Workplace Smoking Bans and Daily Smoking Patterns: Implications for Nicotine Maintenance and Determinants of Smoking in Restricted Environments

Background: Daily smokers are thought to strive to maintain blood nicotine levels above a certain threshold. Workplace smoking bans pose a substantial barrier to nicotine maintenance. Individuals may compensate for time spent in smoking-restricted environments by smoking more before (“anticipatory”) or after work (“make-up” compensation), but this has not been quantitatively examined. Methods: 124 smokers documented smoking occasions over 3 weeks using ecological momentary assessment (EMA), and provided information on nicotine dependence and stringency of workplace smoking policy (full, partial, or no bans). Hierarchical linear modeling examined effects of workplace policy, time of day block, and weekday vs weekend on mean cigarettes per hour (CPH) and simulated nicotine levels based upon EMA smoking data. Nicotine levels were assessed relative to two subject-specific standards of comparison: 1) “optimal maintenance,” levels achieved through evenly-spaced smoking (ΔEvenNL); and 2) “preferred” nicotine levels achieved at comparable times on weekends (%WeekendNL). Moderating effects of dependence, nicotine clearance rate, and home smoking restrictions were examined. Results: Individuals were most likely to change locations to smoke during work hours, regardless of work policy, and frequency of EMA reports of restrictions at work was associated with increased likelihood of changing locations to smoke (OR=1.14, 95% CI 1.08 – 1.21; p=0.0002). Workplace smoking policy, time block, and weekday/weekend interacted to predict CPH (p<0.01), and %WeekendNL (policy*time on weekdays, p<0.05), such that individuals with partial work bans –but not those with full bans - smoked more and had higher nicotine levels at Night (9 pm – bed) on weekdays compared to weekends. There was little evidence for interference with nicotine maintenance, although individuals with full or partial bans demonstrated more frequent low-nicotine (<50%WeekendNL) ‘trough’ events (p=0.04). Conclusion: Smokers may largely compensate for exposure to workplace smoking bans by escaping restrictions. However, full bans may suppress smoking even after they are lifted, perhaps by extinguishing stimulus associations or denormalization of smoking, whereas partial bans may not have these effects. This may suggest a stronger role for contextual factors in driving temporal variations in smoking. There was little evidence of true compensatory smoking to maintain nicotine levels in the face of smoking restrictions

Sexual Selection and the Evolution of Brain Size in Primates

Reproductive competition among males has long been considered a powerful force in the evolution of primates. The evolution of brain size and complexity in the Order Primates has been widely regarded as the hallmark of primate evolutionary history. Despite their importance to our understanding of primate evolution, the relationship between sexual selection and the evolutionary development of brain size is not well studied. The present research examines the evolutionary relationship between brain size and two components of primate sexual selection, sperm competition and male competition for mates. Results indicate that there is not a significant relationship between relative brain size and sperm competition as measured by relative testis size in primates, suggesting sperm competition has not played an important role in the evolution of brain size in the primate order. There is, however, a significant negative evolutionary relationship between relative brain size and the level of male competition for mates. The present study shows that the largest relative brain sizes among primate species are associated with monogamous mating systems, suggesting primate monogamy may require greater social acuity and abilities of deception

Eccentric Viewing Training for Age-Related Macular Disease: Results of a Randomized Controlled Trial (the EFFECT Study)

PURPOSE: Eccentric viewing training for macular disease has been performed for > 40 years, but no large studies including control groups have assessed the benefits of this training. The EFFECT (Eccentric Fixation From Enhanced Clinical Training) study is a large randomized controlled trial of 2 types of eccentric viewing training. DESIGN: Randomized controlled trial. PARTICIPANTS: Two hundred adults with age-related macular disease. METHODS: Participants were randomized to either of the following: (1) a control group; (2) a group receiving supervised reading support; (3) a group receiving 3 sessions of training to optimize the use of their own preferred retinal locus; or (4) a group receiving 3 sessions of biofeedback training of a theoretically optimal trained retinal locus. All participants received standard low-vision rehabilitation. MAIN OUTCOME MEASURES: The primary outcome was patient-reported visual task ability measured on the Activity Inventory instrument at goal level. Secondary outcomes included reading performance and fixation stability. RESULTS: There was no difference between groups on change in task ability (F(3,174) = 1.48, P = 0.22) or on any of the secondary outcome measures. Visual acuity and contrast sensitivity fell in all groups, suggesting that disease progression outweighed any benefit of training. CONCLUSIONS: Eccentric viewing training did not systematically improve task ability, reading performance, or fixation stability in this study. Our results do not support the routine use of eccentric viewing training for people with progressing age-related macular disease, although this training may help people with end-stage disease. Rehabilitation of an inherently progressive condition is challenging. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Multi-proxy validation of glacial-interglacial rainfall variations in southwest Sulawesi

