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A series of lysine-based vinyl sulfone peptidomimetics were synthesised and evaluated for anti-trypanosomal activity against bloodstream forms of T. brucei. This focused set of compounds, varying in the P 3 position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P 3 analogues exhibited sub-micromolar EC 50 values, with thiourea 14, urea 15 and amide 21 representing the most potent anti-trypanosomal derivatives of the series. In order to establish an in vitro selectivity index the most active anti-trypanosomal compounds were also assessed for their impact on cell viability and cytotoxity effects in mammalian cells. Encouragingly, all compounds only reduced cellular metabolic activity in mammalian cells to a modest level and little, or no cytotoxicity, was observed with the series., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: This study aimed to better understand patient and caregiver perspectives on social risk screening across different healthcare settings., Methods: As part of a mixed-methods multisite study, the authors conducted semistructured interviews with a subset of adult patients and adult caregivers of pediatric patients who had completed the Center for Medicare and Medicaid Innovation Accountable Health Communities social risk screening tool between July 2018 and February 2019. Interviews, conducted in English or Spanish, asked about reactions to screening, screening acceptability, preferences for administration, prior screening experiences that informed perspectives, and expectations for social assistance. Basic thematic analysis and constant comparative methods were used to code and develop themes., Results: Fifty interviews were conducted across 10 study sites in 9 states, including 6 primary care clinics and 4 emergency departments. There was broad consensus among interviewees across all sites that social risk screening was acceptable. The following 4 main themes emerged: (1) participants believed screening for social risks is important; (2) participants expressed insight into the connections between social risks and overall health; (3) participants emphasized the importance of patient-centered implementation of social risk screening; and (4) participants recognized limits to the healthcare sector's capacity to address or resolve social risks., Conclusions: Despite gaps in the availability of social risk-related interventions in healthcare settings, patient-centered social risk screening, including empathy and attention to privacy, may strengthen relationships between patients and healthcare teams., Supplement Information: This article is part of a supplement entitled Identifying and Intervening on Social Needs in Clinical Settings: Evidence and Evidence Gaps, which is sponsored by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, Kaiser Permanente, and the Robert Wood Johnson Foundation., (Copyright © 2019 American Journal of Preventive Medicine. All rights reserved.)

Introduction: Despite recent growth in healthcare delivery-based social risk screening, little is known about patient perspectives on these activities. This study evaluates patient and caregiver acceptability of social risk screening., Methods: This was a cross-sectional survey of 969 adult patients and adult caregivers of pediatric patients recruited from 6 primary care clinics and 4 emergency departments across 9 states. Survey items included the Center for Medicare and Medicaid Innovation Accountable Health Communities' social risk screening tool and questions about appropriateness of screening and comfort with including social risk data in electronic health records. Logistic regressions evaluated covariate associations with acceptability measures. Data collection occurred from July 2018 to February 2019; data analyses were conducted in February‒March 2019., Results: Screening was reported as appropriate by 79% of participants; 65% reported comfort including social risks in electronic health records. In adjusted models, higher perceived screening appropriateness was associated with previous exposure to healthcare-based social risk screening (AOR=1.82, 95% CI=1.16, 2.88), trust in clinicians (AOR=1.55, 95% CI=1.00, 2.40), and recruitment from a primary care setting (AOR=1.70, 95% CI=1.23, 2.38). Lower appropriateness was associated with previous experience of healthcare discrimination (AOR=0.66, 95% CI=0.45, 0.95). Higher comfort with electronic health record documentation was associated with previously receiving assistance with social risks in a healthcare setting (AOR=1.47, 95% CI=1.04, 2.07)., Conclusions: A strong majority of adult patients and caregivers of pediatric patients reported that social risk screening was appropriate. Most also felt comfortable including social risk data in electronic health records. Although multiple factors influenced acceptability, the effects were moderate to small. These findings suggest that lack of patient acceptability is unlikely to be a major implementation barrier., Supplement Information: This article is part of a supplement entitled Identifying and Intervening on Social Needs in Clinical Settings: Evidence and Evidence Gaps, which is sponsored by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, Kaiser Permanente, and the Robert Wood Johnson Foundation., (Copyright © 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

This prospective study of 241 women investigated the impact of past behavior and psychological factors on cigarette and alcohol use during pregnancy. Smokers' cigarette use was compared with their alcohol consumption during pregnancy, and drinking among smokers was compared with that of nonsmokers. Only prior smoking directly predicted smokers' cigarette use later in pregnancy, whereas smokers' alcohol use was related to both their previous drinking and their drinking self-efficacy. Among nonsmokers, neither drinking before nor early in pregnancy was related to alcohol use later in pregnancy; only subjects' self-efficacy and their beliefs about the consequences of drinking during pregnancy predicted their subsequent alcohol use. These results are consistent with the notion that greater addictive potential lessens the direct impact of psychological factors on substance use during pregnancy. Further implications of these findings for interventions and other health-related behaviors are also discussed.

