First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.

Effect of pharmacodynamical interaction between nutlin-3a and aspirin in the activation of p53.

BACKGROUND AND OBJECTIVE: p53, an anti-tumour protein, is significantly inactivated in most tumours. A small molecule of nutlin-3a is used to activate its function by repressing (Mouse double minute 2 homolog) Mdm2 protein which inhibits its activity. In cancer patients, a high risk of drug-drug interactions (DDIs) is observed owing to their multi-dosing prescriptions, which may lead them to harmful effects. In the presented work, we have aimed to investigate the effect of pharmacodynamical interaction between two anti-cancer drugs, nutlin-3a and aspirin in the activation of p53 protein. METHODS: We have adapted control system techniques and designed a Proportional-Integral-Derivative (PID) controller. This controller is used to activate p53 protein. A drug interaction parameter is used to incorporate the effect of both drugs. Extensive simulation is performed using two different doses of aspirin, i.e. a low and a high dose of aspirin. RESULTS: The result shows no harmful effects of pharmacodynamical interaction when a low dose is administered along with nutlin-3a. When a high dose of aspirin is administered it acts as input disturbance and leads to undesirable over-expression of p53 protein. This can further harm other growth cells, thus inducing harmful effects. A comparative analysis is also tabulated with different dosing regimens which shows that a combination of nutlin-3a and a low dose of aspirin provides better results than a high dose of aspirin. CONCLUSION: Overall, the work provides an insight to the activation of p53 protein in cancer patients under the presence of pharmacodynamical interaction and might contribute to the effective management of cancer patients.

"Strong Teeth": an early-phase study to assess the feasibility of an oral health intervention delivered by dental teams to parents of young children.

BACKGROUND: Tooth decay (caries) is a significant health burden in young children. There is strong evidence for the benefits of establishing appropriate home-based oral health behaviours in early childhood. Dental teams are well placed to provide this information and there is clear advice on what oral health information should be given to parents. However, research has shown that there is limited guidance, training and resources on how dental teams should deliver this advice. "Strong Teeth" is a complex oral health intervention, using evidence-based resources and training underpinned by behaviour change psychology, to support behaviour change conversations in dental practice. This early phase evaluation aims to assess the feasibility of this intervention, prior to a full-scale trial. METHODS: The study recruited 15 parents of children aged 0-2-years-old and 21 parents of children aged 3-5 years old, from five NHS dental practices across West Yorkshire. Participant demographics, self-reported brushing behaviours, dietary habits, a dental examination and three objective measures of toothbrushing were collected in a home-setting at baseline, then at 2-weeks and 2-months post-intervention. Recruitment, retention and intervention delivery were analysed as key process outcomes. Brushing habits were compared to national toothbrushing guidelines - the Delivering Better Oral Health toolkit (Public Health England). RESULTS: Strong Teeth was feasible to deliver in a General Dental Practice setting in 94% of cases. Feasibility of recruitment (37%) exceeded progression criterion, however retention of participants (75%) was below the progression criterion for the 0-2 age group. More than half of children recruited aged 3-5-years had caries experience (52%). Total compliance to toothbrushing guidance at baseline was low (28%) and increased after the intervention (52%), an improvement that was statistically significant. Dietary habits remained largely unchanged. Plaque scores significantly decreased in the 3-5-year-olds and toothbrushing duration increased in all age groups. CONCLUSION: "Strong Teeth" intervention delivery and data collection in the home setting was feasible. There was a positive indication of impact on reported toothbrushing behaviours. Some amendments to study design, particularly relating to the inclusion of the 0-2-year-old group, should be considered before progression to a full trial. Trial registration ISRCTN Register: ISRCTN10709150. Registered retrospectively 24/7/2019.

Does the Pittsburgh Severity Score predict outcome in esophageal perforation?

