Glycemic treatment deintensification practices in nursing home residents with type 2 diabetes.

BACKGROUND: Older nursing home (NH) residents with glycemic overtreatment are at significant risk of hypoglycemia and other harms and may benefit from deintensification. However, little is known about deintensification practices in this setting. METHODS: We conducted a cohort study from January 1, 2013 to December 31, 2019 among Veterans Affairs (VA) NH residents. Participants were VA NH residents age ≥65 with type 2 diabetes with a NH length of stay (LOS) ≥ 30 days and an HbA1c result during their NH stay. We defined overtreatment as HbA1c <6.5 with any insulin use, and potential overtreatment as HbA1c <7.5 with any insulin use or HbA1c <6.5 on any glucose-lowering medication (GLM) other than metformin alone. Our primary outcome was continued glycemic overtreatment without deintensification 14 days after HbA1c. RESULTS: Of the 7422 included residents, 17% of residents met criteria for overtreatment and an additional 23% met criteria for potential overtreatment. Among residents overtreated and potentially overtreated at baseline, 27% and 19%, respectively had medication regimens deintensified (73% and 81%, respectively, continued to be overtreated). Long-acting insulin use and hyperglycemia ≥300 mg/dL before index HbA1c were associated with increased odds of continued overtreatment (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.14-1.65 and OR 1.35, 95% CI 1.10-1.66, respectively). Severe functional impairment (MDS-ADL score ≥ 19) was associated with decreased odds of continued overtreatment (OR 0.72, 95% CI 0.56-0.95). Hypoglycemia was not associated with decreased odds of overtreatment. CONCLUSIONS: Overtreatment of diabetes in NH residents is common and a minority of residents have their medication regimens appropriately deintensified. Deprescribing initiatives targeting residents at high risk of harms and with low likelihood of benefit such as those with history of hypoglycemia, or high levels of cognitive or functional impairment are most likely to identify NH residents most likely to benefit from deintensification.

Disseminated Intravascular Coagulation and Hemorrhage After Dilation and Evacuation Abortion for Fetal Death.

OBJECTIVE: To examine the association between fetal death and risk of hemorrhage and disseminated intravascular coagulation (DIC) among women undergoing dilation and evacuation (D&E) procedures. METHODS: We conducted a retrospective cohort study of all D&Es at one academic abortion clinic in San Francisco between 2009 and 2013. We abstracted data on fetal death status, demographic characteristics, and complications including hemorrhage and DIC. We examined the risk of hemorrhage and DIC among women with fetal death compared with those without. We conducted unadjusted and adjusted analyses for the outcomes of hemorrhage, DIC, and any complication. RESULTS: Among 92 cases of D&E for fetal death and 4,428 cases of D&E for other reasons, hemorrhage occurred in 10% and 7%, respectively (P=.28), and DIC occurred in 2.0% and 0.2% of the fetal death and nonfetal death cohorts (P<.001). In adjusted analysis, fetal death was associated with 2.9 times higher odds of hemorrhage (95% CI 1.4-6.0). In an unadjusted analysis, fetal death was associated with 12.3 times higher odds of DIC (95% CI 2.6-58.6) and 3.0 times higher odds of any complication (95% CI 1.6-5.9). CONCLUSION: Women undergoing D&E for fetal death are far more likely to experience DIC and hemorrhage than are women without fetal death, yet the absolute risk is low (2%). Although D&E providers should be prepared for DIC and hemorrhage, we do not recommend any specific preoperative preparation because the vast majority of D&E abortions for fetal death are uncomplicated.

Identification of a novel gene regulating amygdala-mediated fear extinction.

Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction. Next, by profiling extinction-driven BLA expression of QTL-linked genes, we nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. We then showed that Ppid was enriched in excitatory and inhibitory BLA neuronal populations, but at lower levels in the extinction-impaired mouse strain. Using a virus-based approach to directly regulate Ppid function, we demonstrated that downregulating BLA-Ppid impaired extinction, while upregulating BLA-Ppid facilitated extinction and altered in vivo neuronal extinction encoding. Next, we showed that Ppid colocalized with the glucocorticoid receptor (GR) in BLA neurons and found that the extinction-facilitating effects of Ppid upregulation were blocked by a GR antagonist. Collectively, our results identify Ppid as a novel gene involved in regulating extinction via functional actions in the BLA, with possible implications for understanding genetic and pathophysiological mechanisms underlying risk for trauma-related disorders.

