19 cases for 13 weeks after first detection on March 21, 2021, eventually reaching dominance after 17 weeks. We describe the growth of Delta variant cases in British Columbia during March 1-June 30, 2021, and apply retrospective counterfactual modeling to examine factors for the initially low COVID-19 case rate after Delta introduction, such as vaccination coverage and nonpharmaceutical interventions. Growth of COVID-19 cases in the first 3 months after Delta emergence was likely limited in British Columbia because additional nonpharmaceutical interventions were implemented to reduce levels of contact at the end of March 2021, soon after variant emergence.

Defective T-cell response to COVID-19 vaccination in acute myeloid leukaemia and myelodysplastic syndromes.

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.

Immediate effects of transcutaneous electrical nerve stimulation on gait patterns in chronic stroke survivors: A single group, pretest-posttest clinical trial.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) has been used to reduce muscle spasticity and improve locomotion in stroke survivors. We speculate that acute changes in gait performance after TENS mediate functional improvement in the long-term. However, no previous study has investigated the effect of TENS on ankle kinetics and kinematics during walking in stroke survivors. PURPOSE: We aimed to investigate whether TENS applied over the paretic leg could rapidly improve the plantar flexion moment and ankle kinematics in chronic stroke survivors with lower limb paresis. METHODS: Twenty chronic stroke survivors were recruited. They underwent 30 min of TENS over the area innervated by the common peroneal nerve on the paretic leg. Three-dimensional (3D) motion capture was performed and ankle plantar flexor spasticity was assessed before and immediately after stimulation. Ankle kinematics and kinetic and spatiotemporal data were collected using 3D motion capture. Ankle plantar flexor spasticity was assessed using the Modified Tardieu Scale. PRINCIPAL RESULTS: A significant increase in the ankle plantar flexion moment of the paretic side during the pre-swing phase was observed immediately after stimulation (p = 0.009, maximal mean difference = 0.035, 95%CI = 0.0125 to 0.0575). The step length of the paretic limb also increased significantly after stimulation (p = 0.023, mean difference = -0.02, 95%CI = -0.04 to -0.004). TENS had no immediate effect on paretic ankle spasticity, as measured by the Modified Tardieu Scale, or on other temporo-spatial parameters. CONCLUSION: The findings support the use of TENS to improve the motor function and gait pattern in chronic stroke survivors. The study indicated that the application of TENS to the paretic leg before gait training might improve rehabilitation outcomes. Future studies investigating the effects of TENS on functional outcomes, the optimal stimulation duration, and assessing spasticity using more sensitive measures are warranted.

SARS-CoV-2 outbreak in a Canadian suburban tertiary hospital necessitating full facility closure: a descriptive observational study.

BACKGROUND: SARS-CoV-2 can cause outbreaks in community- and hospital-based settings. The aim of this study was to provide a detailed epidemiologic account of a hospital-wide SARS-CoV-2 outbreak and provide a description of case evaluations, transmission networks and the interventions implemented to stem the outbreak. METHODS: We conducted a retrospective descriptive study of a hospital-wide SARS-CoV-2 outbreak at the Misericordia Community Hospital (Edmonton) from June 21 to Aug. 14, 2020. We reviewed hospital chart, public health and occupational health records to determine demographics, case type (community- or hospital-acquired), need for critical care and outcome for each case linked to the outbreak (patients, hospital staff, and community and patient visitors). We developed detailed transmission networks using epidemiologic data to determine what variables may have contributed to transmission. RESULTS: Fifty-eight cases of SARS-CoV-2 infection were linked to this hospital outbreak (31 patients, 25 staff members and 2 visitors; 66% female, age range 19-97 years). One patient required critical care, and 11 deaths were recorded (all among inpatients). Most cases were hospital-acquired (91%), and 28% were asymptomatic at the time of diagnosis. The outbreak was composed of 2 clusters driven by protective equipment breaches, premature removal of precautions, transmission in small staff quarters and infection of a staff member after exposure to a wandering patient with dementia and asymptomatic, undetected SARS-CoV-2 infection. INTERPRETATION: A detailed epidemiologic review of this hospital-wide outbreak shows that a SARS-CoV-2 outbreak can involve complex transmission chains and clusters. Multipronged bundled approaches, aggressive contact tracing, and patient and staff prevalence screening are important to help bring such outbreaks under control, along with ongoing vigilance in detecting delayed cases.

