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We experimentally investigate the effects of parametric instabilities on the short-time heating process of periodically driven bosons in 2D optical lattices with a continuous transverse (tube) degree of freedom. We analyze three types of periodic drives: (i) linear along the x-lattice direction only, (ii) linear along the lattice diagonal, and (iii) circular in the lattice plane. In all cases, we demonstrate that the Bose-Einstein condensate (BEC) decay is dominated by the emergence of unstable Bogoliubov modes, rather than scattering in higher Floquet bands, in agreement with recent theoretical predictions. The observed BEC depletion rates are much higher when shaking along both the x and y directions, as opposed to only x or only y. We also report an explosion of the decay rates at large drive amplitudes and suggest a phenomenological description beyond the Bogoliubov theory. In this strongly coupled regime, circular drives heat faster than diagonal drives, which illustrates the nontrivial dependence of the heating on the choice of drive.

This research examined main and interactive associations of perceived risk and worry of health and appearance smoking consequences on motivation to quit and the relative importance of each of these. Hierarchical regressions controlling for other measures found that perceived conditional risk and worry of health consequences were associated with motivation to quit; only conditional risk of appearance consequences was associated with motivation to quit. Relative weights analysis indicated that perceived conditional risk of appearance consequences and worry about health consequences were the most important variables in the model. Consideration of appearance consequences may aid in motivating smokers to try quitting.

Abstract Background Totipotency is the ability of a cell to regenerate a whole organism. Plant somatic embryogenesis (SE) is a remarkable example of totipotency because somatic cells reverse differentiation, respond to an appropriate stimulus and initiate embryo development. Although SE is an ideal system to investigate de-differentiation and differentiation, we still lack a deep molecular understanding of the phenomenon due to experimental restraints. Results We applied the INTACT method to specifically isolate the nuclei of those cells undergoing SE among the majority of non-embryogenic cells that make up a callus. We compared the transcriptome of embryogenic cells to the one of proliferating callus cells. Our analyses revealed that embryogenic cells are transcriptionally rather than metabolically active. Embryogenic cells shut off biochemical pathways involved in carbohydrate and lipid metabolism and activate the transcriptional machinery. Furthermore, we show how early in SE, ground tissue and leaf primordia specification are switched on before the specification of a shoot apical meristem. Conclusions This is the first attempt to specifically profile embryogenic cells among the different cell types that constitute plant in vitro tissue cultures. Our comparative analyses provide insights in the gene networks regulating SE and open new research avenues in the field of plant regeneration.

O objetivo desse trabalho foi comparar o intervalo de tempo de registro de cinco minutos com quatro intervalos de tempo (10, 15, 20 e 30 minutos), para avaliação dos comportamentos comendo, ruminando, em ócio, em pé, apresentados por bovinos confinados individualmente. Foram utilizados 62 machos Nelore desmamados, confinados durante 112 dias. O comportamento foi registrado a cada 28 dias, durante 24h, por observações diretas com rota de amostragem scan e intervalos de registro de 5 minutos, para o cálculo das seguintes características: tempo de alimentação, tempo de ruminação, tempo em ócio, tempo em pé e frequência de alimentação. Foram comparados os intervalos de registro por meio de variâncias, correlações e médias das características. Observou-se para as características, tendência de aumento da variância residual à medida que o intervalo de tempo entre dois registros aumentou, com exceção da frequência alimentar, em que foi observada tendência de diminuição da variância residual com o aumento do intervalo de registro. As médias ajustadas para as medidas de comportamento ingestivo obtidas nos intervalos de registro de 5, 10, 15, 20 e 30 minutos não diferiram significativamente (P>0,05) entre si, com exceção de tempo de alimentação, que apresentou menor valor (P

This study was started with the aim of evaluating different sampling techniques in order to develop a suitable and scientifically sound methodology for measuring the emissions of LFG from landfill surfaces. For this purpose, the work involved a bibliographical and theoretical study aiming to design new sampling equipment, as well as an experimental phase consisting in repeated measurement campaigns for the evaluation and comparison of such equipment on a sample site, i.e. a MSW landfill located in Northern Italy. Two sampling methods were designed and realized: a “flux chamber” and a “static box”. The results of the first sampling campaigns show a good agreement between the two sampling techniques, but further studies will be needed in order to validate those results and study the influence of the meteorological conditions on the measured LFG fluxes.

Smokeless tobacco use among Indian women is increasing despite prevention efforts. Evolutionary theories suggest that reproductive-aged women should be more concerned about immediate threats to reproduction than threats to survival occurring late in life. This study therefore compared an anti-tobacco intervention that emphasized near-term reproductive harms to one involving general harms occurring later in life. Scheduled Tribal women (N = 92) from Karnataka, India participated in this study. At baseline, women reported tobacco use and knowledge of harms, provided a saliva sample to assess use, and randomly viewed either a general harms presentation (GHP) or reproductive harms presentation (RHP). At followup, women reported their use, knowledge of harms and intentions to quit, and provided another saliva sample. At baseline, participants were aware of general harms but not reproductive harms. Both interventions increased knowledge of harms. Women in the RHP condition did not list more harms than women in the GHP condition, however, and the RHP was not more effective in reducing tobacco use than the GHP. In the RHP condition fetal health was particularly salient. In the GHP condition, oral health was highly salient, aligning with the local disease ecology and research on tobacco use and attractiveness.

