Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute ...rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue.
We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection.
The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m
of body-surface area before transplantation to 62 ml per minute per 1.73 m
after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m
in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys.
Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).
The mechanism for spread of SARS-CoV-2 has been attributed to large particles produced by coughing and sneezing. There is controversy whether smaller airborne particles may transport SARS-CoV-2. ...Smaller particles, particularly fine particulate matter (≤ 2.5 µm in diameter), can remain airborne for longer periods than larger particles and after inhalation will penetrate deeply into the lungs. Little is known about the size distribution and location of airborne SARS-CoV-2 RNA.
As a measure of hospital-related exposure, air samples of three particle sizes (> 10.0 µm, 10.0-2.5 µm, and ≤ 2.5 µm) were collected in a Boston, Massachusetts (USA) hospital from April to May 2020 (N = 90 size-fractionated samples). Locations included outside negative-pressure COVID-19 wards, a hospital ward not directly involved in COVID-19 patient care, and the emergency department.
SARS-CoV-2 RNA was present in 9% of samples and in all size fractions at concentrations of 5 to 51 copies m
. Locations outside COVID-19 wards had the fewest positive samples. A non-COVID-19 ward had the highest number of positive samples, likely reflecting staff congregation. The probability of a positive sample was positively associated (r = 0.95, p < 0.01) with the number of COVID-19 patients in the hospital. The number of COVID-19 patients in the hospital was positively associated (r = 0.99, p < 0.01) with the number of new daily cases in Massachusetts.
More frequent detection of positive samples in non-COVID-19 than COVID-19 hospital areas indicates effectiveness of COVID-ward hospital controls in controlling air concentrations and suggests the potential for disease spread in areas without the strictest precautions. The positive associations regarding the probability of a positive sample, COVID-19 cases in the hospital, and cases in Massachusetts suggests that hospital air sample positivity was related to community burden. SARS-CoV-2 RNA with fine particulate matter supports the possibility of airborne transmission over distances greater than six feet. The findings support guidelines that limit exposure to airborne particles including fine particles capable of longer distance transport and greater lung penetration.
Academic hospital nurses were surveyed to assess adherence barriers to a universal povidone-iodine nasal decolonization protocol to prevent Staphylococcus aureus infection. Low training rates, ...inadequate supplies, documentation and tracking challenges, patient refusal, and burnout contributed to suboptimal adherence. Prioritizing education is essential but alone is insufficient for successful protocol adoption.
Understanding the mechanism of SARS‐CoV‐2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of ...repurposable and investigational drugs as potential therapeutics against COVID‐19. These were deduced from the gene expression signature of SARS‐CoV‐2‐infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral–host interactome. We also identified immuno‐modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID‐19 patients, based on the transcriptome of ACE2‐overexpressing A549 cells. Experiments with Vero‐E6 cells infected by SARS‐CoV‐2, as well as independent syncytia formation assays for probing ACE2/SARS‐CoV‐2 spike protein‐mediated cell fusion using HEK293T and Calu‐3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero‐E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID‐19.
SYNOPSIS
A systems pharmacology approach is proposed to identify small molecules and drugs that target host cells and have anti‐SARS‐CoV‐2 effects. Shortlisted drug candidates are experimentally validated.
Host‐targeted antiviral and anti‐cytokine compounds are inferred from the transcriptome data of SARS‐CoV‐2‐infected cells.
Salmeterol exhibits a strong antiviral effect in SARS‐CoV‐2‐infected Vero‐E6 cells.
Syncytia formation assays confirm that linsitinib is a potent inhibitor of viral entry.
Additional compounds are proposed for adjuvant anti‐inflammatory therapies.
A systems pharmacology approach is proposed to identify small molecules and drugs that target host cells and have anti‐SARS‐CoV‐2 effects. Shortlisted drug candidates are experimentally validated.
