Acquired gene alterations in patients treated with ribociclib plus endocrine therapy or endocrine therapy alone using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials.

BACKGROUND: A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials. PATIENTS AND METHODS: Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was performed on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences. RESULTS: The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT vs baseline (P=0.08) was observed. Prevalence of alterations was higher at EOT vs baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar. CONCLUSIONS: This analysis identified acquired gene alterations in patients with HR+/HER2- advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-CDK4/6 inhibitor setting.

STING Agonist Induced Innate Immune Responses Drive Anti-Respiratory Virus Activity In Vitro with Limited Antiviral Efficacy In Vivo.

The emergence of SARS-CoV-2 and seasonal outbreaks of other respiratory viruses highlight the urgent need for broad-spectrum antivirals to treat respiratory tract infections. Stimulator of interferon genes (STING) is a key component of innate immune signaling and plays a critical role in protection of the host against viral infections. Previously the STING agonist diABZI-4, a diamidobenzimidazole-based compound, demonstrated protection against SARS-CoV-2 both in vitro and in vivo. However, its broad-spectrum antiviral activity against other respiratory viruses in human airway epithelial cells, which are the primary targets of these infections, is not well established. In this study, we demonstrated that diABZI-4 stimulated robust innate immune responses protecting lung cells against a wide range of respiratory viruses, including influenza A virus (IAV), common cold coronaviruses, SARS-CoV-2, human rhinovirus (HRV), and human parainfluenza virus. diABZI-4 was highly active in physiologically relevant human airway epithelial tissues grown at the air-liquid interface, blocking replication of IAV, SARS-CoV-2, and HRV in these tissues. Furthermore, treatment of macrophages with diABZI-4 resulted in the secretion of cytokines that protected the primary airway epithelial cells from IAV infection. Despite the promising in vitro pan-antiviral activity, intranasal administration of diABZI-4 in mice provided early, but not sustained, inhibition of IAV replication in the lungs. These data highlight the complexities of the relationship between timing of STING agonist-driven inflammatory responses and viral replication dynamics, emphasizing the development challenge posed by STING agonists as potential therapeutics against respiratory viruses.

Observing emergent hydrodynamics in a long-range quantum magnet.

Identifying universal properties of nonequilibrium quantum states is a major challenge in modern physics. A fascinating prediction is that classical hydrodynamics emerges universally in the evolution of any interacting quantum system. We experimentally probed the quantum dynamics of 51 individually controlled ions, realizing a long-range interacting spin chain. By measuring space-time-resolved correlation functions in an infinite temperature state, we observed a whole family of hydrodynamic universality classes, ranging from normal diffusion to anomalous superdiffusion, that are described by Lévy flights. We extracted the transport coefficients of the hydrodynamic theory, reflecting the microscopic properties of the system. Our observations demonstrate the potential for engineered quantum systems to provide key insights into universal properties of nonequilibrium states of quantum matter.

Scoring system for activation of critical care air transport team for aeromedical evacuation.

BACKGROUND: Our hospital began work on formulating its own critical care air transport team (CCATT) and patient transfer unit (PTU) in 2007. A total of 293 patients have been evacuated by air using the various models of the PTU from April 2008 to February 2017. This study has been undertaken to formulate a protocol for activation of CCATT for aeromedical evacuation that best suits our setup keeping in view the availability of electromedical equipment, manpower and aircrafts. METHODS: The study is a cross-sectional study involving patients who were air evacuated between January 2010 to February 2017. Statistical analysis tests were performed to compare and analyze the two scoring systems to find out the sensitivity and specificity of the two scoring systems and to find out the degree of agreement. RESULTS: The data using each scoring system were compared with actual requirement of CCATT based on recommendation of team leader of each CCATT mission and available data of each patient. It was observed that the old scoring system showed poor agreement with kappa coefficient of 0.162. The new scoring system based on modified early warning physiological score showed good agreement with kappa coefficient of 0.895. CONCLUSION: CCATT can be activated by peripheral medical echelons based on objective criteria rather than subjective ones so that optimal use of resources can be carried out not only in peace time but also during mass casualty scenarios such as natural calamities or war.

Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.