Objective. To determine whether genetic variants suggested by the literature to be associated with physiology and fitness phenotypes predicted differential physiological and subjective responses to a bout of aerobic exercise among inactive but otherwise healthy adults. Method. Participants completed a 30-minute submaximal aerobic exercise session. Measures of physiological and subjective responding were taken before, during, and after exercise. 14 single nucleotide polymorphisms (SNPs) that have been previously associated with various exercise phenotypes were tested for associations with physiological and subjective response to exercise phenotypes. Results. We found that two SNPs in the FTO gene (rs8044769 and rs3751812) were related to positive affect change during exercise. Two SNPs in the CREB1 gene (rs2253206 and 2360969) were related to change in temperature during exercise and with maximal oxygen capacity (VO2 max). The SLIT2 SNP rs1379659 and the FAM5C SNP rs1935881 were associated with norepinephrine change during exercise. Finally, the OPRM1 SNP rs1799971 was related to changes in norepinephrine, lactate, and rate of perceived exertion (RPE) during exercise. Conclusion. Genetic factors influence both physiological and subjective responses to exercise. A better understanding of genetic factors underlying physiological and subjective responses to aerobic exercise has implications for development and potential tailoring of exercise interventions.

Purpose: In this systematic review, the authors examine the prevalence and extent of stigmatizing attitudes among health care professionals (HCPs) and trainees against patients with substance use disorders (SUDs), including research on interventions to reduce stigma., Method: The authors searched 7 databases for articles published from January 1, 2011, through February 15, 2023, that quantified SUD stigma among HCPs or trainees. Inclusion criteria allowed both observational and intervention studies from the United States or Canada to be included in this review. Quality assessment was applied to all included studies; studies were not excluded based on quality., Results: A total of 1,992 unique articles were identified of which 32 articles (17 observational studies and 15 intervention studies), all conducted in the United States, met the inclusion criteria. Half of the included studies (16 of 32) were published in 2020 or later. Most of the intervention studies (13 of 15) used a single-group pre-post design; interventions involved didactics and/or interactions with persons with SUDs. The 32 included studies used a total of 19 different measures of stigma. All 17 observational studies showed some degree of HCP or trainee stigma against patients with SUDs. Most intervention studies (12 of 15) found small but statistically significant reductions in stigma after intervention., Conclusions: SUD stigma exists among HCPs and trainees. Some interventions to reduce this stigma had positive impacts, but future studies with larger, diverse participants and comparison groups are needed. Heterogeneity among studies and stigma measures limits the ability to interpret results across studies. Future rigorous research is needed to determine validated, consensus measures of SUD stigma among HCPs and trainees, identify stigma scores that are associated with clinical outcomes, and develop effective antistigma interventions for HCPs and trainees., (Copyright © 2023 the Association of American Medical Colleges.)

Introduction: National guidelines recommend that patients with chronic noncancer pain prescribed long-term opioid therapy (LTOT) undergo periodic urine drug testing (UDT), yet UDT is performed inconsistently, and little evidence supports the utility of this approach. We examined patient and prescriber factors associated with UDT., Methods: A 1-year retrospective cohort study of 5690 patients prescribed LTOT by 689 clinicians in a network of 13 primary care and specialty clinics. Negative binomial regression examined patient and prescriber factors associated with the number of tests completed, and logistic regression examined prescriber and practice level testing likelihood. Analyses were adjusted for patient and clinician characteristics and accounted for patient clustering within prescribers., Results: A total of 2256 patients (39.6%) had UDT completed at least once. More UDT completion was associated with Black patient race and receipt of more opioid prescriptions, as well as with clinician testing compliance., Conclusions: UDT was relatively infrequent in patients prescribed LTOT and associated with patient factors not known to confer greater opioid-related risk, such as race. In addition, there was significant clinician-driven variation in UDT. Given the uncertain clinical utility of such testing, these findings signal the need for strategies to address potential biases in the use of UDT., Competing Interests: Conflict of interest: None., (© Copyright by the American Board of Family Medicine.)

In October of 2021, California enacted SB 428, the ACEs Equity Act, which mandates commercial insurance coverage of adverse childhood experiences (ACEs) screening in addition to ACEs screening already covered for the state's Medicaid enrollees. California is the first state to expand ACEs screening coverage, but it is possible other states may follow similar paths given the increasing interest in policy action to address ACEs. Increase in stress and trauma among Americans and evidence of the disproportionate impact ACEs have on historically marginalized and disadvantaged communities has increased the urgency with which policy makers, clinicians and researchers have sought to address ACEs and encourage trauma-informed care delivery to better meet the needs of patients. Family practice and other primary care providers are at the core of prevention and are arguably the largest group of stakeholders at the forefront of movements toward increasing ACEs screenings. However, debate persists among policy makers, clinicians, and researchers on whether the ACEs screening approach improves outcomes and avoids harms. In this health policy article, we describe key issues under debate with regards to ACEs screening and estimate potential change in screening utilization and expenditures due to the new ACEs legislation in California. The lessons being learned in California are applicable to other states and the US as a whole., Competing Interests: Conflict of interest: None., (© Copyright 2022 by the American Board of Family Medicine.)