Speleothem δ18O is widely used as a proxy for rainfall amount in the tropics on glacial-interglacial to interannual scales. However, uncertainties in the interpretation of this renowned proxy pose a vexing problem in tropical paleoclimatology. Here, we present paired multi-proxy geochemical measurements for stalagmites from southwest Sulawesi, Indonesia, and confirm changes in rainfall amount across ice age terminations. Collectively, the stalagmites span two glacial-interglacial transitions from ~380,000 to 330,000 and 230,000 to 170,000 years ago. Mg/Ca in the slow-growing stalagmites is affected by water moving through the karst and prior calcite precipitation, making it a good proxy for changes in local rainfall. When paired, Mg/Ca and δ18O corroborate prominent shifts from drier glacials to wetter interglacials in the core of the Australasian monsoon domain. These shifts in rainfall occur 4,000-7,000 years later than glacial-interglacial increases in global temperature and the associated response of Sulawesi vegetation, determined by speleothem δ13C

Multiloop Calculations in the String-Inspired Formalism: The Single Spinor-Loop in QED

We use the worldline path-integral approach to the Bern-Kosower formalism for developing a new algorithm for calculation of the sum of all diagrams with one spinor loop and fixed numbers of external and internal photons. The method is based on worldline supersymmetry, and on the construction of generalized worldline Green functions. The two-loop QED $\beta$ -- function is calculated as an example.Comment: uuencoded ps-file, 20 pages, 2 figures, final revised version to appear in Phys. Rev.

Retrieving landscape freeze/thaw state fromSoil Moisture Active Passive (SMAP) radar and radiometer measurements

Over one-third of the global land area undergoes a seasonal transition between predominantly frozen and non-frozen conditions each year, with the land surface freeze/thaw (FT) state a significant control on hydrological and biospheric processes over northern land areas and at high elevations. The NASA Soil Moisture Active Passive (SMAP) mission produced a daily landscape FT product at 3-km spatial resolution derived from ascending and descending orbits of SMAP high-resolution L-band (1.4 GHz) radar measurements. Following the failure of the SMAP radar in July 2015, coarser (36-km) footprint SMAP radiometer inputs were used to develop an alternative daily passive microwave freeze/thaw product. In this study, in situ observations are used to examine differences in the sensitivity of the 3-km radar versus the 36-km radiometer measurements to the landscape freeze/thaw state during the period of overlapping instrument operation. Assessment of the retrievals at high-latitude SMAP core validation sites showed excellent agreement with in situ flags, exceeding the 80% SMAP mission accuracy requirement. Similar performance was found for the radar and radiometer products using both air temperature and soil temperature derived FT reference flags. There was a tendency for SMAP thaw retrievals to lead the surface flags due to the influence of wet snow cover conditions on both the radar and radiometer signal. Comparison with other satellite derived FT products showed those derived from passive measurements (SMAP radiometer; Aquarius radiometer; Advanced Microwave Scanning Radiometer - 2) retrieved less frozen area than the active products (SMAP radar; Aquarius radar)

Development and Validation of a Prediction Model for Perinatal Arterial Ischemic Stroke in Term Neonates

Importance: Perinatal arterial ischemic stroke (PAIS) is a focal brain injury in term neonates that is identified postnatally but is presumed to occur near the time of birth. Many pregnancy, delivery, and fetal factors have been associated with PAIS, but early risk detection is lacking; thus, targeted treatment and prevention efforts are currently limited. Objective: To develop and validate a diagnostic risk prediction model that uses common clinical factors to predict the probability of PAIS in a term neonate. Design, Setting, and Participants: In this diagnostic study, a prediction model was developed using multivariable logistic regression with registry-based case data collected between January 2003, and March 2020, from the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and Alberta Pregnancy Outcomes and Nutrition study. Criteria for inclusion were term birth and no underlying medical conditions associated with stroke diagnosis. Records with more than 20% missing data were excluded. Variable selection was based on peer-reviewed literature. Data were analyzed in September 2021. Exposures: Clinical pregnancy, delivery, and neonatal factors associated with PAIS as common data elements across the 4 registries. Main Outcomes and Measures: The primary outcome was the discriminative accuracy of the model predicting PAIS, measured by the concordance statistic (C statistic). Results: Of 2571 term neonates in the initial analysis (527 [20%] case and 2044 [80%] control individuals; gestational age range, 37-42 weeks), 1389 (54%) were male, with a greater proportion of males among cases compared with controls (318 [60%] vs 1071 [52%]). The final model was developed using 1924 neonates, including 321 cases (17%) and 1603 controls (83%), and 9 clinical factors associated with risk of PAIS in term neonates: maternal age, tobacco exposure, recreational drug exposure, preeclampsia, chorioamnionitis, intrapartum maternal fever, emergency cesarean delivery, low 5-minute Apgar score, and male sex. The model demonstrated good discrimination between cases and controls (C statistic, 0.73; 95% CI, 0.69-0.76) and good model fit (Hosmer-Lemeshow P = .20). Internal validation techniques yielded similar C statistics (0.73 [95% CI, 0.69-0.77] with bootstrap resampling, 10-fold cross-validated area under the curve, 0.72 [bootstrap bias-corrected 95% CI, 0.69-0.76]), as did a sensitivity analysis using cases and controls from Alberta, Canada, only (C statistic, 0.71; 95% CI, 0.65-0.77). Conclusions and Relevance: The findings suggest that clinical variables can be used to develop and internally validate a model to predict the risk of PAIS in term neonates, with good predictive performance and strong internal validity. Identifying neonates with a high probability of PAIS who could then be screened for early diagnosis and treatment may be associated with reductions in lifelong morbidity for affected individuals and their families