Safety of Deep Sedation Without Intubation for Second-Trimester Dilation and Evacuation.

OBJECTIVE: To estimate the incidence of pulmonary aspiration and other anesthesia-related adverse events in women undergoing dilation and evacuation (D&E) under intravenous deep sedation without tracheal intubation in an outpatient setting. METHODS: We reviewed all D&Es done under anesthesiologist-administered intravenous deep sedation without tracheal intubation between February 2009 and April 2013. The study's primary outcome was pulmonary aspiration; secondary outcomes included other anesthesia-related complications. We calculated the incidence of anesthesia-related adverse events as well as a 95% CI around the point estimate. RESULTS: During the 51-month study period, 4,481 second-trimester abortions were completed. Of these, 2,523 (56%) were done under deep sedation without tracheal intubation, 652 (26%) between 14 and 19 6/7 weeks of gestation, and 1,871 (74%) between 20 and 24 weeks of gestation. Seven cases of anesthesia-related complications were identified: two cases of pulmonary aspiration (0.08%, 95% CI 0.01-0.29%), four cases of upper airway obstruction (0.016%, 95% CI 0.04-0.41%), and one case of lingual nerve injury (0.04%, 95% CI 0.001-0.22%). CONCLUSION: Deep sedation without tracheal intubation for women undergoing D&E has a low incidence of anesthesia-related complications.

Obesity as a Risk Factor for Complications After Second-Trimester Abortion by Dilation and Evacuation.

OBJECTIVE: To evaluate the association between obesity (body mass index [BMI] 30 or higher) and dilation and evacuation (D&E) complications. METHODS: We conducted a retrospective cohort study of women who underwent D&E abortion from February 2009 to April 2013 at a hospital-based abortion practice in California. We evaluated the association between obesity and risk of complication after D&E using logistic regression. We defined complications a priori as cervical laceration, hemorrhage, uterine atony, anesthesia complications, uterine perforation, disseminated intravascular coagulation, and retained products of conception. We defined major complications as those requiring hospitalization, transfusion, or further surgical intervention. RESULTS: Complications occurred in 442 of 4,520 D&Es (9.8%), with equal proportions in obese and nonobese women (9.8%). Major complications occurred in 78 (1.7%) patients. After adjustment for age, ethnicity, prior vaginal delivery, prior cesarean delivery, and gestational duration, there was no association between BMI and D&E complications. Any individual complication was associated with each additional week of gestation (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.3-1.4), prior vaginal delivery (OR 1.5, 95% CI 1.2-1.9) and prior cesarean delivery (OR 1.8, 95% CI 1.4-2.3). Major complications were associated with each additional week of gestation (OR 1.3, 95% CI 1.1-1.4) and cesarean delivery (OR 1.8, 95% CI 1.1-3.1). CONCLUSION: We found no association between obesity and D&E complications. Our findings are consistent with previous studies demonstrating that later gestational duration is associated with an increased risk of complications. Obesity may not warrant referral to a high-risk abortion center, particularly because referral-associated delay might increase the risk of complications. LEVEL OF EVIDENCE: II.

Induction of fetal demise before pregnancy termination: practices of family planning providers.

OBJECTIVES: Our survey aimed to characterize the practice of inducing fetal demise before pregnancy termination among abortion providers, including its technical aspects and why providers have chosen to adopt it. STUDY DESIGN: We conducted a survey of Family Planning Fellowship-trained or Fellowship-affiliated Family Planning (FP) subspecialists about their practice of inducing fetal demise, including questions regarding the circumstances in which they would induce demise, techniques used and rationales for choosing whether to adopt this practice. RESULTS: Of the 169 FP subspecialists we surveyed, 105 (62%) responded. About half (52%) of respondents indicated that they routinely induced fetal demise before terminations in the second trimester. Providers' practices varied in the gestations at which they started inducing demise as well as the techniques used. Respondents provided legal, technical and psychological reasons for their decisions to induce demise. CONCLUSION: Inducing fetal demise before second-trimester abortions is common among US FP specialists for multiple reasons. The absence of professional guidelines or robust data may contribute to the variance in the current practice patterns of inducing demise. IMPLICATIONS: Our study documents the widespread practice of inducing fetal demise before second-trimester abortion and further describes wide variation in providers' methods and rationales for inducing demise. It is important for abortion providers as a professional group to come to a formal consensus on the appropriate use of these techniques and to determine whether such practices should be encouraged, tolerated or even permitted.

Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J×129S1/SvImJ inbred mouse cross.

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6×S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans.

Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes.

Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.

Reward-related behavioral paradigms for addiction research in the mouse: performance of common inbred strains.

The mouse has emerged as a uniquely valuable species for studying the molecular and genetic basis of complex behaviors and modeling neuropsychiatric disease states. While valid and reliable preclinical assays for reward-related behaviors are critical to understanding addiction-related processes, and various behavioral procedures have been developed and characterized in rats and primates, there have been relatively few studies using operant-based addiction-relevant behavioral paradigms in the mouse. Here we describe the performance of the C57BL/6J inbred mouse strain on three major reward-related paradigms, and replicate the same procedures in two other commonly used inbred strains (DBA/2J, BALB/cJ). We examined Pavlovian-instrumental transfer (PIT) by measuring the ability of an auditory cue associated with food reward to promote an instrumental (lever press) response. In a separate experiment, we assessed the acquisition and extinction of a simple stimulus-reward instrumental behavior on a touch screen based task. Reinstatement of this behavior was then examined following either continuous exposure to cues (conditioned reinforcers, CRs) associated with reward, brief reward and CR exposure, or brief reward exposure followed by continuous CR exposure. The third paradigm examined sensitivity of an instrumental (lever press) response to devaluation of food reward (a probe for outcome insensitive, habitual behavior) by repeated pairing with malaise. Results showed that C57BL/6J mice displayed robust PIT, as well as clear extinction and reinstatement, but were insensitive to reinforcer devaluation. DBA/2J mice showed good PIT and (rewarded) reinstatement, but were slow to extinguish and did not show reinforcer devaluation or significant CR-reinstatement. BALB/cJ mice also displayed good PIT, extinction and reinstatement, and retained instrumental responding following devaluation, but, unlike the other strains, demonstrated reduced Pavlovian approach behavior (food magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research.

Measuring anxiety- and locomotion-related behaviours in mice: a new way of using old tests.

RATIONALE: Batteries of tests that are thought to measure different aspects of anxiety-related behaviour are used to characterise mice after genetic or pharmacological manipulation. However, because of the potentially confounding effects of repeated testing and natural intra-individual variations in behaviour over time, subjecting mice to a succession of tests is not ideal. OBJECTIVES: The aim of this study was to investigate, in mice, the utility of an integrated apparatus that combines three classical tests of anxiety, the open field, elevated plus maze (EPM) and light/dark box. METHODS: Mice from four different strains (CD-1, BALB/cJ, DBA/2J, C57BL/6J) were used in a series of five experiments where their behaviour was observed for 15 min in the integrated apparatus. Responses to anxiety-modulating drugs and 2-day repeated testing were evaluated. RESULTS: CD-1 mice explored the apparatus thoroughly, providing measures from all areas throughout the entire testing session. Factor analysis showed that measures of locomotion and anxiety-related behaviour were dissociable. BALB/cJ, DBA/2J and C57BL/6J showed markedly different behavioural profiles, largely consistent with previous studies examining individual tests. Avoidance of aversive environments did not increase with repeated testing. In CD-1 mice, the anxiolytics diazepam and alprazolam (4 and 2 mg/kg, respectively) increased the approach towards the EPM open arms. Alprazolam also had sedative effects, whereas the anxiogenic pentylenetetrazole had no effects. CONCLUSIONS: These findings suggest that the triple test is sensitive to genetic/pharmacological influences on anxiety and locomotion and that, by providing quasi-simultaneous measures from three different apparatuses, it may represent an alternative to the use of test batteries.