Esophageal perforation is an uncommon and challenging surgical emergency associated with high rates of morbidity and mortality. At present, no consensus exists on optimal management of the condition. The Pittsburgh Severity Score (PSS) is a tool intended to stratify perforation severity and guide treatment. However, there is a paucity of literature examining the validity of the score or its application in a UK population. This study aims to validate the PSS and explore its use in stratifying patients with esophageal perforation into distinct subgroups with differential outcomes in an independent UK study population.All patients treated for esophageal perforation at Queen Elizabeth Hospital, Birmingham between September 2003 and October 2017 were included in this study. Cases were identified using a combination of ICD-10 and OPCS informatics search codes and prospective case collection. Data relating to the clinical presentation, diagnosis, management, and outcome of cases were recorded using a preformed data collection form. PSS predictive performance was assessed against five outcomes: rates of post-perforation and post-operative complications, in-hospital mortality, length of intensive care (ICU/HDU) stay, and total length of hospital stay.A total of 87 cases were identified, consisting of 48 (55%) iatrogenic perforations, 24 (28%) cases of spontaneous (Boerhaave's) perforation, and 15 perforations due to other etiologies (17%). Operative management was favored in this series, with 47% of all perforations being treated surgically. Overall in-hospital mortality was 13%, coupled with a median length of hospital stay of 24 days (interquartile range [IQR]: 12-49), of which a median of 2 days was spent in intensive care facilities (IQR: 0-14). A total of 46% of patients developed post-perforation complications, with 59% of the operatively managed cohort developing complications post-operatively.The PSS was not found to be significantly predictive of post-perforation complications (area under the ROC curve [AUROC]: 0.62, p = 0.053) or in-hospital mortality (AUROC: 0.69, p = 0.057) for the cohort as a whole. However, a subgroup analysis found the accuracy of the PSS to vary considerably by etiology, being significantly predictive of post-perforation complications within the subgroup of Boerhaave's perforations (AUROC: 0.86, p = 0.004).In conclusion, we found that the PSS has some utility in stratifying esophageal perforation severity and predicting specific patient outcomes. However, it appears to be of more value when applied to the subgroup of patients with Boerhaave's perforations.

Ellipsometric-based novel DNA biosensor for label-free, real-time detection of Bordetella parapertussis.

Pertussis (or whooping cough) is a contagious disease mainly affecting infants and children and predominantly caused by Bordetella pertussis followed by Bordetella parapertussis. B. parapertussis causes a milder cough but usually symptomatically appears like B. pertussis infection. Thus the epidemiology of illness caused by B. parapertussis is not well understood. In this study, a sensitive and specific method for the rapid diagnosis of B. parapertussis is presented. The covalent immobilization of thiol-terminated DNA oligonucleotides (ss DNA SAM) on a silicon surface by disulfide bond formation is investigated with atomic force microscopy (AFM) and ellipsometry. The measurements indicated an average layer thickness of 5 ± 0.84 nm for 2 µg/µl concentration and 24 h incubation time. This thickness changed to 8.4 ± 0.92 nm for the same concentration (2 µg/µl) by altering the incubation time to 48 h. Ellipsometric data recorded before and after hybridization of B. parapertussis revealed an increase in mean grain area from 91 nm2 to 227 nm2 and a change in the refractive index from 1.489 to 1.648 for 2 µg/µl B. parapertussis, respectively. This change in the refractive index was used to evaluate the amount of adsorbed molecules and their density. The results showed that the density of adsorbed molecules increased from 0.2 to 0.97 g/cm3 after B. parapertussis attachment, respectively. To confirm the hybridization of B. parapertussis to ss DNA SAM, the ds DNA SAM was denatured and the ss DNA SAM surface was reproduced with an average height variation of 6.42 ± 0.75 nm. This showed the stability of the DNA film that can be tuned by varying the concentration and incubation time, thus providing a robust method for the label-free detection of B. parapertussis other than routinely used PCR detection.

Search for the Exotic Meson X(5568) with the Collider Detector at Fermilab.

A search for the exotic meson X(5568) decaying into the B_{s}^{0}π^{±} final state is performed using data corresponding to 9.6 fb^{-1} from pp[over ¯] collisions at sqrt[s]=1960 GeV recorded by the Collider Detector at Fermilab. No evidence for this state is found and an upper limit of 6.7% at the 95% confidence level is set on the fraction of B_{s}^{0} produced through the X(5568)→B_{s}^{0}π^{±} process.

Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots.

Pyrazinamide-resistant mycobacterium tuberculosis isolates from Khyber Pakhtunkhwa and rpsA mutations.