Improving the diagnostic accuracy for major depressive disorder using machine learning algorithms integrating clinical and near-infrared spectroscopy data.

BACKGROUND: Given that major depressive disorder (MDD) is both biologically and clinically heterogeneous, a diagnostic system integrating neurobiological markers and clinical characteristics would allow for better diagnostic accuracy and, consequently, treatment efficacy. OBJECTIVE: Our study aimed to evaluate the discriminative and predictive ability of unimodal, bimodal, and multimodal approaches in a total of seven machine learning (ML) models-clinical, demographic, functional near-infrared spectroscopy (fNIRS), combinations of two unimodal models, as well as a combination of all three-for MDD. METHODS: We recruited 65 adults with MDD and 68 matched healthy controls, who provided both sociodemographic and clinical information, and completed the HAM-D questionnaire. They were also subject to fNIRS measurement when participating in the verbal fluency task. Using the nested cross validation procedure, the classification performance of each ML model was evaluated based on the area under the receiver operating characteristic curve (ROC), balanced accuracy, sensitivity, and specificity. RESULTS: The multimodal ML model was able to distinguish between depressed patients and healthy controls with the highest balanced accuracy of 87.98 ± 8.84% (AUC = 0.92; 95% CI (0.84-0.99) when compared with the uni- and bi-modal models. CONCLUSIONS: Our multimodal ML model demonstrated the highest diagnostic accuracy for MDD. This reinforces the biological and clinical heterogeneity of MDD and highlights the potential of this model to improve MDD diagnosis rates. Furthermore, this model is cost-effective and clinically applicable enough to be established as a robust diagnostic system for MDD based on patients' biosignatures.

Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells.

Transplantation is an effective treatment of many clinical disorders, but the mechanisms that regulate immunological tolerance are uncertain and remain central to improving patient outcome. Hemopoietic stem cell transplantation (SCT) often establishes "mixed chimerism" in which immune cells from both the donor and patient coexist in vivo in a setting of immunological tolerance. We studied immune function in 69 patients within 2 months following SCT; 37 were fully donor and 32 displayed mixed chimerism. The proportion of T regulatory (Treg) cells was increased during mixed chimerism and comprised equal numbers of donor and host-derived regulatory cells. This was associated with a tolerogenic PD-L1+ profile on dendritic cells. Importantly, effector T cells from patients with mixed chimerism exhibited reduced cytotoxicity against host target cells in vitro, but this was restored following depletion of CD4+ Treg cells. These data show that Treg cells play a major role in sustaining immunological tolerance during mixed chimerism. These insights should help to guide novel interventions to improve clinical transplantation.

Patient, tumor, and healthcare factors associated with regional variability in lung cancer survival: a Spanish high-resolution population-based study.

PURPOSE: The third most frequently diagnosed cancer in Europe in 2018 was lung cancer; it is also the leading cause of cancer death in Europe. We studied patient and tumor characteristics, and patterns of healthcare provision explaining regional variability in lung cancer survival in southern Spain. METHODS: A population-based cohort study included all 1196 incident first invasive primary lung cancer (C33-C34 according to ICD-10) cases diagnosed between 2010 and 2011 with follow-up until April 2015. Data were drawn from local population-based cancer registries and patients' hospital medical records from all public and private hospitals from two regions in southern Spain. RESULTS: There was evidence of regional differences in lung cancer late diagnosis (58% stage IV in Granada vs. 65% in Huelva, p value < 0.001). Among patients with stage I, only 67% received surgery compared with 0.6% of patients with stage IV. Patients treated with a combination of radiotherapy, chemotherapy, and surgery had a 2-year mortality risk reduction of 94% compared with patients who did not receive any treatment (excess mortality risk 0.06; 95% CI 0.02-0.16). Geographical differences in survival were observed between the two regions: 35% vs. 26% at 1-year since diagnosis. CONCLUSIONS: The observed geographic differences in survival between regions are due in part to the late cancer diagnosis which determines the use of less effective therapeutic options. Results from our study justify the need for promoting lung cancer early detection strategies and the harmonization of the best practice in lung cancer management and treatment.

