Comparison of gastrointestinal side effects from different doses of azithromycin for the treatment of gonorrhoea.

OBJECTIVES: Azithromycin is commonly used to treat Neisseria gonorrhoeae. We compared its gastrointestinal side effects using 1 g single, 2 g single or 2 g split (i.e. 1 g plus 1 g 6-12 h later) dosing, representing our clinic's changing guidelines over the study period. METHODS: We recruited consecutive sexual health clinic patients who received azithromycin (and 500 mg ceftriaxone) for uncomplicated gonorrhoea. Each patient received a text message 48 h after their attendance to complete a questionnaire. RESULTS: Patients received 1 g single (n = 271), 2 g single (218) or 2 g split (105) doses. Vomiting was less common for 1 g versus 2 g single dose [1.1% versus 3.7%; risk difference (RD): -2.6%; 95% CI: -0.2 to -5.4] and 2 g split versus 2 g single dose (0.9% versus 3.7%; RD: -2.8%; 95% CI: -0.3 to -5.8). Nausea was less common for 1 g versus 2 g single dose (13.7% versus 43.1%; RD: -29.5%; 95% CI: -21.7 to -37.2) and 2 g split versus 2 g single dose (16.4% versus 43.1%; RD: -26.8; 95% CI: -17.2 to -36.3). Diarrhoea was less common for 1 g versus 2 g single dose (25.5% versus 50.9%; RD: -25.5%; 95% CI: -17.0 to -33.9) and 2 g split versus 2 g single dose (30.9% versus 50.9%; RD: -20.0; 95% CI: -9.1 to -30.9). Almost all were willing to retake the same dosing for gonorrhoea in the future: 97% for 1 g single; 94% for 2 g single; and 97% for 2 g split dose. CONCLUSIONS: Azithromycin 2 g split dose for gonorrhoea resulted in significantly less vomiting, nausea and diarrhoea than a 2 g single dose.

Introduction of a modified analgesic ladder in the emergency depart-ment: Effect on oxycodone use for back pain.

OBJECTIVE: The aim of this study was to assess the introduction of an analgesic ladder and targeted education on oxycodone use for patients presenting to the emergency department (ED). DESIGN: A retrospective pre-post implementation study was conducted. Data were extracted for patients presenting from June to July 2016 (preintervention) and June to July 2017 (post-intervention). SETTING: The EDs of a major metropolitan health service and an affiliated community-based hospital. PARTICIPANTS: Patients with back pain where nonpharmacological interventions such as mobilization and physiotherapy are recommended as the mainstay of treatment. INTERVENTIONS: A modified analgesic ladder introduced in May 2017. The ladder promoted the use of simple analgesics such as paracetamol and nonsteroidal anti-inflammatory drug (NSAIDs) prior to opioids and tramadol in preference to oxycodone in selected patients. MAIN OUTCOME MEASURE(S): The proportion of patients prescribed oxycodone and total doses administered. RESULTS: There were 107 patients pre and 107 post-intervention included in this study. After implementation of the analgesic ladder, 78 (72.9 percent) preintervention patients and 55 (51.4 percent) post-intervention patients received oxycodone in ED (p = 0.001). The median oxycodone doses administered in the ED was 14 mg (interquartile range: 5-20 mg) and 5 mg (interquartile range: 5-10 mg; p < 0.001), respectively. On discharge from hospital, a prescription for oxycodone was issued for 36 (33.6 percent) patients preintervention and 26 (24.3 percent) patients post-intervention (p = 0.13). CONCLUSIONS: Among patients with back pain, implementation of a modified analgesic ladder was associated with a statistically significant but modest reduction in oxycodone prescription. Consideration of multifaceted interventions to produce major and sustained changes in opioid prescribing is required.

Microbiota of newborn meconium is associated with maternal anxiety experienced during pregnancy.

Little is known about whether a mother's psychological state during pregnancy influences her offspring's microbiome. This study examined whether maternal anxiety, depression, and stress during pregnancy is associated with the diversity of meconium microbiome, the first internal discharge, in 75 newborns from an existing birth cohort study. The meconium microbiome was profiled using multibarcode16S rRNA sequencing at V3-V4 hypervariable region followed by taxonomic assignment to the green gene 16S references at 97% similarity and diversity analysis at the genus level. Results showed that the meconium contained diversified microbiota, and greater pregnancy-related anxiety was significantly associated with a less diverse meconium microbiota community (p = 0.001). At the specific taxa level, greater pregnancy-related anxiety was correlated with a lower level of the Enterococcaceae family (p = 2e-4, Spearman rho = -0.43). These findings support a significant role of prenatal maternal mood in the early-life bacteria colonization of their offspring.

Attention Measures of Accuracy, Variability, and Fatigue Detect Early Response to Donepezil in Alzheimer's Disease: A Randomized, Double-blind, Placebo-Controlled Pilot Trial.