Importance: Patients prescribed long-term opioid therapy are increasingly undergoing dose tapering. Recent studies suggest that tapering is associated with short-term risks of substance misuse, overdose, and mental health crisis, although lower opioid dose could reduce risks of adverse events over the longer term., Objective: To assess the longer-term risks of overdose or mental health crisis associated with opioid dose tapering., Design, Setting, and Participants: This is a cohort study using an exposure-crossover analysis. Data were obtained from the OptumLabs Data Warehouse, which includes deidentified medical and pharmacy claims and enrollment records for commercial insurance and Medicare Advantage enrollees, representing a diverse mixture of ages, races, ethnicities, and geographical regions across the US. Participants were US adults who underwent opioid dose tapering from 2008 to 2017 after a 12-month baseline period of stable daily dosing of 50 morphine milligram equivalents or higher and who had at least 1 month of long-term follow-up during a postinduction period beginning 12 months after taper initiation. Data analysis was performed from October 2021 to April 2022., Exposures: Opioid tapering, defined as 15% or more relative reduction in mean daily dose during any of 6 overlapping 60-day windows within a 7-month follow-up period after the stable baseline period., Main Outcomes and Measures: Emergency or hospital encounters for drug overdose or withdrawal and mental health crisis (depression, anxiety, or suicide attempt). Outcome counts were assessed in pretaper and postinduction periods (from 12 to 24 months after taper initiation)., Results: The study included 21 515 tapering events among 19 377 patients with a mean (SD) of 9.1 (2.7) months of postinduction follow-up per event (median [IQR], 10 [8-11] months). Patients had a mean (SD) age of 56.9 (11.2) years, 11 581 (53.8%) were female, and 8217 (38.2%) had commercial insurance (vs Medicare Advantage). In conditional negative binomial regression analyses, adjusted incidence rate ratios for the postinduction period compared with the pretaper period were 1.57 (95% CI, 1.42-1.74) for overdose or withdrawal and 1.52 (95% CI, 1.35-1.71) for mental health crisis., Conclusions and Relevance: These findings suggest that opioid tapering was associated with increased rates of overdose, withdrawal, and mental health crisis extending up to 2 years after taper initiation.

Background: Multimorbidity is common, and care is impacted by patient life context. Effective, efficient interventions to improve patient-centered outcomes such as perceived treatment burden are limited. There is a need for interventions that integrate patient contextual information into primary care encounters to improve such outcomes. Patient life context is a multitude of factors that influence a patient's life and healthcare, including social determinants of health and broader elements such as family and work demands., Methods: This pilot randomized controlled trial (RCT) protocol will compare standard pre-visit planning to context-informed pre-visit planning that incorporates the patient's life context, for patients with diabetes plus other chronic comorbid conditions. Primary outcomes include measures of trial protocol and intervention feasibility and acceptability: physician study and visit perceived burden, patient satisfaction, and patient, physician and staff experience with the trial. Additional measurements of intervention impact include: initial estimates of effect size on patient treatment burden and other patient-oriented outcomes, change in glycemic control, and other intermediate medical outcomes., Discussion: This intervention is novel as it collects patient life context information using a direct person-to-person approach, allows physicians to review the information prior to patient arrival at the clinic and, where appropriate, incorporate it when negotiating treatment plans, and is longitudinal, summarizing evolving contextual information over time. This pilot RCT has the potential to demonstrate trial protocol and intervention feasibility and acceptability, and estimate effect size on patient and provider outcomes, to inform for a future, definitive RCT.Trial Registration: This trial was registered at ClinicalTrials.gov prior to patient enrollment: NCT04568382., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Importance: Opioid-related mortality and national prescribing guidelines have led to tapering of doses among patients prescribed long-term opioid therapy for chronic pain. There is limited information about risks related to tapering, including overdose and mental health crisis., Objective: To assess whether there are associations between opioid dose tapering and rates of overdose and mental health crisis among patients prescribed stable, long-term, higher-dose opioids., Design, Setting, and Participants: Retrospective cohort study using deidentified medical and pharmacy claims and enrollment data from the OptumLabs Data Warehouse from 2008 to 2019. Adults in the US prescribed stable higher doses (mean ≥50 morphine milligram equivalents/d) of opioids for a 12-month baseline period with at least 2 months of follow-up were eligible for inclusion., Exposures: Opioid tapering, defined as at least 15% relative reduction in mean daily dose during any of 6 overlapping 60-day windows within a 7-month follow-up period. Maximum monthly dose reduction velocity was computed during the same period., Main Outcomes and Measures: Emergency or hospital encounters for (1) drug overdose or withdrawal and (2) mental health crisis (depression, anxiety, suicide attempt) during up to 12 months of follow-up. Discrete time negative binomial regression models estimated adjusted incidence rate ratios (aIRRs) of outcomes as a function of tapering (vs no tapering) and dose reduction velocity., Results: The final cohort included 113 618 patients after 203 920 stable baseline periods. Among the patients who underwent dose tapering, 54.3% were women (vs 53.2% among those who did not undergo dose tapering), the mean age was 57.7 years (vs 58.3 years), and 38.8% were commercially insured (vs 41.9%). Posttapering patient periods were associated with an adjusted incidence rate of 9.3 overdose events per 100 person-years compared with 5.5 events per 100 person-years in nontapered periods (adjusted incidence rate difference, 3.8 per 100 person-years [95% CI, 3.0-4.6]; aIRR, 1.68 [95% CI, 1.53-1.85]). Tapering was associated with an adjusted incidence rate of 7.6 mental health crisis events per 100 person-years compared with 3.3 events per 100 person-years among nontapered periods (adjusted incidence rate difference, 4.3 per 100 person-years [95% CI, 3.2-5.3]; aIRR, 2.28 [95% CI, 1.96-2.65]). Increasing maximum monthly dose reduction velocity by 10% was associated with an aIRR of 1.09 for overdose (95% CI, 1.07-1.11) and of 1.18 for mental health crisis (95% CI, 1.14-1.21)., Conclusions and Relevance: Among patients prescribed stable, long-term, higher-dose opioid therapy, tapering events were significantly associated with increased risk of overdose and mental health crisis. Although these findings raise questions about potential harms of tapering, interpretation is limited by the observational study design.

