Objective
Commonly used endoscopic grading scales, such as the nasal polyp scale, inadequately describe the degree of polyposis found postoperatively in the paranasal sinus cavities. The purpose of ...this study was to create a novel grading system that more accurately characterizes polyp recurrence in postoperative sinus cavities, the Postoperative Polyp Scale (POPS).
Methods
A modified Delphi method was utilized to establish the POPS using consensus opinion among 13 general otolaryngologists, rhinologists, and allergists. Postoperative endoscopy videos from 50 patients with chronic rhinosinusitis with nasal polyps were reviewed by 7 fellowship‐trained rhinologists and scored according to the POPS. Videos were rated again 1 month later by the same reviewers, and scores were assessed for test–retest and inter‐rater reliability.
Results
Overall inter‐rater reliability for the first and second reviews of the 52 videos was Kf = 0.49 (95% CI 0.42–0.57) and Kf = 0.50 (95% CI 0.42–0.57) for the POPS. Intra‐rater reliability showed near‐perfect test–retest reliability for the POPS with Kf = 0.80 (95% CI 0.76–0.84).
Conclusion
The POPS is an easy‐to‐use, reliable, and novel objective endoscopic grading scale that more accurately describes polyp recurrence in the postoperative state which will be useful in the future for measuring the efficacy of various medical and surgical interventions.
Level of Evidence
5 Laryngoscope, 133:2885–2890, 2023
The Post‐Operative Polyp Scale (POPS) is a new endoscopic grading instrument for the evaluation of polyp recurrence in CRSwNP patients who have had standard ESS. We demonstrate that the POPS is easy to use and has good inter‐ and intra‐rater reliability. The POPS more accurately describes polyp recurrence in the postoperative state, which may be useful in the future for measuring the efficacy of various medical and surgical interventions.
Women with cosmetic breast implants have significantly lower rates of subsequent breast cancer than the general population (relative risk, 0.63; 95 percent CI, 0.56 to 0.71). The authors hypothesize ...that breast implant-induced local inflammation stimulates immunosurveillance recognition of breast tumor antigen.
Sera were collected from two cohorts of healthy women: women with long-term breast implants (i.e., breast implants for >6 months) and breast implant-naive women. Antibody responses to breast tumor antigens were tested by enzyme-linked immunosorbent assay and compared between cohorts by unpaired t test. Of the implant-naive cohort, nine women underwent breast augmentation, and antibody responses before and after implant placement were compared by paired t test.
Sera were collected from 104 women: 36 (34.6 percent) long-term breast implants and 68 (65.4 percent) implant-naive women. Women with long-term breast implants had higher antibody responses than implant-naive women to mammaglobin-A (optical density at 450 nm, 0.33 versus 0.22; p = 0.003) and mucin-1 (optical density at 450 nm, 0.42 versus 0.34; p = 0.02). There was no difference in antibody responses to breast cancer susceptibility gene 2, carcinoembryonic antigen, human epidermal growth factor receptor-2, or tetanus. Nine women with longitudinal samples preoperatively and 1 month postoperatively demonstrated significantly elevated antibody responses following implant placement to mammaglobin-A (mean difference, 0.13; p = 0.0002) and mucin-1 (mean difference 0.08; p = 0.02). There was no difference in postimplant responses to other breast tumor antigens, or tetanus.
Women with long-term breast implants have higher antibody recognition of mammaglobin-A and mucin-1. This study provides the first evidence of implant-related immune responses to breast cancer antigens.
Therapeutic, V.
High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial ...activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by liquid chromatography-mass spectrometry are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as
HRR defects confer synthetic lethality to PARP ...inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by
mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify
reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.
The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show
reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance.
.
Summary Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of ...disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million 192·7 million to 231·1 million global DALYs), smoking (148·6 million 134·2 million to 163·1 million), high fasting plasma glucose (143·1 million 125·1 million to 163·5 million), high BMI (120·1 million 83·8 million to 158·4 million), childhood undernutrition (113·3 million 103·9 million to 123·4 million), ambient particulate matter (103·1 million 90·8 million to 115·1 million), high total cholesterol (88·7 million 74·6 million to 105·7 million), household air pollution (85·6 million 66·7 million to 106·1 million), alcohol use (85·0 million 77·2 million to 93·0 million), and diets high in sodium (83·0 million 49·3 million to 127·5 million). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation.