Unique features and clinical importance of acute alloreactive immune responses.

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.

Maternal L-carnitine supplementation improves glucose and lipid profiles in female offspring of dams exposed to cigarette smoke.

Sex differences in disease susceptibility due to maternal programming have been reported. We previously observed that maternal smoking induced renal disease and neurological changes are restricted to males, while both male and female offspring develop metabolic disorders. We have also found that maternal L-carnitine supplementation during gestation and lactation can significantly improve glucose intolerance and hyperlipidaemia in male offspring. This study aimed to determine whether such beneficial effects can also occur in female offspring. Balb/c female mice were exposed to cigarette smoke (SE) 6 weeks prior to gestation, during gestation and lactation. A subgroup of the SE dams was given L-carnitine (1.5 mmol/L in drinking water) during gestation and lactation. Female offspring were studied at 20 days (weaning) and 13 weeks (adulthood). Maternal smoking increased liver weight (%) and blood glucose levels at 20 days, as well as glucose intolerance and plasma triglycerides levels at adulthood (P < .05). The hepatic lipid metabolic marker adipose triglyceride lipase was downregulated in the SE offspring at 20 days (P < .05). At 13 weeks, the hepatic pro-inflammatory markers IL-1ß and TNF-α mRNA expression were upregulated, while the anti-inflammatory marker IL-10 mRNA expression was downregulated in the SE offspring (P < .05). Liver fibrosis was apparent at 20 days and 13 weeks. Maternal L-carnitine supplementation either normalised or suppressed the detrimental effects induced by maternal smoke exposure (P < .05). We conclude that maternal L-carnitine supplementation improves metabolic parameters in the female offspring of SE dams.

Measurement of the Electron Antineutrino Oscillation with 1958 Days of Operation at Daya Bay.

We report a measurement of electron antineutrino oscillation from the Daya Bay Reactor Neutrino Experiment with nearly 4 million reactor ν[over ¯]_{e} inverse ß decay candidates observed over 1958 days of data collection. The installation of a flash analog-to-digital converter readout system and a special calibration campaign using different source enclosures reduce uncertainties in the absolute energy calibration to less than 0.5% for visible energies larger than 2 MeV. The uncertainty in the cosmogenic ^{9}Li and ^{8}He background is reduced from 45% to 30% in the near detectors. A detailed investigation of the spent nuclear fuel history improves its uncertainty from 100% to 30%. Analysis of the relative ν[over ¯]_{e} rates and energy spectra among detectors yields sin^{2}2θ_{13}=0.0856±0.0029 and Δm_{32}^{2}=(2.471_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the normal hierarchy, and Δm_{32}^{2}=-(2.575_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the inverted hierarchy.

Evolution of the Reactor Antineutrino Flux and Spectrum at Daya Bay.

The Daya Bay experiment has observed correlations between reactor core fuel evolution and changes in the reactor antineutrino flux and energy spectrum. Four antineutrino detectors in two experimental halls were used to identify 2.2 million inverse beta decays (IBDs) over 1230 days spanning multiple fuel cycles for each of six 2.9 GW_{th} reactor cores at the Daya Bay and Ling Ao nuclear power plants. Using detector data spanning effective ^{239}Pu fission fractions F_{239} from 0.25 to 0.35, Daya Bay measures an average IBD yield σ[over ¯]_{f} of (5.90±0.13)×10^{-43} cm^{2}/fission and a fuel-dependent variation in the IBD yield, dσ_{f}/dF_{239}, of (-1.86±0.18)×10^{-43} cm^{2}/fission. This observation rejects the hypothesis of a constant antineutrino flux as a function of the ^{239}Pu fission fraction at 10 standard deviations. The variation in IBD yield is found to be energy dependent, rejecting the hypothesis of a constant antineutrino energy spectrum at 5.1 standard deviations. While measurements of the evolution in the IBD spectrum show general agreement with predictions from recent reactor models, the measured evolution in total IBD yield disagrees with recent predictions at 3.1σ. This discrepancy indicates that an overall deficit in the measured flux with respect to predictions does not result from equal fractional deficits from the primary fission isotopes ^{235}U, ^{239}Pu, ^{238}U, and ^{241}Pu. Based on measured IBD yield variations, yields of (6.17±0.17) and (4.27±0.26)×10^{-43} cm^{2}/fission have been determined for the two dominant fission parent isotopes ^{235}U and ^{239}Pu. A 7.8% discrepancy between the observed and predicted ^{235}U yields suggests that this isotope may be the primary contributor to the reactor antineutrino anomaly.