Exposure to particulate matter (PM) could increase both susceptibility to SARS-CoV-2 infection and severity of COVID-19 disease. Prior studies investigating associations between PM and COVID-19 ...morbidity have only considered PM2.5 or PM10, rather than PM1. We investigated the associations between daily-diagnosed COVID-19 morbidity and average exposures to ambient PM1 starting at 0 through 21 days before the day of diagnosis in 12 cities in China using a two-step analysis: a time-series quasi-Poisson analysis to analyze the associations in each city; and then a meta-analysis to estimate the overall association. Diagnosed morbidities and PM1 data were obtained from National Health Commission in China and China Meteorological Administration, respectively. We found association between short-term exposures to ambient PM1 with COVID-19 morbidity was significantly positive, and larger than the associations with PM2.5 and PM10. Percent increases in daily-diagnosed COVID-19 morbidity per IQR/10 PM1 for different moving averages ranged from 1.50% (−1.20%, 4.30%) to 241% (95%CI: 80.7%, 545%), with largest values for exposure windows starting at 17 days before diagnosis. Our results indicate that smaller particles are more highly associated with COVID-19 morbidity, and most of the effects from PM2.5 and PM10 on COVID-19 may be primarily due to the PM1. This study will be helpful for implementing measures and policies to control the spread of COVID-19.
•The first attempt to examine the association between PM1 and COVID-19 morbidity.•Short-term exposure to ambient PM1 is associated with COVID-19 morbidity.•Smaller particles are more highly associated with COVID-19 morbidity.
We report the molecular recognition of the Au(CN)2 – anion, a crucial intermediate in today’s gold mining industry, by α-cyclodextrin. Three X-ray single-crystal ...superstructuresKAu(CN)2⊂α-cyclodextrin, KAu(CN)2⊂(α-cyclodextrin)2, and KAg(CN)2⊂(α-cyclodextrin)2demonstrate that the binding cavity of α-cyclodextrin is a good fit for metal-coordination complexes, such as Au(CN)2 – and Ag(CN)2 – with linear geometries, while the K+ ions fulfill the role of linking α-cyclodextrin tori together as a result of K+···O ion−dipole interactions. A 1:1 binding stoichiometry between Au(CN)2 – and α-cyclodextrin in aqueous solution, revealed by 1H NMR titrations, has produced binding constants in the order of 104 M–1. Isothermal calorimetry titrations indicate that this molecular recognition is driven by a favorable enthalpy change overcoming a small entropic penalty. The adduct formation of KAu(CN)2⊂α-cyclodextrin in aqueous solution is sustained by multiple C–H···π and C–H···anion interactions in addition to hydrophobic effects. The molecular recognition has also been investigated by DFT calculations, which suggest that the 2:1 binding stoichiometry between α-cyclodextrin and Au(CN)2 – is favored in the presence of ethanol. We have demonstrated that this molecular recognition process between α-cyclodextrin and KAu(CN)2 can be applied to the stripping of gold from the surface of activated carbon at room temperature. Moreover, this stripping process is selective for Au(CN)2 – in the presence of Ag(CN)2 –, which has a lower binding affinity toward α-cyclodextrin. This molecular recognition process could, in principle, be integrated into commercial gold-mining protocols and lead to significantly reduced costs, energy consumption, and environmental impact.
Radon is a prevalent carcinogenic gas and the leading cause of lung cancer in the United States besides smoking. As the residential environment is the primary source of radon exposure, accessible and ...accurate measurements of radon in this environment are essential. However, no radon monitors have been evaluated that are inexpensive enough for regular household use. In this study, we examine two household-grade, continuous monitoring devices, the Ecosense RadonEye and EcoQube. We compare them to two research-grade instruments, the Durridge Company Rad7 and the Rad Elec Inc. E-PERM. In our study, the Ecosense household radon monitors performed accurately and can be used by homeowners and researchers alike as an affordable and reliable radon sensor.
Implications: The ability of homeowners and renters to regularly monitor the radon levels inside their home is an important preventative health measure. However, low-cost instrumentation is needed that can provide accurate radon measurements. In this study, we show that the affordable Ecosense continuous monitors produce results that are in line with expensive research-grade instruments in a residential environment, over a range of concentrations. The Ecosense monitors may be suitable for home use, and they may provide a solution that can be used by policymakers and home-dwellers alike to improve regular radon monitoring in residences.