The effect of bilateral pelvic, hypogastric, or pudendal neurectomy on oxytocin-induced facilitation of lordosis behavior was examined in ovariectomized, estrogen, and progesterone primed female rats. Oxytocin-induced facilitation of lordosis behavior was significantly decreased following bilateral pelvic, or combined bilateral pelvic and hypogastric neurectomy. Hypogastric only or pudendal only neurectomy had no effect on the facilitation of lordosis behavior after systemic administration of oxytocin. These results suggest that the integrity of the pelvic nerve is necessary and sufficient to mediate the stimulatory effects of systemically administered oxytocin on receptivity.

Rats were exposed to repeated sessions of inescapable footshock, and behavioral depression was subsequently assessed by measuring escape performance during exposure to escapable shock in a different testing environment. Free-running circadian activity rhythms were assessed using running wheels for approximately three weeks before and after administration of inescapable shock. Several animals showed lengthening of free-running period and decreases in activity level following shock. Similar effects were also seen in rats that were removed from their running wheels, placed within the shock apparatus, and not given shock, but not in nonhandled control animals. Furthermore, period lengthening in shocked and handled rats was positively correlated with escape performance, suggesting that circadian rhythm alterations occurred in those animals that were best able to cope with shock or handling-related stressors. In contrast, individual differences in circadian period and activity level during baseline conditions were not predictive of either escape performance or circadian rhythm alterations. These results suggest that successful behavioral adaptation to stress may be associated with alterations of circadian rhythmicity.

Two studies explore the relationship between rhythmicity and behavioral depression. Behavioral depression was induced using inescapable footshock, and assessed by measuring subsequent responses to escapable shock, in rats housed under different light-dark conditions. Experiment 1 compared escape performance in free-running and entrained animals following inescapable shock. Free-running and entrained animals did not exhibit differential vulnerability to the effects of inescapable shock. In addition, there were no systematic effects on phase following shock. However, several free-running animals showed increased circadian period following shock, and lengthening of period was significantly correlated with escape performance. Individual differences in baseline period or phase were not predictive of escape performance. In Experiment 2, "aftereffects" of entrainment to long or short light-dark cycles were utilized to create groups of animals with long or short free-running periods. After the administration of inescapable shock, escape performance was tested. There were no significant differences among experimental groups in escape performance. These results suggest that plasticity of circadian period, but not baseline period per se, may be associated with the ability to adapt to environmental challenges.

Abnormal thyroid status and affective disorders have been associated in the human clinical literature. It has recently been shown that pretreatment with thyroid hormone can prevent escape deficits produced by inescapable shock in an animal analogue of depression. In this report we provide evidence that hypothyroid status can produce an escape deficit in rats. While sham-operated rats improved their performance on a simple escape task over three days of testing, thyroparathyroidectomized rats showed a pronounced decrease in their responses. Markov transition analysis was used to obtain conditional probabilities of escaping given a prior escape or failure to escape for the two groups. This analysis shows that the structure of the data set may be similar for the two groups. These results suggest that if intact rats learn to escape, then hypothyroid rats may learn not to escape.

The patterns of food intake, water intake and body weight of the female rat during the estrous cycle and pregnancy were determined. During the 4-day estrous cycle, intake and body weight were reduced on the day of ovulation. In contrast, animals with 5-day estrous cycles reduced intake and body weight for 2 days, the day prior to ovulation as well as on the day of ovulation. Intake of pregnant rats around the time of birth was compared to that of cycling females and similarities were observed. The peripartum pattern of food intake was systematically related to the length of the gestation period. Rats that littered 22 days after mating showed depressed food intake only on the day of birth. Those with 23-day gestation periods decreased food intake both on the day of birth and on the following day. The similarities in the intake patterns during 4- and 5-day estrous cycle to that of the peripartum segment of 22- and 23-day pregnancies suggest that there may be common neuroendocrine factors controlling these behaviors during the two reproductive periods.

The number of pre-ejaculatory intromissions a female rat receives affects the probability of becoming progestational and transporting sperm into the uterus. We now report that the number of intromissions a male rat delivers affects his ejaculatory performance. Males and females were given different copulatory experience by switching females during mating. When either the male or female had few intromissions, few sperm were recovered and the copulatory plugs fit less well. Intromission-dependent sperm recovery was also observed in a review of 94 copulatory tests drawn from archival data. Several possible mechanisms are discussed, including poor placement of the copulatory plug and reduced sperm output. The potential significance for reproductive success in social mating situations is discussed.