An integrative paradigm to impart quality to correlative science

Correlative studies are a primary mechanism through which insights can be obtained about the bioactivity and potential efficacy of candidate therapeutics evaluated in early-stage clinical trials. Accordingly, well designed and performed early-stage correlative studies have the potential to strongly influence further clinical development of candidate therapeutic agents, and correlative data obtained from early stage trials has the potential to provide important guidance on the design and ultimate successful evaluation of products in later stage trials, particularly in the context of emerging clinical trial paradigms such as adaptive trial design

Validation of a HLA-A2 tetramer flow cytometric method, IFNgamma real time RT-PCR, and IFNgamma ELISPOT for detection of immunologic response to gp100 and MelanA/MART-1 in melanoma patients

<p>Abstract</p> <p>Background</p> <p>HLA-A2 tetramer flow cytometry, IFNγ real time RT-PCR and IFNγ ELISPOT assays are commonly used as surrogate immunological endpoints for cancer immunotherapy. While these are often used as research assays to assess patient's immunologic response, assay validation is necessary to ensure reliable and reproducible results and enable more accurate data interpretation. Here we describe a rigorous validation approach for each of these assays prior to their use for clinical sample analysis.</p> <p>Methods</p> <p>Standard operating procedures for each assay were established. HLA-A2 (A*0201) tetramer assay specific for gp100_209(210M)and MART-1_26–35(27L), IFNγ real time RT-PCR and ELISPOT methods were validated using tumor infiltrating lymphocyte cell lines (TIL) isolated from HLA-A2 melanoma patients. TIL cells, specific for gp100 (TIL 1520) or MART-1 (TIL 1143 and TIL1235), were used alone or spiked into cryopreserved HLA-A2 PBMC from healthy subjects. TIL/PBMC were stimulated with peptides (gp100₂₀₉, gp100_pool, MART-1_27–35, or influenza-M1 and negative control peptide HIV) to further assess assay performance characteristics for real time RT-PCR and ELISPOT methods. Validation parameters included specificity, accuracy, precision, linearity of dilution, limit of detection (LOD) and limit of quantification (LOQ). In addition, distribution was established in normal HLA-A2 PBMC samples. Reference ranges for assay controls were established.</p> <p>Results</p> <p>The validation process demonstrated that the HLA-A2 tetramer, IFNγ real time RT-PCR, and IFNγ ELISPOT were highly specific for each antigen, with minimal cross-reactivity between gp100 and MelanA/MART-1. The assays were sensitive; detection could be achieved at as few as 1/4545–1/6667 cells by tetramer analysis, 1/50,000 cells by real time RT-PCR, and 1/10,000–1/20,000 by ELISPOT. The assays met criteria for precision with %CV < 20% (except ELISPOT using high PBMC numbers with %CV < 25%) although flow cytometric assays and cell based functional assays are known to have high assay variability. Most importantly, assays were demonstrated to be effective for their intended use. A positive IFNγ response (by RT-PCR and ELISPOT) to gp100 was demonstrated in PBMC from 3 melanoma patients. Another patient showed a positive MART-1 response measured by all 3 validated methods.</p> <p>Conclusion</p> <p>Our results demonstrated the tetramer flow cytometry assay, IFNγ real-time RT-PCR, and INFγ ELISPOT met validation criteria. Validation approaches provide a guide for others in the field to validate these and other similar assays for assessment of patient T cell response. These methods can be applied not only to cancer vaccines but to other therapeutic proteins as part of immunogenicity and safety analyses.</p