Seizures are rare during repetitive transcranial magnetic stimulation (rTMS) treatment, but estimating risk is difficult because of study heterogeneity and sampling limitations. Moreover, there are ...few studies comparing rates between device manufacturers.
The objective of this study was to calculate rTMS seizure rates across various FDA-cleared devices in naturalistic clinical settings.
In July and August 2018, approximately 500 members of the Clinical TMS Society (CTMSS) were electronically surveyed about seizures in their practices. Seizures were distinguished from non-seizures by a remote semi-structured interview with a Board-certified neurologist and Co-Chair of the CTMSS Standards Committee. Exact Poisson calculations were used to estimate seizure rates and confidence intervals across the four most widely used manufacturers.
The survey was completed by 134 members, with 9 responses excluded because of data inconsistencies. In total, 18 seizures were reported in 586,656 sessions and 25,526 patients across all device manufacturers. The overall seizure rate was 0.31 (95% CI: 0.18, 0.48) per 10,000 sessions, and 0.71 (95% CI: 0.42, 1.11) per 1000 patients. The Brainsway H-coil seizure rate of 5.56 per 1000 patients (95% CI: 2.77,9.95) was significantly higher (p < 0.001) than the three most widely used figure- 8 coil devices’ combined seizure rate of 0.14 per 1000 patients (95% CI: 0.01, 0.51).
The absolute risk of a seizure with rTMS is low, but generic Brainsway H-coil treatment appears to be associated with a higher relative risk than generic figure- 8 coil treatment. Well-designed prospective studies are warranted to further investigate this risk.
•Clinical TMS Society Members were surveyed about TMS seizures in their practices.•Reported seizures were reviewed by a Board-certified neurologist.•18 seizures were reported in 586,656 sessions and 25,526 patients across devices.•Overall seizure rate was 0.31 per 10,000 sessions and 0.71 per 1000 patients.•H-coil seizure rate was significantly higher than figure- 8 coil seizure rate.
To determine if older patients with breast cancer have cognitive impairment before systemic therapy.
Participants were patients with newly diagnosed nonmetastatic breast cancer and matched friend or ...community controls age > 60 years without prior systemic treatment, dementia, or neurologic disease. Participants completed surveys and a 55-minute battery of 17 neuropsychological tests. Biospecimens were obtained for APOE genotyping, and clinical data were abstracted. Neuropsychological test scores were standardized using control means and standard deviations (SDs) and grouped into five domain z scores. Cognitive impairment was defined as any domain z score two SDs below or ≥ two z scores 1.5 SDs below the control mean. Multivariable analyses evaluated pretreatment differences considering age, race, education, and site; comparisons between patient cases also controlled for surgery.
The 164 patient cases and 182 controls had similar neuropsychological domain scores. However, among patient cases, those with stage II to III cancers had lower executive function compared with those with stage 0 to I disease, after adjustment (P = .05). The odds of impairment were significantly higher among older, nonwhite, less educated women and those with greater comorbidity, after adjustment. Patient case or control status, anxiety, depression, fatigue, and surgery were not associated with impairment. However, there was an interaction between comorbidity and patient case or control status; comorbidity was strongly associated with impairment among patient cases (adjusted odds ratio, 8.77; 95% CI, 2.06 to 37.4; P = .003) but not among controls (P = .97). Only diabetes and cardiovascular disease were associated with impairment among patient cases.
There were no overall differences between patients with breast cancer and controls before systemic treatment, but there may be pretreatment cognitive impairment within subgroups of patient cases with greater tumor or comorbidity burden.
Summary Background We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical ...phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Methods Between January and August, 2010, 18–26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ1–42 , total tau and phospho-tau181 concentrations, and plasma Aβ1–42 concentrations and Aβ1–42 :Aβ1–40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ1–42 concentrations (p=0·008) and plasma Aβ1–42 concentrations (p=0·01) than non-carriers. Interpretation Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ1–42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Funding Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.
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