Pyrazinamide (PZA) is a key first-line antibiotic used for the short-course treatment of drug-sensitive and multidrug-resistant (MDR) isolates of tuberculosis. PZA exhibits potent action against semi-dormant bacilli in acidic environments. However, mutations that occur in target genes may cause technical difficulties in the diagnosis of PZA resistance during drug susceptibility testing. The objective of the current study is to identify mutations in pncAWT rpsA and rpsAWT panD genes among PZA-resistant isolates of Mycobacterium tuberculosis (MTB) circulating in the Pashtun dominant region, Khyber Pakhtunkhwa, Pakistan. We selected 18 PZA-resistant pncAWT strains from the Provincial Tuberculosis Reference Laboratory (PTRL) Khyber Pakhtunkhwa to investigate mutations in the coding region of rpsA and panD genes. The experiments were repeated for drug susceptibility testing using MGIT 960 automated system. In addition, eighteen PZA-resistant rpsA genes along with 5 susceptible strains and one H37Rv strain were sequenced. All 18 isolates were PZA-resistant. The majority of these isolates exhibited multidrug resistance (MDR) (13/18). We identified 14 non-synonymous and one synonymous mutation in the coding region of rpsA in 11 strains. All mutations were scattered throughout the gene and not reported previously. Further, we did not identify any mutation in 7 rpsAWT panD genes. Mutations in rpsA but not in panD occur in PZA-resistant pncAWT MTB isolates circulating in Khyber Pakhtunkhwa, Pakistan.

On p53 revival using system oriented drug dosage design.

We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The claimed dosage strategy achieves the p53 response in the first case. However, for the induction of oscillations, it is shown through bifurcation analysis that to achieve oscillating behavior of p53 inhibition of Mdm2 is not enough, rather antirepression of the p53-Mdm2 complex is also needed which leads to the need of a new drug design paradigm.

A replication study of 49 Type 2 diabetes risk variants in a Punjabi Pakistani population.

AIM: The burden of Type 2 diabetes is alarmingly high in South Asia, a region that has many genetically diverse ethnic populations. Genome-wide association studies (GWAS) conducted largely in European populations have identified a number of loci predisposing to Type 2 diabetes risk, however, the relevance of such genetic loci in many South Asian sub-ethnicities remains elusive. The aim of this study was to replicate 49 single nucleotide polymorphisms (SNPs) previously identified through GWAS in Punjabis living in Pakistan. METHODS: We examined the association of 49 SNPs in 853 Type 2 diabetes cases and 1945 controls using additive logistic regression models after adjusting for age and gender. RESULTS: Of the 49 SNPs investigated, eight showed a nominal association (P < 0.05) that also remained significant after controlling for the false discovery rate. The most significant association was found for rs7903146 at the TCF7L2 locus. For a per unit increase in the risk score comprising of all the 49 SNPs, the odds ratio in association with Type 2 diabetes risk was 1.16 (95% CI 1.13-1.19, P < 2.0E-16). CONCLUSION: These results suggest that some Type 2 diabetes susceptibility loci are shared between Europeans and Punjabis living in Pakistan.

Search for Resonances Decaying to Top and Bottom Quarks with the CDF Experiment.

We report on a search for charged massive resonances decaying to top (t) and bottom (b) quarks in the full data set of proton-antiproton collisions at a center-of-mass energy of √[s]=1.96 TeV collected by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.5 fb(-1). No significant excess above the standard model background prediction is observed. We set 95% Bayesian credibility mass-dependent upper limits on the heavy charged-particle production cross section times branching ratio to tb. Using a standard model extension with a W'→tb and left-right-symmetric couplings as a benchmark model, we constrain the W' mass and couplings in the 300-900 GeV/c(2) range. The limits presented here are the most stringent for a charged resonance with mass in the range 300-600 GeV/c(2) decaying to top and bottom quarks.

Constraints on models of the Higgs boson with exotic spin and parity using decays to bottom-antibottom quarks in the full CDF data set.