The purpose of this experiment was to investigate the relationship between daily patterns of wheel running activity and feeding behavior. Wheel running and bar pressing for food were continuously recorded from rats which had concurrent access to both wheels and food. In a second condition, wheel running and (non-reinforced) bar pressing were recorded during food deprivation. In a third condition, bar pressing for food was recorded while wheel running was prevented. During ad lib access to wheels and food, both behaviors occurred primarily during the dark phase of the light-dark cycle. However, the nocturnal distribution of these responses differed: the early dark hours were primarily devoted to running, while feeding occurred in small, frequent meals. Maximal food intake occurred during the late dark hours, when meals were larger and less frequent, and there was little running. During three days of complete food deprivation, both wheel running and meal initiation attempts (as indicated by nonreinforced bar pressing) maintained their normal daily patterns. However, during wheel deprivation, changes occurred in the temporal distribution of meals which equalized early and late dark food intake. These results show that the availability of an alternative activity, like wheel running, can be an important determinant of daily feeding patterns. However, the daily pattern of wheel running is not influenced by food availability. Different behaviors may show differential plasticity in the coordination of an overall daily behavioral program.

In one session, a male rat may ejaculate 6 or 7 times, preceding each ejaculation with multiple intromissions. The potency of each successive ejaculation was investigated by examining the number of sperm later recovered from the genital tracts in one group of females and determining the number of embryos which were developing in another group of females. In nine older males (223-402 days), sperm and embryo number reached a peak at the third ejaculation; in fewer than 25% of mating sessions were these numbers maximal at the first ejaculation. In four younger males (103-172 days), two consistently showed maximal sperm output at the first ejaculation and two consistently peaked beyond it. However, despite these variations in sperm output, embryo counts in younger males were uniformly above 10 until the seventh ejaculation. Both age and ejaculation number had demonstrable effects on fertility.

When female Norway rats (Rattus norvegicus) become pregnant at the postpartum estrus they nurse this first litter concurrently with the gestation of a second litter. This second gestation is of variable length (23-31 days in this study) We investigated the behavior of mothers and their older litters around the time the second litter was born. Six female rats gave birth and were mated at the postpartum estrus. Continuous videotaped observation of each female and litter began approximately 3 days before, and continued for 3 days after the birth of the second litter. We found that suckling behavior and nest attendance by the older litter did not necessarily end when the second litter was born. When the gestation length of the second litter was short (23-25 days) older pups continued to spend time in the nest and to nurse along with their newborn siblings. These older pups also spent much time on the nest even in the absence of their mother. When gestation was long (27-31 days) older pups were weaned before the birth of the second litter and spent less time on the nest with the newborns. Stereotyped attacks by the female against her weanling age pups were seen both pre- and postpartum. This maternal aggression did not appear to deter suckling and nest attendance by the weanlings.

In the present study, we demonstrate that natural or artificial vaginal stimulation exerts a powerful effect on autonomic activity, as measured by pupillary diameter. Pupillary diameter was recorded approximately 3-5 sec after copulatory mounts, intromissions, ejaculations or experimenter delivered stimulation. The pupil was magnified 43X and its diameter was measured directly from a calibrated video screen. Mating tests were performed on 13 female rats which received at least one complete ejaculatory series. Compared to the premount (baseline) value (1.01 mm), mean pupillary diameters were significantly greater during (a) mounts without intromissions (1.20 mm; 20% increase), (b) mounts with intromissions (1.34 mm; 33% increase), or (c) ejaculation (1.49 mm; 48% increase). Mean pupillary diameter during the post-ejaculatory interval (0.95 mm; 6% decrease) did not differ significantly from the premount baseline. Since the mean pupillary diameter at the last intromission before ejaculation was significantly larger (by 18%) than the diameter at the first intromission, repeated intromissions may generate a gradually increasing net sympathetic response reaching a peak at ejaculation. In order to identify the adequate stimuli for increasing pupillary diameter, we applied external genital stimulation (flank-perineal palpation), internal genital stimulation (probing the vaginal cervix with a glass rod), or both combined. Vaginal stimulation alone produced near-maximal pupillary dilatation; external genital stimulation was less effective, and combined internal and external genital stimulation was more effective. Thus, vaginal afferent activity is an adequate stimulus to produce pupillary dilatation. Furthermore, bilateral pelvic neurectomy markedly attenuated the effect of vaginal stimulation on dilating the pupil. Since pupillary diameter is at least partly a function of autonomic tone, this "bioassay" indicates that genital stimulation may produce a net sympathetic activating effect.