The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone 1 is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR. Repeat oral administration revealed diminished exposures over time, which prohibited further progression. A medicinal chemistry campaign was initiated to understand and abolish activation of PXR in order to increase systemic exposures. Rational structure-activity relationship investigations utilizing cocrystal structures and a de novo pharmacophore model resulted in compounds devoid of PXR activation. These studies culminated in the first orally active CaSR antagonist 8 suitable for progression. Cocrystallography, the pharmacophore model employed, and additional observations reported herein supported rational elimination of PXR activation and have applicability across diverse chemical classes to help erase PXR-driven drug-drug interactions.

Stepwise interventions for improving hand hygiene compliance in a level 3 academic neonatal intensive care unit in north India.

OBJECTIVE: We evaluated effect of sequentially introducing four WHO-recommended interventions to promote hand-hygiene compliance in tertiary-care NICU. STUDY DESIGN: Four dedicated research nurses directly observed doctors and nurses to record success in hand-hygiene opportunities at randomly selected NICU beds and randomly sampled time-slots in four phases (of 4-weeks each): I-Baseline, II-Self-directed learning; III-Participatory learning; IV-Closed-Circuit Television (CCTV); and V-CCTV-plus (with feedback). FINDINGS: Hand-hygiene compliance changed from 61.8% (baseline) to 77% (end) with overall relative change: 24.6% (95% CI 18, 32; p value= 0.003); compared with preceding phase, relative changes of 21% (15, 28; <0.001), 4% (0, 8; 0.008), -10% (-13, -6; <0.001), and 10% (5, 15; <0.001) during phases II, III, IV, and V, respectively were observed. Rise in hand-hygiene compliance was higher for after-WHO-moments (12.7%; upto 2.5-folds for moment 5, <0.001) compared to before-WHO-moments (5.2%). Educational interventions, feedback and monitoring WHO moments can improve hand-hygiene compliance significantly among health-care providers in NICU.

Strength of Association between Infarct Volume and Clinical Outcome Depends on the Magnitude of Infarct Size: Results from the ESCAPE-NA1 Trial.

BACKGROUND AND PURPOSE: Infarct volume is an important predictor of clinical outcome in acute stroke. We hypothesized that the association of infarct volume and clinical outcome changes with the magnitude of infarct size. MATERIALS AND METHODS: Data were derived from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, in which patients with acute stroke with large-vessel occlusion were randomized to endovascular treatment plus either nerinetide or a placebo. Infarct volume was manually segmented on 24-hour noncontrast CT or DWI. The relationship between infarct volume and good outcome, defined as mRS 0-2 at 90 days, was plotted. Patients were categorized on the basis of visual grouping at the curve shoulders of the infarct volume/outcome plot. The relationship between infarct volume and adjusted probability of good outcome was fitted with linear or polynomial functions as appropriate in each group. RESULTS: We included 1099 individuals in the study. Median infarct volume at 24 hours was 24.9 mL (interquartile range [IQR] = 6.6-92.2 mL). On the basis of the infarct volume/outcome plot, 4 infarct volume groups were defined (IQR = 0-15 mL, 15.1-70 mL, 70.1-200 mL, >200 mL). Proportions of good outcome in the 4 groups were 359/431 (83.3%), 219/337 (65.0%), 71/201 (35.3%), and 16/130 (12.3%), respectively. In small infarcts (IQR = 0-15 mL), no relationship with outcome was appreciated. In patients with intermediate infarct volume (IQR = 15-200 mL), there was progressive importance of volume as an outcome predictor. In infarcts of > 200 mL, outcomes were overall poor. CONCLUSIONS: The relationship between infarct volume and clinical outcome varies nonlinearly with the magnitude of infarct size. Infarct volume was linearly associated with decreased chances of achieving good outcome in patients with moderate-to-large infarcts, but not in those with small infarcts. In very large infarcts, a near-deterministic association with poor outcome was seen.

Effectiveness and safety of dolutegravir two-drug regimens in virologically suppressed people living with HIV: a systematic literature review and meta-analysis of real-world evidence.