Context: Health plan disenrollment has been associated with higher mortality in patients with opioid use disorder. Insurance loss and health plan disenrollment might be downstream social consequences of opioid misuse and overdose that may heighten patient mortality risks during a period of heightened need for professional assistance. Objective: To test hypotheses that: 1) overdose events in patients prescribed long-term opioids are associated with subsequent health plan disenrollment; and 2) buprenorphine initiation after overdose would attenuate this association. Study Design: Retrospective cohort study. Setting and Dataset: Data from the Optum Labs Data Warehouse which includes de-identified medical and pharmacy claims and enrollment records for commercial and Medicare Advantage enrollees. The database contains longitudinal health information on patients, representing a mixture of ages, ethnicities, and geographical regions across the United States. Population studied: Adults (aged ≥18 years) prescribed stable, opioid therapy for a 6-month baseline period (≥90% of days covered, <10% monthly fluctuation from 6-month average, average daily dose ≥10 morphine milligram equivalents). Outcome Measures: Health plan disenrollment during up to one year of follow-up. Negative binomial regression estimated adjusted incidence rate ratios of disenrollment by incident overdose and buprenorphine initiation after overdose. Results: We identified 556,676 patients who were followed up after 1,119,100 stable periods of opioid therapy. During follow-up, 17.5% of person-periods ended in health plan disenrollment. Overdose events during follow-up were associated with health plan disenrollment with a dose-response relationship [adjusted incidence rate ratio (aIRR) for 1 overdose event = 1.29 (95% CI: 1.24-1.35); aIRR for ≥2 overdose events = 1.51 (1.43-1.59)]. Among patients with overdose events, subsequent buprenorphine initiation was associated with substantially reduced risk of health plan disenrollment [aIRR 0.36 (0.17-0.74)]. Conclusions: Overdose events in patients prescribed long-term opioids may portend other social consequences, such as health insurance loss, which may exacerbate patient risk at a time of heightened need and vulnerability. Buprenorphine may mitigate the risk of health plan disenrollment in opioid-prescribed patients who overdose., Competing Interests: Authors report none, (2023 Annals of Family Medicine, Inc.)