Two temporal variables have been implicated in the timing of postpartum heat in Norway rats: time of day and time since parturition. The nature of the interaction between these variables is not clearly understood. We extend previous observations on this problem to freely behaving animals continuously videotaped during parturition and postpartum mating in a seminatural habitat. The timing of postpartum mating is best described by a model in which an interval timer is coupled to a circadian gating mechanism. Interactions between circadian and interval timing mechanisms may be widespread in the neuroendocrine control of behavior.

Artificial stimuli were used to study transient changes in responsiveness of female hamsters in natural estrus to tactile stimuli occurring during mating. Tactile stimulation just lateral to the vagina produces a transient facilitation of responses to stimulation of the contralateral side, while tactile stimulation of the midline produces a short-term inhibition of lateral movement in response to tactile stimulation. These short-term changes in responsiveness are probably an integral part of the basic sexual responses of the female hamster that contribute to insertion during copulatory attempts.

The paraventricular nucleus of the hypothalamus (PVN) is thought to be a part of the neural circuit comprising the melatonin rhythm generating system (MRGS). Electrical stimulation of the PVN during the early lights-on period significantly elevated urinary 6-hydroxymelatonin content to nearly 50% of night levels; stimulation during the lights-off period did not produce significant changes. In contrast to the effects of PVN stimulation, stimulation of surrounding brain areas was without effect at either time. This observation confirms the participation of the PVN in the MRGS.

Rats maintained on limited-access daily feeding schedules develop food-anticipatory activity rhythms which coexist with the photic circadian activity rhythm. These food anticipatory rhythms appear to depend upon a food-entrainable circadian oscillator which is separate and distinct from the light-entrainable circadian oscillator system. This study explored the long-term behavior of the putative food-entrainable oscillator in the presence and in the absence of a feeding schedule, and under light-dark cycles and constant light. The results suggest that a food-entrainable oscillator can show persisting self-sustained oscillations in the absence of a feeding schedule, and that the food- and light-entrainable circadian oscillators may show varying degrees of coupling, depending upon feeding conditions. Such a flexible coupling arrangement may allow the oscillator system to function as a "continuously consulted clock" in the adaptive temporal coordination of behavior with stable and unstable environmental periodicities.

This paper describes a "stretching response" which occurs in some female laboratory rats during the course of mating. It is most obviously characterized by an indentation of the abdominal wall and tonic limb and pelvic movements, which occur in irregularly spaced pulses of variable duration. The response was not seen in 10 rats in which intromissions had been prevented by a vaginal mask. In contrast, stretching was displayed by 9 of 10 non-masked subjects. This indicates that vagino-cervical stimulation is necessary for the induction of the stretching response. Vagino-cervical stimulation delivered by a plunger assembly was found to be sufficient to induce the response in 9 of 10 rats. Temporal summation of this stimulation was seen and ovarian hormones were found to increase the amount of stretching. Hypotheses concerning causes and effects of the stretching response are presented.

Circadian rhythms and levels of wheelrunning were studied in thyroidectomized, parathyroidectomized, thyro-parathyroidectomized, and sham-operated male rats. Animals were entrained to a 12:12 light:dark schedule, then exposed to constant dim red illumination, and then given a diet containing lithium. Under constant conditions, free-running circadian activity rhythms were shorter, and levels of activity were greater, in thyroidectomized and thyroparathyroidectomized animals. Lithium reversed these effects, lengthening free-running circadian periods in all groups, with a greater reduction of activity observed in animals with thyroids removed. Parathyroidectomy had no clear effects. Since lithium slowed circadian rhythms and reduced activity even in the absence of intact thyroid or parathyroid glands, these effects may have been due to the action of lithium at some other site. The same may be true of other thyroid suppressors reported to affect circadian rhythms. These findings may be relevant to the biological substrates of major affective disorders in humans, which have been associated with abnormalities of thyroid function, abnormally short circadian rhythms, abnormal activity levels, and responsiveness to lithium therapy.

In the rat, the transport of sperm from the vagina, where they are deposited at ejaculation, into the uterus is not automatic. Various behavioral and physiological factors influence this transport process: the number of pre-ejaculatory intromissions, the duration of immobility at ejaculation, and the fit of the copulatory plug. The interplay of these three factors in producing adequate sperm transport, and their relations with each other, were examined in 52 female rats that received various numbers of pre-ejaculatory intromissions (from 0 to more than 15). The number of intromissions was strongly related to all other measures. Ejaculatory immobility was associated with better fitting copulatory plugs when females received few intromissions. Sperm transport was most strongly predicted by plug fit. Intromissions were a major predictor of good fitting copulatory plugs and transcervical sperm transport; immobility did not mediate intromission's influence and did not have a major independent role.