Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal ...unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy.
We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806.
Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 95% CI 0·62–1·15). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment.
Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered.
National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Temporary conductive hearing loss (CHL) can lead to hearing impairments that persist beyond resolution of the CHL. In particular, unilateral CHL leads to deficits in auditory skills that rely on ...binaural input (e.g., spatial hearing). Here, we asked whether single neurons in the auditory midbrain, which integrate acoustic inputs from the two ears, are altered by a temporary CHL. We introduced 6 weeks of unilateral CHL to young adult chinchillas via foam earplug. Following CHL removal and restoration of peripheral input, single-unit recordings from inferior colliculus (ICC) neurons revealed the CHL decreased the efficacy of inhibitory input to the ICC contralateral to the earplug and increased inhibitory input ipsilateral to the earplug, effectively creating a higher proportion of monaural responsive neurons than binaural. Moreover, this resulted in a ∼10 dB shift in the coding of a binaural sound location cue (interaural-level difference, ILD) in ICC neurons relative to controls. The direction of the shift was consistent with a compensation of the altered ILDs due to the CHL. ICC neuron responses carried ∼37% less information about ILDs after CHL than control neurons. Cochlear peripheral-evoked responses confirmed that the CHL did not induce damage to the auditory periphery. We find that a temporary CHL altered auditory midbrain neurons by shifting binaural responses to ILD acoustic cues, suggesting a compensatory form of plasticity occurring by at least the level of the auditory midbrain, the ICC.
Early life stress (ELS) exposure alters brain development, increasing vulnerability for mental illness in adulthood, including depression. Despite this association, there are no approved ...pharmacotherapies to protect against the emergence of mental illness resulting from ELS. Recent preclinical work showed that oxytocin (OT) administration in adulthood reduced depressive-like behaviour in male rats with a history of ELS. However, the ability of an OT treatment regime in adolescence, a critical developmental window for the OT system, to prevent the expression of depressive-like behaviours following ELS has not been investigated. Therefore, the present study aimed to determine whether chronic OT administration can ameliorate the enduring effects of ELS on depressive-like behaviours in both male and female rats. Following birth, Long Evans rat pups (N = 107) underwent maternal separation (MS) for either 15 min (MS15) or 6 h (MS360) on postnatal days (PND) 1–21. During adolescence (PND 28–42), rats received a daily injection of either OT (1 mg/kg) or saline. During adulthood (PND 57 onwards), effort-related motivation was measured using a model of effortful choice (EC), while behavioural despair was measured using the forced swim test (FST). Lastly, body and organ weights were measured to examine the physiological impacts of ELS and chronic OT administration. Overall, in both sexes, MS360 increased behavioural despair yet had no impact on effort-related motivation. Importantly, adolescent OT administration prevented the MS360-induced increase in behavioural despair in both males and females. Additionally, MS360 resulted in persistent reductions in body weight in both sexes post-weaning and increased spleen weight in males and adrenal weight in females. OT treatment had no impact on body weight in either sex, but prevented the MS-induced increase in adrenal gland weight in females. Overall, these findings have important implications for using oxytocin as a preventative pharmacotherapy after ELS.
•Maternal separation (MS) increased behavioural despair in male and female rats•Adolescent oxytocin (OT) treatment prevented behavioural despair induced by MS•MS had no effect on effort-related motivation in males or females•OT prevented the MS-induced increase in adrenal gland weight in females
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rationale
Stress exposure during adolescence contributes to developing a methamphetamine (METH) use disorder. However, most of the studies investigating addiction-related behaviours include only male ...rodents, despite METH addiction rates being higher in females. Furthermore, animal studies investigating the effects of stress on methamphetamine addiction have used only basic self-administration models which may not be sensitive to the effects of stress.
Objectives
This project explored whether adolescent isolation stress exposure increases the incidence of four key addiction-related behaviours in female rats.
Methods
Thirty-two female rat pups were caged in groups of four or individually during adolescence from postnatal (PND) day 22, with the latter being re-socialised in groups of four on PND 43. In adulthood, rats were tested for addiction-like behaviours in a METH self-administration paradigm modelling motivation to take METH, persistence in drug-seeking behaviour when METH was not available, resistance to extinction, and propensity to reinstate after a period of withdrawal.
Results
Adolescent social isolation resulted in lower METH intake during acquisition; however, the paradigm modelling drug-seeking when the drug was unavailable engendered intermittent METH bingeing in all rats, abolishing the group differences in intake during this phase. Adolescent social isolation also accelerated extinction of non-reinforced lever pressing, and increased stress-primed reinstatement, compared to the group-housed rats.
Conclusions
Adolescent social isolation stress alters various methamphetamine addiction-like behaviours in female rats.
Full text
Available for:
DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
As public awareness of medical radiation exposure increases, there has been heightened awareness among patients and physicians of the importance of holistic benefit-and-risk discussions in shared ...medical decision making.
We examine the rationale for informed consent and risk communication, draw on the literature on the psychology of radiation risk communication to increase understanding, examine methods commonly used to communicate radiation risk, and suggest strategies for improving communication about medical radiation benefits and risk.
The century-old duplex theory of sound localization posits that low- and high-frequency sounds are localized with two different acoustical cues, interaural time and level differences (ITDs and ILDs), ...respectively. While behavioral studies in humans and behavioral and neurophysiological studies in a variety of animal models have largely supported the duplex theory, behavioral sensitivity to ILD is curiously invariant across the audible spectrum. Here we demonstrate that auditory midbrain neurons in the chinchilla (Chinchilla lanigera) also encode ILDs in a frequency-invariant manner, efficiently representing the full range of acoustical ILDs experienced as a joint function of sound source frequency, azimuth, and distance. We further show, using Fisher information, that nominal "low-frequency" and "high-frequency" ILD-sensitive neural populations can discriminate ILD with similar acuity, yielding neural ILD discrimination thresholds for near-midline sources comparable to behavioral discrimination thresholds estimated for chinchillas. These findings thus suggest a revision to the duplex theory and reinforce ecological and efficiency principles that hold that neural systems have evolved to encode the spectrum of biologically relevant sensory signals to which they are naturally exposed.