Importance: A 2016 Centers for Disease Control and Prevention prescribing guideline cautioned against higher-dose long-term opioid therapy and recommended tapering daily opioid doses by approximately 10% per week if the risks outweigh the benefits. Warnings have since appeared regarding potential hazards of rapid opioid tapering., Objectives: To characterize US trends in opioid dose tapering among patients prescribed long-term opioids from 2008 to 2017 and identify patient-level variables associated with tapering and a more rapid rate of tapering., Design, Setting, and Participants: This retrospective cohort study used deidentified medical and pharmacy claims and enrollment records for 100 031 commercial insurance and Medicare Advantage enrollees, representing a diverse mixture of ages, races/ethnicities, and geographical regions across the United States. Adults with stable, higher-dosage (mean, ≥50 morphine milligram equivalents [MMEs]/d) opioid prescriptions for a 12-month baseline period and 2 or more months of follow-up from January 1, 2008, to December 31, 2017, were included in the study., Main Outcomes and Measures: Tapering was defined as 15% or more relative reduction in mean daily MME during any of 6 overlapping 60-day windows within a 7-month follow-up period. The rate of tapering was computed as the maximum monthly percentage dose reduction., Results: Among the 100 031 participants (53 452 [53.4%] women; mean [SD] age, 57.6 [11.8] years), from 2008 to 2015, the age- and sex-standardized percentage of patients tapering daily opioid doses increased from 10.5% to 13.7% (adjusted incidence rate ratio [aIRR] per year, 1.05 [95% CI, 1.05-1.06]) before increasing to 16.2% in 2016 and 22.4% in 2017 (aIRR in 2016-2017 vs 2008-2015, 1.20 [95% CI, 1.16-1.25]). Patient-level covariates associated with tapering included female sex (aIRR, 1.13 [95% CI, 1.10-1.15]) and higher baseline dose (aIRR for ≥300 MMEs/d vs 50-89 MMEs/d, 2.57 [95% CI, 2.48-2.65]). Among patients tapering daily opioid doses, the mean (SD) maximum dose reduction was 27.6% (17.0%) per month, and 18.8% of patients had a maximum tapering rate exceeding 40% per month (ie, faster than 10% per week). More rapid dose reduction was associated with 2016-2017 vs 2008-2015 (adjusted difference, 1.4% [95% CI, 0.8%-2.1%]) and higher baseline dose (adjusted difference, 2.7% [95% CI, 2.2%-3.3%] for 90-149 vs 50-89 MMEs/d)., Conclusions and Relevance: Patients using long-term opioid therapy are increasingly undergoing dose tapering, particularly women and those prescribed higher doses; in addition, dose tapering has become more common since 2016. Many patients undergoing tapering reduce daily doses at a rapid maximum rate.

We experimentally investigate the effects of parametric instabilities on the short-time heating process of periodically-driven bosons in 2D optical lattices with a continuous transverse (tube) degree of freedom. We analyze three types of periodic drives: (i) linear along the x -lattice direction only, (ii) linear along the lattice diagonal, and (iii) circular in the lattice plane. In all cases, we demonstrate that the BEC decay is dominated by the emergence of unstable Bogoliubov modes, rather than scattering in higher Floquet bands, in agreement with recent theoretical predictions. The observed BEC depletion rates are much higher when shaking both along x and y directions, as opposed to only x or only y . We also report an explosion of the decay rates at large drive amplitudes, and suggest a phenomenological description beyond Bogoliubov theory. In this strongly-coupled regime, circular drives heat faster than diagonal drives, which illustrates the non-trivial dependence of the heating on the choice of drive.

We present a piezo-driven translatable mirror with excellent pointing stability, capable of driving at frequencies up to tens of kilohertz. Our system uses a tripod of piezo actuators with independently controllable drive voltages, where the ratios of the individual drive voltages are tuned to minimize residual tilting. Attached to a standard ∅ = 12.7 mm mirror, the system has a resonance-free mechanical bandwidth up to 51 kHz, with displacements up to 2 μm at 8 kHz. The maximum static steering error is 5.5 μrad/μm displaced, and the dynamic steering error is lower than 0.6 μrad μm -1 . This simple design should be useful for a large set of optical applications where tilt-free displacements are required, and we demonstrate its application in an ensemble of cold atoms trapped in periodically driven optical lattices.

Importance: Prior studies suggesting clinician fulfillment or denial of requests affects patient satisfaction included limited adjustment for patient confounders. The studies also did not examine distinct request types, yet patient expectations and clinician fulfillment or denial might vary among request types., Objective: To examine how patient satisfaction with the clinician is associated with clinician denial of distinct types of patient requests, adjusting for patient characteristics., Design, Setting, and Participants: Cross-sectional observational study of 1319 outpatient visits to family physicians (n = 56) by 1141 adults at one Northern California academic health center., Main Outcomes and Measures: We used 6 Consumer Assessment of Healthcare Providers and Systems Clinician and Group Adult Visit Survey items to measure patient satisfaction with the visit physician. Standardized items were averaged to form the satisfaction score (Cronbach α = 0.80), which was then percentile-transformed. Seven separate linear mixed-effects models examined the adjusted mean differences in patient satisfaction percentile associated with denial of each of the following requests (if present)-referral, pain medication, antibiotic, other new medication, laboratory test, radiology test, or other test-compared with fulfillment of the respective requests. The models adjusted for patient sociodemographics, weight, health status, personality, worry over health, prior visit with clinician, and the other 6 request categories and their dispositions., Results: The mean (SD) age of the 1141 patients was 45.6 (16.1) years, and 902 (68.4%) were female. Among 1319 visits, 897 (68.0%) included at least 1 request; 1441 (85.2%) were fulfilled. Requests by category were referral, 294 (21.1%); pain medication, 271 (20.5%); antibiotic, 107 (8.1%); other new medication, 271 (20.5%); laboratory test, 448 (34.0%); radiology test, 153 (11.6%); and other tests, 147 (11.1%). Compared with fulfillment of the respective request type, clinician denials of requests for referral, pain medication, other new medication, and laboratory test were associated with worse satisfaction (adjusted mean percentile differences, -19.75 [95% CI, -30.75 to -8.74], -10.72 [95% CI, -19.66 to -1.78], -20.36 [95% CI, -29.54 to -11.18], and -9.19 [95% CI, -17.50 to -0.87]), respectively., Conclusions and Relevance: Clinician denial of some types of requests was associated with worse patient satisfaction with the clinician, but not for others, when compared with fulfillment of the requests. In an era of patient satisfaction-driven compensation, the findings suggest the need to train clinicians to deal effectively with requests, potentially enhancing patient and clinician experiences.