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT.

The graft-versus-leukemia (GVL) effect of allogeneic hemopoietic stem cell transplantation (allo-HSCT) is mediated by the donor immune system and acts to decrease the rate of disease relapse. Although studies of posttransplant immune reconstitution have identified correlates of clinical outcome, the number and profile of mature immune cells infused with the stem cell graft is also likely to be an important determinant and has been relatively poorly studied. We characterized immune cells within the stem cell graft of 107 patients who underwent T-cell-depleted allo-HSCT and related this to clinical outcome. The number of natural killer (NK) cells and T cells that were infused varied markedly between patients, but T-cell dose was not an important factor in subsequent outcome. In contrast, the number of NK cells was a powerful determinant of the risk of disease relapse. Patients who received an NK cell dose below the median level of 6.3 × 106 cells per kg had a relapse rate of 40% at 2 years posttransplant compared with only 6% for those whose stem cell graft contained a dose above this value. Analysis of NK subsets showed that this effect was mediated primarily by the CD56dim population of mature effector cells and that high-level expression of the activatory protein DNAM on donor NK cells was also strongly protective. These observations offer important insights into the mechanism of GVL and suggest that optimization studies of the number of NK cells within the stem cell graft should be considered as a means to reduce disease relapse.

Improved Search for a Light Sterile Neutrino with the Full Configuration of the Daya Bay Experiment.

This Letter reports an improved search for light sterile neutrino mixing in the electron antineutrino disappearance channel with the full configuration of the Daya Bay Reactor Neutrino Experiment. With an additional 404 days of data collected in eight antineutrino detectors, this search benefits from 3.6 times the statistics available to the previous publication, as well as from improvements in energy calibration and background reduction. A relative comparison of the rate and energy spectrum of reactor antineutrinos in the three experimental halls yields no evidence of sterile neutrino mixing in the 2×10^{-4}≲|Δm_{41}^{2}|≲0.3 eV^{2} mass range. The resulting limits on sin^{2}2θ_{14} are improved by approx imately a factor of 2 over previous results and constitute the most stringent constraints to date in the |Δm_{41}^{2}|≲0.2 eV^{2} region.

Limits on Active to Sterile Neutrino Oscillations from Disappearance Searches in the MINOS, Daya Bay, and Bugey-3 Experiments.

Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the Liquid Scintillator Neutrino Detector (LSND) and MiniBooNE experiments in a minimally extended four-neutrino flavor framework. Stringent limits on sin^{2}2θ_{µe} are set over 6 orders of magnitude in the sterile mass-squared splitting Δm_{41}^{2}. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for Δm_{41}^{2}<0.8 eV^{2} at 95% CL_{s}.

Measurement of the Reactor Antineutrino Flux and Spectrum at Daya Bay.

This Letter reports a measurement of the flux and energy spectrum of electron antineutrinos from six 2.9 GWth nuclear reactors with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls in the Daya Bay experiment. Using 217 days of data, 296 721 and 41 589 inverse ß decay (IBD) candidates were detected in the near and far halls, respectively. The measured IBD yield is (1.55±0.04) ×10(-18) cm(2) GW(-1) day(-1) or (5.92±0.14) ×10(-43) cm(2) fission(-1). This flux measurement is consistent with previous short-baseline reactor antineutrino experiments and is 0.946±0.022 (0.991±0.023) relative to the flux predicted with the Huber-Mueller (ILL-Vogel) fissile antineutrino model. The measured IBD positron energy spectrum deviates from both spectral predictions by more than 2σ over the full energy range with a local significance of up to ∼4σ between 4-6 MeV. A reactor antineutrino spectrum of IBD reactions is extracted from the measured positron energy spectrum for model-independent predictions.

New measurement of antineutrino oscillation with the full detector configuration at Daya Bay.