OBJECTIVES: Dolutegravir (DTG) is widely recommended within three-drug regimens. However, similar efficacy and tolerability have also been achieved with DTG within two-drug regimens in clinical trials. This study evaluated the real-world effectiveness and discontinuations in people living with HIV-1 (PLHIV) switching to DTG with lamivudine (3TC) or rilpivirine (RPV). METHODS: This was a one-arm meta-analysis utilizing data from a systematic literature review. Data from real-world evidence studies of DTG + RPV and DTG + 3TC were extracted, pooled and analysed. The primary outcome was the proportion of patients with viral failure (VF; ≥ 50 copies/mL in two consecutive measurements and/or ≥ 1000 copies/mL in a single measurement) at week 48 (W48) and week 96 (W96). Other outcomes included virological suppression (VS; < 50 copies/mL) and discontinuations (W48 and W96). Estimates were calculated for VF, VS as per snapshot (VSS) and on treatment analysis (VSOT), and discontinuations. RESULTS: Pooled mean estimates of VF for DTG + 3TC and DTG + RPV were 0.8% [95% confidence interval (CI): 0.4-1.3] and 0.6% (95% CI: 0.0-1.6), respectively, at W48. VSS rate at W48 was 85.0% (95% CI: 82.3-87.5) for DTG + 3TC regimen and 92.4% (95% CI: 85.0-97.7) in the DTG + RPV regimen. The DTG + 3TC and DTG + RPV regimens led to discontinuations in 13.6% (95% CI: 11.1-16.2) and 7.2% (95% CI: 2.1-14.4) of patients, respectively, at W48. Similar results were observed at W96. CONCLUSIONS: Treatment with DTG + 3TC or DTG + RPV in clinical practice provides a low rate of VF and a high rate of VS when initiated in virologically suppressed PLHIV with diverse backgrounds.

Mobile app based pictorial identification key for Indian anophelines.

BACKGROUND & OBJECTIVES: Malaria control strategies for a particular area largely depends on the correct identification of the mosquito species prevalent in that area. This study aimed to develop an android mobile app named 'Pictorial Indian anophelines key', which can be used to identify the 58 species of Indian female adult anophelines based on morphological characteristics. METHODS: The pre-requisite to use this app requires a minimum basic knowledge of mosquito morphological characteristics and features. The user needs to view the collected mosquito under a dissecting binocular microscope and has to select the observations on the app presented in the form of labelled picture format. The app uses a divide and conquer algorithm which narrows the selection from genus level to final identification of species. RESULTS: The app is user-friendly, quick and it accurately identifies the mosquito species in a maximum of six consecutive clicks. The result displays a complete image of identified mosquito along with its quick identification features. It can be used for both subgenus Cellia and Anopheles. INTERPRETATION & CONCLUSION: This pictorial key-based mobile app could be helpful for entomologists, malariologists, researchers, public health workers as well as students in the quick and correct identification of anopheline mosquitoes prevalent in India which in turn could be helpful in devising appropriate approaches towards malaria control and prevention. The app can be modified as per future requirements.

Obese patients and robotic colorectal surgery: systematic review and meta-analysis.

BACKGROUND: Obesity is a major health problem, demonstrated to double the risk of colorectal cancer. The benefits of robotic colorectal surgery in obese patients remain largely unknown. This meta-analysis evaluated the clinical and pathological outcomes of robotic colorectal surgery in obese and non-obese patients. METHODS: MEDLINE, Embase, Global Health, Healthcare Management Information Consortium (HMIC) and Midwives Information and Resources Service (MIDIRS) databases were searched on 1 August 2018 with no language restriction. Meta-analysis was performed according to PRISMA guidelines. Obese patients (BMI 30 kg/m2 or above) undergoing robotic colorectal cancer resections were compared with non-obese patients. Included outcome measures were: operative outcomes (duration of surgery, conversion to laparotomy, blood loss), postoperative complications, hospital length of stay and pathological outcomes (number of retrieved lymph nodes, positive circumferential resection margins and length of distal margin in rectal surgery). RESULTS: A total of 131 full-text articles were reviewed, of which 12 met the inclusion criteria and were included in the final analysis. There were 3166 non-obese and 1420 obese patients. A longer duration of surgery was documented in obese compared with non-obese patients (weighted mean difference -21·99 (95 per cent c.i. -31·52 to -12·46) min; P < 0·001). Obese patients had a higher rate of conversion to laparotomy than non-obese patients (odds ratio 1·99, 95 per cent c.i. 1·54 to 2·56; P < 0·001). Blood loss, postoperative complications, length of hospital stay and pathological outcomes were not significantly different in obese and non-obese patients. CONCLUSION: Robotic surgery in obese patients results in a significantly longer duration of surgery and higher conversion rates than in non-obese patients. Further studies should focus on better stratification of the obese population with colorectal disease as candidates for robotic procedures.