Strong dipole-exchange interactions due to spontaneously produced contaminant states can trigger rapid dephasing in many-body Rydberg ensembles [E. Goldschmidt et al ., PRL 116, 113001 (2016)]. Such broadening has serious implications for many proposals to coherently use Rydberg interactions, particularly Rydberg dressing proposals. The dephasing arises as a runaway process where the production of the first contaminant atoms facilitates the creation of more contaminant atoms. Here we study the time dependence of this process with stroboscopic approaches. Using a pump-probe technique, we create an excess "pump" Rydberg population and probe its effect with a different "probe" Rydberg transition. We observe a reduced resonant pumping rate and an enhancement of the excitation on both sides of the transition as atoms are added to the pump state. We also observe a timescale for population growth significantly shorter than predicted by homogeneous mean-field models, as expected from a clustered growth mechanism where high-order correlations dominate the dynamics. These results support earlier works and confirm that the time scale for the onset of dephasing is reduced by a factor which scales as the inverse of the atom number. In addition, we discuss several approaches to minimize these effects of spontaneous broadening, including stroboscopic techniques and operating at cryogenic temperatures. It is challenging to avoid the unwanted broadening effects, but under some conditions they can be mitigated.

Limited information is available concerning the regulation of growth hormone-releasing hormone (GHRH) gene expression in the hypothalamus, largely because of the lack of a suitable cellular model. In an attempt to immortalize hypothalamic GHRH-producing neurons, we have generated a transgenic mouse model which expresses the simian virus 40 (SV40) T-antigen gene (Tag) under the control of the GHRH gene promoter. The transgene contains approximately 5 kb of mouse GHRH gene sequences, including 3.5 kb of the 5'-flanking region, the entire hypothalamic exon 1 and 1.5 kb of intron 1, fused to the SV40 Tag gene. This construct was microinjected into fertilized oocytes. Fourteen of 96 mice born had integrated the transgene. These mice were fertile and showed no signs of central or peripheral tumors. The pattern of expression of the SV40 Tag gene was analyzed in four different transgenic lines by RT-PCR. The tissues tested include: hypothalamus, pituitary, cortex, cerebellum, spinal cord, adrenal, testis, spleen and lung. Transgene expression was consistently detected in the hypothalamus of all lines. In addition, SV40 Tag expression was also detected in the hypothalamus by Northern blot analysis in two of the transgenic lines. SV40 Tag expression was also detected in the testis of all transgenic lines by RT-PCR. This result was not expected since the GHRH gene sequences present in the transgene do not include the testis-specific transcription initiation site previously described. This suggests that GHRH gene expression in the mouse testis can be directed by regulatory sequences located downstream of the testis specific transcription start site. We conclude that the promoter region of the GHRH gene included in this construct contains the regulatory elements necessary to drive hypothalamic and testis expression in vivo. In addition, all mice from one of the transgenic lines developed cataracts in both eyes. SV40 Tag expression was detected not only in eyes with cataracts, but also, to a lesser extent, in eyes from other transgenic lines. Furthermore, the endogenous GHRH gene was found to be expressed in the eyes of normal mice.

The physiological role of endogenous circulating GH-releasing hormone (GHRH) and somatostatin (SRIH) on spontaneous pulsatile and neostigmine-induced secretion of GH was investigated in adult rams actively immunized against each neuropeptide. All animals developed antibodies at concentrations sufficient for immunoneutralization of GHRH and SRIH levels in hypophysial portal blood. In the anti GHRH group, plasma GH levels were very low; the amplitude of GH pulses was strikingly reduced, although their number was unchanged. No stimulation of GH release was observed after neostigmine administration. The reduction of GH secretion was associated with a decreased body weight and a significant reduction in plasma IGF-I concentration. In the anti-SRIH group, no changes in basal and pulsatile GH secretion or the GH response to neostigmine were observed as compared to controls. Body weight was not significantly altered and plasma IGF-I levels were reduced in these animals. These results suggest that in sheep, circulating SRIH (in the systemic and hypophysial portal vasculature) does not play a significant role in pulsatile and neostigmine-induced secretion of GH. The mechanisms of its influence on body weight and production of IGF-I remain to be determined.