A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as ...hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49 S was an excellent TRPV1 antagonist (K i(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49 S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49 S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49 S made additional hydrophobic interactions with the hydrophobic region.
The growing demand on water resources has increased interest in wastewater reclamation for potable reuse, in which rejection of organic micropollutants such as disinfection by-products (DBPs), ...endocrine disrupting compounds (EDCs), and pharmaceutically active compounds (PhACs) is of great concern. The objective of this study was to investigate the rejection of DBPs, EDCs, and PhACs by nanofiltration (NF) and reverse osmosis (RO) membranes as a function of their physico-chemical properties and initial feed water concentration. Experimental results indicated that negatively charged compounds could be rejected very effectively (i.e., >90%) regardless of other physico-chemical properties of the tested compounds due to electrostatic exclusion. No time-dependency was observed for rejection of charged compounds. In contrast, rejection of non-charged compounds was generally lower (<90% except for one case) and influenced mainly by the molecular size of the compounds. A clear time-dependency was observed for rejection of non-charged compounds, attributable to compound adsorption on the membrane. It was demonstrated that feed water concentration influenced rejection efficiency of the membrane. Experiments conducted at a low ng/l concentration range resulted in lower rejection efficiency as compared to experiments conducted at a μg/l range, suggesting the need to conduct experiments at the relevant concentration of interest.
Abstract
Background
The role of SARS-CoV-2 viral load in predicting contagiousness, disease severity, transmissibility, and clinical decision-making continues to be an area of great interest. ...However, most studies have been in adults and have evaluated SARS-CoV-2 loads using cycle thresholds (Ct) values, which are not standardized preventing consistent interpretation critical to understanding clinical impact and utility. Here, a quantitative SARS-CoV-2 reverse-transcription digital PCR (RT-dPCR) assay normalized to WHO International Units was applied to children at risk of severe disease diagnosed with COVID-19 at St. Jude Children’s Research Hospital between March 28, 2020, and January 31, 2022.
Methods
Demographic and clinical information from children, adolescents, and young adults treated at St. Jude Children’s Research Hospital were abstracted from medical records. Respiratory samples underwent SARS-CoV-2 RNA quantitation by RT-dPCR targeting N1 and N2 genes, with sequencing to determine the genetic lineage of infecting virus.
Results
Four hundred and sixty-two patients aged 0–24 years (median 11 years old) were included during the study period. Most patients were infected by the omicron variant (43.72%), followed by ancestral strain (22.29%), delta (13.20%), and alpha (2.16%). Viral load at presentation ranged from 2.49 to 9.14 log10 IU/mL, and higher viral RNA loads were associated with symptoms (OR 1.32; CI 95% 1.16–1.49) and respiratory disease (OR 1.23; CI 95% 1.07–1.41). Viral load did not differ by SARS-CoV-2 variant, vaccination status, age, or baseline diagnosis.
Conclusions
SARS-CoV-2 RNA loads predict the presence of symptomatic and respiratory diseases. The use of standardized, quantitative methods is feasible, allows for replication, and comparisons across institutions, and has the potential to facilitate consensus quantitative thresholds for risk stratification and treatment.
Results on two-particle angular correlations for charged particles emitted in proton-proton collisions at center-of-mass energies of 0.9, 2.36, and 7 TeV are presented, using data collected with the ...CMS detector over a broad range of pseudorapidity (
η
) and azimuthal angle (
ϕ
). Short-range correlations in Δ
η
, which are studied in minimum bias events, are characterized using a simple “independent cluster” parametrization in order to quantify their strength (cluster size) and their extent in
η
(cluster decay width). Long-range azimuthal correlations are studied differentially as a function of charged particle multiplicity and particle transverse momentum using a 980 nb
−1
data set at 7 TeV. In high multiplicity events, a pronounced structure emerges in the two-dimensional correlation function for particle pairs with intermediate
p
T
of 1–3 GeV/
c
, 2.0 < |Δ
η
| < 4
.
8 and Δ
ϕ
≈ 0. This is the first observation of such a long-range, near-side feature in two-particle correlation functions in
pp
or
collisions.
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