A search for particles with the same mass and couplings as those of the standard model Higgs boson but different spin and parity quantum numbers is presented. We test two specific alternative Higgs boson hypotheses: a pseudoscalar Higgs boson with spin-parity J^{P}=0^{-} and a gravitonlike Higgs boson with J^{P}=2^{+}, assuming for both a mass of 125 GeV/c^{2}. We search for these exotic states produced in association with a vector boson and decaying into a bottom-antibottom quark pair. The vector boson is reconstructed through its decay into an electron or muon pair, or an electron or muon and a neutrino, or it is inferred from an imbalance in total transverse momentum. We use expected kinematic differences between events containing exotic Higgs bosons and those containing standard model Higgs bosons. The data were collected by the CDF experiment at the Tevatron proton-antiproton collider, operating at a center-of-mass energy of sqrt[s]=1.96 TeV, and correspond to an integrated luminosity of 9.45 fb^{-1}. We exclude deviations from the predictions of the standard model with a Higgs boson of mass 125 GeV/c^{2} at the level of 5 standard deviations, assuming signal strengths for exotic boson production equal to the prediction for the standard model Higgs boson, and set upper limits of approximately 30% relative to the standard model rate on the possible rate of production of each exotic state.

Good on paper: the gap between programme theory and real-world context in Pakistan's Community Midwife programme.

OBJECTIVE: To understand why skilled birth attendance-an acknowledged strategy for reducing maternal deaths-has been effective in some settings but is failing in Pakistan and to demonstrate the value of a theory-driven approach to evaluating implementation of maternal healthcare interventions. DESIGN: Implementation research was conducted using an institutional ethnographic approach. SETTING AND POPULATION: National programme and local community levels in Pakistan. METHODS: Observations, focus group discussions, and in-depth interviews were conducted with 38 Community Midwives (CMWs), 20 policymakers, 45 healthcare providers and 136 community members. A critical policy document review was conducted. National and local level data were brought together. MAIN OUTCOMES: Alignment of programme theory with real-world practice. RESULTS: Data revealed gaps between programme theory, assumptions and reality on the ground. The design of the programme failed to take into account: (1) the incongruity between the role of a midwife and dominant class and gendered norms that devalue such a role; (2) market and consumer behaviour that prevented CMWs from establishing private practices; (3) the complexity of public-private sector cooperation. Uniform deployment policies failed to consider existing provider density and geography. CONCLUSIONS: Greater attention to programme theory and the 'real-world' setting during design of maternal health strategies is needed to achieve consistent results in different contexts.

Measurement of the inclusive leptonic asymmetry in top-quark pairs that decay to two charged leptons at CDF.

We measure the inclusive forward-backward asymmetry of the charged-lepton pseudorapidities from top-quark pairs produced in proton-antiproton collisions and decaying to final states that contain two charged leptons (electrons or muons). The data are collected with the Collider Detector at Fermilab and correspond to an integrated luminosity of 9.1 fb(-1). We measure the leptonic forward-backward asymmetry, A(FB)(ℓ), to be 0.072 ± 0.060 and the leptonic pair forward-backward asymmetry, A(FB)(ℓℓ), to be 0.076 ± 0.082. The measured values can be compared with the standard model predictions of A(FB)(ℓ) = 0.038 ± 0.003 and A(FB)(ℓℓ) = 0.048 ± 0.004, respectively. Additionally, we combine the A(FB)(ℓ) result with a previous determination from a final state with a single lepton and hadronic jets and obtain A(FB)(ℓ) = 0.090(-0.026)(+0.028).

Search for s-channel single-top-quark production in events with missing energy plus jets in pp collisions at sqrt[s] = 1.96 TeV.

The first search for single-top-quark production from the exchange of an s-channel virtual W boson using events with an imbalance in the total transverse energy, b-tagged jets, and no identified leptons is presented. Assuming the electroweak production of top quarks of mass 172.5 GeV/c(2) in the s channel, a cross section of 1.12(-0.57)(+0.61) (stat+syst) pb with a significance of 1.9 standard deviations is measured. This measurement is combined with the result obtained from events with an imbalance in total transverse momentum, b-tagged jets, and exactly one identified lepton, yielding a cross section of 1.36(-0.32)(+0.37) (stat+syst) pb, with a significance of 4.2 standard deviations.

Evidence for s-channel single-top-quark production in events with one charged lepton and two jets at CDF.