The mechanisms involved in the genesis of pulsatile GH secretion are not well understood. Recently, methods for hypophyseal portal blood collection in conscious sheep became available. Using this method, GHRH and SRIH secretion into hypophyseal portal blood (HPB) and GH release from the pituitary gland were simultaneous assessed and the relationship between GHRH and SRIH changes in HPB and GH in peripheral blood was investigated. In 23 rams (9-11 month old, 35-45 kg bw), 126 hours of HPB were analysed. Fifty-four spontaneous GH peaks were detected. The majority of GH peaks (48.1%) was associated with an increased portal GHRH and a fall in somatostatin concentrations. A simultaneous increase in GHRH and somatostatin levels was observed in 18.5% of GH peaks while 12.9% of peaks occurred with a fall in SRIH and no modification in GHRH concentrations. Finally, 5/54 (9.3%) GH peaks occurred without any modification in portal GHRH and SRIH release. Our data indicate that the GHRH/SRIH interplay is complex. The occurrence of spontaneous GH peaks may be due not only to a coordinate increase in GHRH and reduction in SRIH release similar to male rat, but also to other patterns of GHRH/SRIH secretion.

The acute effect of a new GH-releasing peptide, hexarelin (1 mg, iv), on GH secretion and the mechanisms involved in its changes were investigated in conscious sheep. Peripheral GH levels and GH-releasing hormone (GHRH) and somatostatin concentrations in hypophysial portal blood were measured in six rams. An increase in jugular GH levels was observed 15 min after hexarelin injection (9.1 +/- 1.8 vs. 3.9 +/- 0.8 ng/ml; P < 0.05). This was associated with a stimulation of GHRH release into hypophysial portal blood (145.4 +/- 19.9 vs. 59.2 +/- 10.8 pg/ml; P < 0.01) without a change in somatostatin secretion. Our data indicate that GH-releasing peptide-induced GH stimulation in the sheep involves an activation of GHRH neurons in addition to the previously demonstrated direct effect on the pituitary cells.

The effects of acute stress on growth hormone (GH) secretion and the mechanisms involved in its changes have been investigated in sheep. An acute isolation-restraint stress induced a rapid and significant increase in jugular GH levels in 12 out of 14 rams. GH-releasing hormone (GHRH) and somatostatin secretion during the same stress were studied in 5 animals prepared for hypophysial portal blood collection. A 3.5-fold increase in portal GHRH levels was observed concomitantly with a slight elevation in portal somatostatin. Portal corticotropin-releasing hormone (CRH) and jugular cortisol plasma levels increased during the same stress. Our data suggest that an isolation-restraint stress stimulates GH secretion in the sheep and that GHRH may be responsible for GH response.

The action of serotonin on growth hormone (GH) secretion is controversial because of interspecies differences and lack of specificity of serotoninergic drugs. Serotonin (5-HT) appears to inhibit GH release in the sheep and in man. We have investigated the site of action of tianeptine, a 5-HT uptake enhancer, in sheep since it is possible to collect hypophysial portal blood for the simultaneous determination of growth hormone-releasing hormone (GHRH) and somatostatin in this species under conscious, unstressed conditions. Tianeptine injection (10 mg/kg i.v.) resulted in a significant, immediate and short-lasting (30 min) increase in peripheral GH (+750%; P < 0.01) and hypophysial portal GHRH (+180%; P < 0.01). No change in the secretion of somatostatin was recorded during the same time. These data suggest that serotoninergic inputs are inhibitory to GH secretion. Tianeptine acts centrally to stimulate GH secretion in the sheep and its effect is mediated through changes in GHRH but not somatostatin release into hypophysial portal blood.

GH secretion is stimulated by the administration of an alpha 2-adrenergic agonist, clonidine, in several species, including man. This action is probably mediated at the level of the hypothalamus, where the drug may act through inhibition of somatostatin (SRIH) and/or stimulation of GH-releasing hormone (GHRH) release. We have investigated the mode and site of action of clonidine in sheep, because it is possible to collect hypophysial portal blood for the simultaneous determination of GHRH and SRIH in this species under conscious unstressed conditions. Clonidine injection (0.3 mg, iv) resulted in a significant, immediate, and short-lasting (30-min) increase in peripheral GH (14.4 +/- 3.1 vs. 4.8 +/- 1.1 ng/ml; P < 0.01) and portal GHRH (2.7 +/- 0.5 vs. 1.0 +/- 0.2 pg/min; P < 0.01) levels. No change in SRIH secretion was recorded during the same period. Next, we tested the effect of clonidine in sheep actively immunized against GHRH or SRIH. The alpha 2-adrenergic agonist did not affect GH secretion in the anti-GHRH group, whereas immunization against SRIH did not modify the GH response. Finally, we observed that clonidine did not influence GH release from cultured ovine pituitary cells. These data suggest that clonidine acts centrally to stimulate hypophysial GH secretion in the sheep and that this effect is mediated through changes in GHRH, but not SRIH, release into hypophysial portal blood.

All kind of stress produce an endocrine response. These hormonal responses can serve as stress indicators. The main peripheral endocrine responses to stress are the activation of adrenal corticoids, the stimulation of Growth Hormone (GH) and prolactin secretion, and the inhibition of insulin and gonadal secretion. Except for the inhibition of insulin release, all these hormonal variations depend on the adenohypophysis activity: stimulation of Adrenocorticotrophin hormone (ACTH), GH and prolactin, and inhibition of gonadotrophins (LH-FSH) secretions. Several lines of evidence demonstrate that specific hypothalamic Neuro-hormones stimulate or inhibit the hypophysial activity in response to stress. However, due to methodological difficulties, only measurements of peripheral hormones can be used as stress indicators.