ANTECEDENTES: La obesidad es un grave problema de salud; se ha demostrado que duplica el riesgo de cáncer colorrectal (colorectal cáncer, CRC). Los beneficios de la cirugía robótica colorrectal en pacientes obesos siguen siendo en gran medida desconocidos. Este metaanálisis evalúa los resultados clínicos y patológicos en la cirugía colorrectal robótica en pacientes obesos y no obesos. MÉTODOS: Se realizaron búsquedas bibliográficas en las bases de datos MEDLINE, EMBASE, Global Health, HMIC y MIDIRS el 1 de agosto de 2018 sin restricción de idioma. Este metaanálisis se realizó de acuerdo con las directrices PRISMA. Los pacientes obesos (IMC ≥ 30 kg/m2 ) sometidos a resecciones robóticas de CRC se compararon con pacientes no obesos. Las medidas de resultado incluidas fueron: resultados operatorios (duración de la operación, conversión a laparotomía, pérdidas hemáticas), complicaciones postoperatorias, duración de la estancia hospitalaria y resultados patológicos (número de ganglios linfáticos identificados, márgenes de resección circunferencial positivos y longitud del margen distal en la cirugía del cáncer de recto). RESULTADOS: Se revisaron 131 artículos de texto completo, de ellos, 12 artículos cumplieron los criterios de inclusión y se incluyeron en el análisis final. Hubo 3.166 pacientes no obesos y 1.420 pacientes obesos. Se registró un mayor tiempo operatorio en pacientes obesos en comparación con pacientes no obesos (diferencia media ponderada -21,989; i.c. del 95% −31,516 a 12,461, P < 0,005). Los pacientes obesos tuvieron una tasa de conversión más alta que los pacientes no obesos (i.c. del 95% 1,541 a 2,565, P < 0,005). Las pérdidas hemáticas, las complicaciones postoperatorias y la duración de la estancia hospitalaria no mostraron diferencias significativas. No hubo diferencias significativas en los resultados patológicos entre pacientes obesos y no obesos. CONCLUSIÓN: La cirugía robótica en pacientes obesos se asocia con un tiempo quirúrgico significativamente mayor y tasas de conversión más altas que en pacientes no obesos. Otros estudios deberían centrarse en estratificar mejor a los pacientes obesos con enfermedad colorrectal como candidatos a cirugía robótica.

Leveraging antibacterial efficacy of silver loaded chitosan nanoparticles on layer-by-layer self-assembled coated cotton fabric.

The present study relates to form a self-assembled coating on cotton fabric using layer-by-layer (L-B-L) technique to impart antimicrobial property. Poly(styrenesulfonate) (PSS) and synthesised silver loaded chitosan (CS-Ag) nanoparticles were used as anionic and cationic agents, respectively, for the L-B-L electrostatic assembly of polyelectrolytes. The alternate L-B-L deposition of PSS and CS-Ag nanoparticles on fabric was done up to 15 bi-layers, which was confirmed by measuring the change in depth of colour of fabric after each single layer deposition. Scanning electron micrographs showed the successful deposition of CS-Ag nanoparticles as the topmost surface layer of coated fabric, which was further reaffirmed by X-ray photoelectron spectroscopy analysis. Results of both qualitative and quantitative analysis showed enhancement in the antibacterial activity of fabric coated L-B-L with CS-Ag nanoparticles (using minimal loading of silver) with respect to that of fabric coated L-B-L with chitosan (CS) nanoparticles. This was further substantiated by sustained release of Ag+ from fabric coated L-B-L with CS-Ag nanoparticles, as observed by atomic absorption spectroscopy. Besides, no adverse effect on the physical and mechanical properties of the fabric, such as air-permeability, tensile strength and bending (flexural) rigidity, was observed after L-B-L coating of nanoparticles.