We report a new measurement of electron antineutrino disappearance using the fully constructed Daya Bay Reactor Neutrino Experiment. The final two of eight antineutrino detectors were installed in the summer of 2012. Including the 404 days of data collected from October 2012 to November 2013 resulted in a total exposure of 6.9×10^{5} GW_{th} ton days, a 3.6 times increase over our previous results. Improvements in energy calibration limited variations between detectors to 0.2%. Removal of six ^{241}Am-^{13}C radioactive calibration sources reduced the background by a factor of 2 for the detectors in the experimental hall furthest from the reactors. Direct prediction of the antineutrino signal in the far detectors based on the measurements in the near detectors explicitly minimized the dependence of the measurement on models of reactor antineutrino emission. The uncertainties in our estimates of sin^{2}2θ_{13} and |Δm_{ee}^{2}| were halved as a result of these improvements. An analysis of the relative antineutrino rates and energy spectra between detectors gave sin^{2}2θ_{13}=0.084±0.005 and |Δm_{ee}^{2}|=(2.42±0.11)×10^{-3} eV^{2} in the three-neutrino framework.

Search for a light sterile neutrino at Daya Bay.

A search for light sterile neutrino mixing was performed with the first 217 days of data from the Daya Bay Reactor Antineutrino Experiment. The experiment's unique configuration of multiple baselines from six 2.9 GW(th) nuclear reactors to six antineutrino detectors deployed in two near (effective baselines 512 m and 561 m) and one far (1579 m) underground experimental halls makes it possible to test for oscillations to a fourth (sterile) neutrino in the 10(-3) eV(2)<|Δm(41)(2) |< 0.3 eV(2) range. The relative spectral distortion due to the disappearance of electron antineutrinos was found to be consistent with that of the three-flavor oscillation model. The derived limits on sin(2) 2θ(14) cover the 10(-3) eV(2) ≲ |Δm(41)(2)| ≲ 0.1 eV(2) region, which was largely unexplored.

Spectral measurement of electron antineutrino oscillation amplitude and frequency at Daya Bay.

A measurement of the energy dependence of antineutrino disappearance at the Daya Bay reactor neutrino experiment is reported. Electron antineutrinos (ν¯(e)) from six 2.9 GW(th) reactors were detected with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls. Using 217 days of data, 41 589 (203 809 and 92 912) antineutrino candidates were detected in the far hall (near halls). An improved measurement of the oscillation amplitude sin(2)2θ(13)=0.090(-0.009)(+0.008) and the first direct measurement of the ν¯(e) mass-squared difference |Δm(ee)2|=(2.59(-0.20)(+0.19))×10(-3) eV2 is obtained using the observed ν¯(e) rates and energy spectra in a three-neutrino framework. This value of |Δm(ee)2| is consistent with |Δm(µµ)2| measured by muon neutrino disappearance, supporting the three-flavor oscillation model.

The volumetric relationship of white matter lesion and contrast-enhanced lesion in delayed radiation brain injury: an MRI-based study.

PURPOSE: This study investigated the volumetric relationship of white matter lesion (WML) and contrast-enhanced lesion (CEL) in delayed radiation brain injury (RBI) during the course of evolution. MATERIALS AND METHODS: MRI results in 45 patients with RBI after receiving radiation for nasopharyngeal carcinoma were analyzed. In total there were 75 lobes with RBI and 114 MRI examinations in this study. WML and CEL lesion volumes were measured. The lesion volume change of less than 5% or 0.25 cm(3) was regarded as being static. RESULTS: The average WML volume was 16.33 cm(3) (ranging 0.11 cm(3) to 102.83 cm(3)), and the average CEL volume was 3.15 cm(3) (ranging 0.03 cm(3) to 27.85 cm(3)). WML was larger than CEL in 164 measurements, and CEL was larger than WML in 10 measurements. In 64.3% follow-ups WML and CEL evolved in the same pattern; and in most follow-ups (93.8%) WML and CEL did not evolve in the opposite directions. A larger WML volume tended to have a larger CEL volume though this relationship was not linear. CONCLUSION: Evolution of WML and CEL tended to follow the same pattern. WML tended to be larger than CEL, and larger WML tended to be associated with larger CEL.