We report evidence for s-channel single-top-quark production in proton-antiproton collisions at center-of-mass energy sqrt[s] = 1.96 TeV using a data set that corresponds to an integrated luminosity of 9.4 fb(-1) collected by the Collider Detector at Fermilab. We select events consistent with the s-channel process including two jets and one leptonically decaying W boson. The observed significance is 3.8 standard deviations with respect to the background-only prediction. Assuming a top-quark mass of 172.5 GeV/c(2), we measure the s-channel cross section to be 1.41(-0.42)(+0.44) pb.

Measurement of B(t→Wb)/B(t→Wq) in top-quark-pair decays using dilepton events and the full CDF Run II data set.

We present a measurement of the ratio of the top-quark branching fractions R=B(t→Wb)/B(t→Wq), where q represents any quark flavor, in events with two charged leptons, imbalance in total transverse energy, and at least two jets. The measurement uses proton-antiproton collision data at center-of-mass energy 1.96 TeV, corresponding to an integrated luminosity of 8.7 fb^{-1} collected with the Collider Detector at Fermilab during Run II of the Tevatron. We measure R to be 0.87±0.07, and extract the magnitude of the top-bottom quark coupling to be |V_{tb}|=0.93±0.04, assuming three generations of quarks. Under these assumptions, a lower limit of |V_{tb}|>0.85(0.87) at 95% (90%) credibility level is set.

Measurement of the single top quark production cross section and |Vtb| in events with one charged lepton, large missing transverse energy, and jets at CDF.

We report a measurement of single top quark production in proton-antiproton collisions at a center-of-mass energy of sqrt[s]=1.96 TeV using a data set corresponding to 7.5 fb(-1) of integrated luminosity collected by the Collider Detector at Fermilab. We select events consistent with the single top quark decay process t→Wb→ℓνb by requiring the presence of an electron or muon, a large imbalance of transverse momentum indicating the presence of a neutrino, and two or three jets including at least one originating from a bottom quark. An artificial neural network is used to discriminate the signal from backgrounds. We measure a single top quark production cross section of 3.04(-0.53)(+0.57) pb and set a lower limit on the magnitude of the coupling between the top quark and bottom quark |Vtb|>0.78 at the 95% credibility level.

Measurements of direct CP-violating asymmetries in charmless decays of bottom baryons.

We report final measurements of direct CP-violating asymmetries in charmless decays of neutral bottom hadrons to pairs of charged hadrons with the upgraded Collider Detector at the Fermilab Tevatron. Using the complete √s=1.96 TeV proton-antiproton collisions data set, corresponding to 9.3 fb⁻¹ of integrated luminosity, we measure A(Λ(b)°â†’pπ⁻)=+0.06±0.07(stat)±0.03(syst) and A(Λ(b)°â†’pK⁻)=-0.10±0.08(stat)±0.04(syst), compatible with no asymmetry. In addition we measure the CP-violating asymmetries in B(s)°â†’K⁻π⁺ and B°â†’K⁺π⁻ decays to be A(B(s)°â†’K⁻π⁺)=+0.22±0.07(stat)±0.02(syst) and A(B°â†’K⁺π⁻)=-0.083±0.013(stat)±0.004(syst), respectively, which are significantly different from zero and consistent with current world averages.

First search for exotic Z Boson decays into photons and neutral pions in hadron collisions.

A search for forbidden and exotic Z boson decays in the diphoton mass spectrum is presented for the first time in hadron collisions, based on data corresponding to 10.0 fb(-1) of integrated luminosity from proton-antiproton collisions at √s = 1.96 TeV collected by the CDF experiment. No evidence of signal is observed, and 95% credibility level Bayesian upper limits are set on the branching ratios of decays of the Z boson to a photon and neutral pion (which is detected as a photon), a pair of photons, and a pair of neutral pions. The observed branching ratio limits are 2.01 × 10(-5) for Z → π(0)γ, 1.46 × 10(-5) for Z → γγ, and 1.52 × 10(-5) for Z → π(0)π(0). The Z → π(0)γ and Z → γγ limits improve the most stringent results from other experiments by factors of 2.6 and 3.6, respectively. The Z → π(0)π(0) branching ratio limit is the first experimental result on this decay.