Author Correction: Self-verifying variational quantum simulation of lattice models.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Remote wireless vital signs monitoring on the ward for early detection of deteriorating patients: A case series.

INTRODUCTION: Remote wireless monitoring is a new technology that allows the continuous recording of ward patients' vital signs, supporting nurses by measuring vital signs frequently and accurately. A case series is presented to illustrate how these systems might contribute to improved patient surveillance. METHODS AND RESULTS: Five hospitals in three European countries installed a remote wireless vital signs monitoring system on medical or surgical wards. Heart rate, respiratory rate and temperature were measured by the system every 2 min. Four cases of (paroxysmal) atrial fibrillation are presented, two cases of sepsis and one case each of pyrexia, cardiogenic pulmonary edema and pulmonary embolisms. All cases show that the remote monitoring system revealed the first signs of ventilatory and circulatory deterioration before a change in the trends of the respective values became obvious by manual vital signs measurement. DISCUSSION: This case series illustrates that a wireless remote vital signs monitoring system on medical and surgical wards has the potential to reduce time to detect deteriorating patients.

Maternal depression and its association with responsive feeding and nutritional status of infants: A cross-sectional study from a rural medical college in central India.

Context: Globally, around half of all under-5 deaths are attributable to undernutrition. The magnitude of child undernutrition in India is one of the highest in the world. Responsive feeding that has the potential to optimize nutrition and development depends on a "healthy mother". Objectives: The objective of this study was to find out the magnitude and determinants of maternal depression among mothers of infants who attended immunization clinic in a rural medical college in central India and observe its association with infant-feeding practices and nutritional status of infants. Study Design: This was an analytical cross-sectional study. Materials and Methods: Study was conducted among consecutively chosen 300 mothers and their infants who visited the immunization clinic of hospital during May-September, 2016. Data were collected individually by interviewing each mother, and anthropometry of her infant was done. The mothers with depression were diagnosed according to the 10-item Edinburgh Postnatal Depression Scale. Magnitude of depression has been reported using frequency and percentage, whereas association has been studied using prevalence odds ratio with 95% confidence interval (CI) and logistic regression at 0.05 significance level. Results: The magnitude of maternal depression was 19% (95% CI 14.4-23.5). Mothers with depression had significantly higher odds for not indulging in responsive feeding. Maternal education had significant association with maternal depression after adjusting for other variables. Conclusions: Burden of maternal depression is high among mothers of infants who attended immunization clinic in a rural medical college in central India and is significantly associated with nonresponsive feeding practices.

Ecogenetics of lead toxicity and its influence on risk assessment.

Lead (Pb) toxicity is a public health problem affecting millions worldwide. Advances in 'omic' technology have paved the way to toxico-genomics which is currently revolutionizing the understanding of interindividual variations in susceptibility to Pb toxicity and its functional consequences to exposure. Our objective was to identify, comprehensively analyze, and curate all the potential genetic and epigenetic biomarkers studied to date in relation to Pb toxicity and its association with diseases. We screened a volume of research articles that focused on Pb toxicity and its association with genetic and epigenetic signatures in the perspective of occupational and environmental Pb exposure. Due to wide variations in population size, ethnicity, age-groups, and source of exposure in different studies, researchers continue to be skeptical on the topic of the influence of genetic variations in Pb toxicity. However, surface knowledge of the underlying genetic factors will aid in elucidating the mechanism of action of Pb. Moreover, in recent years, the application of epigenetics in Pb toxicity has become a promising area in toxicology to understand the influence of epigenetic mechanisms such as DNA methylation, chromatin remodeling, and small RNAs for the regulation of genes in response to Pb exposure during early life. Growing evidences of ecogenetic understanding (both genetic and epigenetic processes) in a dose-dependent manner may help uncover the mechanism of action of Pb and in the identification of susceptible groups. Such studies will further help in refining uncertainty factors and in addressing risk assessment of Pb poisoning.

Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.