GH secretion is stimulated by the administration of cholinesterase inhibitors (such as pyridostigmine and neostigmine) in several species, including man. On the basis of indirect experiments, it has been postulated that this action is mediated by a decrease in hypothalamic somatostatin release. We have investigated the effect of neostigmine in sheep, since it is possible to collect hypophysial portal blood for GH-releasing hormone (GHRH) and somatostatin determination in this species under a conscious unstressed state. First, after i.v. injection of neostigmine (1 mg), a significant increase in plasma GH levels and an unequivocal potentiation of the GH response to GHRH were observed. Then, we observed that i.v. injection of neostigmine (1 mg) induced an immediate, short-lasting (30 min), and marked increase in GHRH (126.1 +/- 17 vs. 14.5 +/- 2.1 pg/ml; P < 0.01) levels in hypophysial portal blood of rams chronically implanted with perihypophysial cannulae. No change in somatostatin secretion was recorded during the same period. These data suggest that the stimulating effect of cholinergic drugs on GH secretion is mediated by stimulation of GHRH release. A direct effect of neostigmine at the level of pituitary gland is possible and may explain the potentiation of GHRH-induced GH release.

The effects of rapid changes of circulating cortisol levels on ACTH secretion and on corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) concentrations into hypophysial portal blood were studied in six adult rams. Pharmacological adrenalectomy was obtained by 3 h metyrapone infusion (100 mg.kg-1.h-1). Blockade of cortisol synthesis induced a tenfold increase of plasma ACTH levels accompanied by a moderate increase of CRF secretion (150% vs preinjection levels) and a large increment of AVP secretion (535% vs preinjection levels). ACTH levels remained high during the 3 h following the end of metyrapone infusion. During the same period, CRF secretion was still elevated (231% vs preinjection levels), while AVP secretion was further stimulated (2,151% vs preinjection levels). Subsequent hydrocortisone infusion (66 micrograms.kg-1.h-1) for 2 h induced a rapid decrease of both ACTH and AVP secretion, while CRF levels in hypophysial portal blood still remained elevated. These data suggest that changes in ACTH secretion induced by acute modifications of the negative glucocorticoid feedback are, in addition to the well documented direct effect of cortisol on the corticotropes, mainly mediated by variations of hypothalamic AVP secretion.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) and to an acute injection of CRF were determined in intact as well as in actively antiarginine vasopressin (AVP)-immunized rams. All immunized sheep developed antibodies to AVP, displayed diabetes insipidus, and looked healthy in spite of their lower gain weight. Basal secretion and diurnal variations of ACTH and cortisol were unaltered in the group of anti-AVP-immunized animals. In contrast, ACTH and cortisol responses to both types of stress and CRF injection were significantly reduced compared to those in controls. These results suggest that endogenous AVP plays a physiological role in the corticotropic response to stress. However, endogenous AVP does not appear to affect basal secretion and diurnal variations of ACTH and cortisol.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) or to an acute injection of lysine-vasopressin were studied in intact and anti-corticotropin-releasing factor (CRF) actively immunized rams. Immunization was obtained by the injection of synthetic ovine CRF coupled to BSA with carbodiimide. All animals developed antibodies anti-CRF and displayed an alteration of their general condition and a body weight reduction. The mean basal ACTH and cortisol secretion as well as the number and mean amplitude of diurnal pulses of these hormones was significantly reduced in the group of anti-CRF immunized rams. However, the reduction in all three parameters was much more pronounced for cortisol than for ACTH. No ACTH and cortisol response to insulin-induced hypoglycemia and isolation-restraint stress was observed. The stimulating action of lysine-vasopressin on ACTH release was significantly reduced as compared to controls. These results indicate that CRF is a major physiological component of the ovine hypothalamo-hypophysial-adrenal axis and participates in the events that regulate ACTH and cortisol diurnal variations and response to stress.

BIM 23014 is a somatostatin analog displaying an increased biological half life due to resistance to enzymatic degradation. This peptide inhibits GH release directly at the level of pituitary somatotrophs. In addition, an action of BIM 23014 at the level of the hypothalamus is possible since somatostatinergic fibers and receptors have been identified on GH-RH neurons. To evaluate the effect of BIM 23014 on GH-RH secretion, hypophysial portal blood (HPB) was continuously collected in conscious sheep. Twelve rams (40-45 kg, 9-month-old) with chronically implanted perihypophysial cannulae were i.v. injected with BIM 23014 (1 mg) or saline. HPB and jugular blood were collected for 3-5 hours before and after the injection for the determinations of GH-RH and GH concentrations respectively. The acute injection of BIM 23014 induced a rapid decrease of plasma GH within the first two hours. Simultaneously, GH-RH in HPB decreased significantly. After reaching a nadir, GH concentrations increased to values greater than baseline. A similar rebound in GH-RH levels in HPB was also observed. These data indicate that BIM 23014 acts at the level of GH-RH hypothalamic neurons, in addition to its well-know effect on the pituitary gland.