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver ...function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question.
The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks' gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks' gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks' gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care.
Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines.
ISRCTN registry, ID: ISRCTN91918806 . Prospectively registered on 27 August 2015.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We sought to understand how patients and physicians conceptualize uncertainty in the permanent contraception decision-making process.PURPOSEWe sought to understand how patients and physicians ...conceptualize uncertainty in the permanent contraception decision-making process.In 2022-2023, we interviewed postpartum patients with a documented desire for permanent contraception (n = 81) and their delivering physicians (n = 67). Eligible patients gave birth at one of our four study hospitals in California, Ohio, Illinois, and Alabama. We used rapid content analysis and thematic content analysis to develop and refine themes related to uncertainty in permanent contraceptive decision-making.BASIC PROCEDURESIn 2022-2023, we interviewed postpartum patients with a documented desire for permanent contraception (n = 81) and their delivering physicians (n = 67). Eligible patients gave birth at one of our four study hospitals in California, Ohio, Illinois, and Alabama. We used rapid content analysis and thematic content analysis to develop and refine themes related to uncertainty in permanent contraceptive decision-making.Most patients reported full certainty in their decision regarding permanent contraception, although some expressed doubts. After receiving permanent contraception, some patients discussed grief but overall affirmed their decision. One patient said they wished they had considered other contraceptive options. Physicians reported using a range of strategies to safeguard from patient regret, including ensuring patients were 100% certain with their decision, inferring certainty based on their characteristics, asking patients to think through all scenarios that could affect decision-making, and repeat counseling during multiple interactions.MAIN FINDINGSMost patients reported full certainty in their decision regarding permanent contraception, although some expressed doubts. After receiving permanent contraception, some patients discussed grief but overall affirmed their decision. One patient said they wished they had considered other contraceptive options. Physicians reported using a range of strategies to safeguard from patient regret, including ensuring patients were 100% certain with their decision, inferring certainty based on their characteristics, asking patients to think through all scenarios that could affect decision-making, and repeat counseling during multiple interactions.Patient experiences reveal the depth, fluidity, and nuance of patients' contraceptive decision-making processes. Physicians sometimes failed to grapple with this nuance by centering potential regret in their counseling. Personalized and supportive contraceptive counseling that acknowledges the complexity of contraceptive decision-making is imperative. Shared decision-making can help ensure patients can make informed and autonomous decisions about their reproductive lives.PRINCIPAL CONCLUSIONSPatient experiences reveal the depth, fluidity, and nuance of patients' contraceptive decision-making processes. Physicians sometimes failed to grapple with this nuance by centering potential regret in their counseling. Personalized and supportive contraceptive counseling that acknowledges the complexity of contraceptive decision-making is imperative. Shared decision-making can help ensure patients can make informed and autonomous decisions about their reproductive lives.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dramatic improvements in measuring genetic variation across agriculturally relevant populations (genomics) must be matched by improvements in identifying and measuring relevant trait variation in ...such populations across many environments (phenomics). Identifying the most critical opportunities and challenges in genome to phenome (G2P) research is the focus of this paper. Previously (Genome Biol, 23(1):1-11, 2022), we laid out how Agricultural Genome to Phenome Initiative (AG2PI) will coordinate activities with USA federal government agencies expand public-private partnerships, and engage with external stakeholders to achieve a shared vision of future the AG2PI. Acting on this latter step, AG2PI organized the "Thinking Big: Visualizing the Future of AG2PI" two-day workshop held September 9-10, 2022, in Ames, Iowa, co-hosted with the United State Department of Agriculture's National Institute of Food and Agriculture (USDA NIFA). During the meeting, attendees were asked to use their experience and curiosity to review the current status of agricultural genome to phenome (AG2P) work and envision the future of the AG2P field. The topic summaries composing this paper are distilled from two 1.5-h small group discussions. Challenges and solutions identified across multiple topics at the workshop were explored. We end our discussion with a vision for the future of agricultural progress, identifying two areas of innovation needed: (1) innovate in genetic improvement methods development and evaluation and (2) innovate in agricultural research processes to solve societal problems. To address these needs, we then provide six specific goals that we recommend be implemented immediately in support of advancing AG2P research.
Physiological and anatomical studies have suggested that alligators have unique adaptations for spatial hearing. Sound localization cues are primarily generated by the filtering of sound waves by the ...head. Different vertebrate lineages have evolved external and/or internal anatomical adaptations to enhance these cues, such as pinnae and interaural canals. It has been hypothesized that in alligators, directionality may be enhanced via the acoustic coupling of middle ear cavities, resulting in a pressure difference receiver (PDR) mechanism. The experiments reported here support a role for a PDR mechanism in alligator sound localization by demonstrating that (1) acoustic space cues generated by the external morphology of the animal are not sufficient to generate location cues that match physiological sensitivity, (2) continuous pathways between the middle ears are present to provide an anatomical basis for coupling, (3) the auditory brainstem response shows some directionality, and (4) eardrum movement is directionally sensitive. Together, these data support the role of a PDR mechanism in crocodilians and further suggest this mechanism is a shared archosaur trait, most likely found also in the extinct dinosaurs.
PDF