OBJECTIVE: Donepezil is widely used to treat Alzheimer's disease (AD), but detecting early response remains challenging for clinicians. Acetylcholine is known to directly modulate attention, particularly under high cognitive conditions, but no studies to date test whether measures of attention under high load can detect early effects of donepezil. We hypothesized that load-dependent attention tasks are sensitive to short-term treatment effects of donepezil, while global and other domain-specific cognitive measures are not. METHOD: This longitudinal, randomized, double-blind, placebo-controlled pilot trial (ClinicalTrials.gov Identifier: NCT03073876) evaluated 23 participants newly diagnosed with AD initiating de novo donepezil treatment (5 mg). After baseline assessment, participants were randomized into Drug (n = 12) or Placebo (n = 11) groups, and retested after approximately 6 weeks. Cognitive assessment included: (a) attention tasks (Foreperiod Effect, Attentional Blink, and Covert Orienting tasks) measuring processing speed, top-down accuracy, orienting, intra-individual variability, and fatigue; (b) global measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, Dementia Rating Scale); and (c) domain-specific measures (memory, language, visuospatial, and executive function). RESULTS: The Drug but not the Placebo group showed benefits of treatment at high-load measures by preserving top-down accuracy, improving intra-individual variability, and averting fatigue. In contrast, other global or cognitive domain-specific measures could not detect treatment effects over the same treatment interval. CONCLUSIONS: The pilot-study suggests that attention measures targeting accuracy, variability, and fatigue under high-load conditions could be sensitive to short-term cholinergic treatment. Given the central role of acetylcholine in attentional function, load-dependent attentional measures may be valuable cognitive markers of early treatment response.

Training on the Use of Technology to Collect Patient-Reported Outcome Data Electronically in Clinical Trials: Best Practice Recommendations from the ePRO Consortium.

Electronic capture of patient-reported outcome (PRO) data has many advantages over paper-based data collection. Regulatory agencies have consistently supported the use of electronic PRO (ePRO) data capture and recommended participant and site staff training on the correct use of electronic data capture systems. The objective of this paper is to outline best practice recommendations for training end users, including site staff and study participants, on the use of ePRO technology in clinical trials to enable consistent, accurate, and complete data collection. Site personnel should be trained on study-specific as well as technology-specific topics and be given instructions on whom to contact to obtain technical support. Optimal training takes place over time using multiple modalities, including hands-on, face-to-face training at an investigator meeting or directly in the clinical site; remote training via webinar or teleconference; interactive on-demand self-paced-training via e-learning modalities; and supplemented by proxy training performed by study clinical research associates. Like site personnel training, study participants should be provided with individual, hands-on training by site staff at the initiation of the trial and in conjunction with interactive electronic training modules that can be accessed on-demand throughout the duration of the trial. The recommendations put forth in this paper provide a structured framework for the training that site personnel and study participants need to optimize the advantages trials can gain from using ePRO data collection systems.

More than skin deep. Ten year follow-up of delayed cutaneous adverse drug reactions (CADR).

AIMS: To determine the gaps in practice regarding appropriate ADR documentation and risk communication for patients diagnosed with severe cutaneous adverse drug reactions (CADR). METHODS: This was a retrospective observational cohort study conducted using hospital coding and databases to identify inpatients diagnosed with CADR from January 2004 to August 2014. Hospital discharge summaries, ADR reports and pharmacy dispensing records were reviewed for ADR documentation. Patients still living in Australia and who did not opt out of being contacted were invited to be surveyed by telephone to determine their understanding of recommendations, re-exposure rates and long-term effects. RESULTS: Of 85 patients identified, median age was 59 (IQR 44-72) years and 47.1% were male. The most common diagnosis was TENS (49.4%). Ten patients (11.8%) died as inpatients. Of the 81 patients with a drug-related causality, 47 (58%) had appropriate documentation in all three required medical record platforms. Of the 56 eligible patients, 38 (67.9%) were surveyed; 13% had no information provided upon discharge and 26.3% patients had a mismatch in knowledge of implicated medications. No surveyed patient had a relapse of CADR, but 23.7% had a subsequent unrelated allergic reaction. Thirteen patients (34.2%) reported long-term effects. CONCLUSIONS: We found gaps in the accuracy of ADR documentation and communication of risk at discharge, which indicated risks to patient safety. Electronic systems are being developed to improve documentation. Written information about CADR is being provided at discharge to improve patient understanding and knowledge.

Influence of prenatal maternal stress on umbilical cord blood cytokine levels.

PURPOSE: Prenatal maternal stress (PNMS) is known to influence fetal programming and development. Thus far, the effects of PNMS on the developing immune system have mainly been documented in animal studies. This study aimed to examine the association between PNMS and immune cytokine profiles in the umbilical cord blood of newborn human infants. METHODS: PNMS, including perceived stress, numbers of stressful life events experiences (both partner and health related), and state and trait anxiety, was assessed with five questionnaires and interviews from 43 pregnant women during the second trimester. Seven key cytokines important for immune function, i.e., IL-12, IL-1ß, IL-4, IL-5, IL-6, IL-8, and TNF-α, were analyzed in cord blood by bead-based ELISA method (Luminex 200). Logistic regression was used to estimate the associations of PNMS scores and cytokine levels. RESULTS: Increased levels of IL-1ß, IL-4, IL-5, IL-6, and IL-8 were significantly associated with at least one of the maternal stress assessments, while the levels of IL-12 and TNF-α were not significantly associated with any of the PNMS measurements examined. CONCLUSION: These preliminary findings suggest that PNMS may influence cytokine levels in newborn infants, in particular Th2-related cytokines. This report supports previous findings in animal studies and could suggest that newborns born to mothers with elevated PNMS have a predisposition to immune-related disorders.

The effects of age and physical health on processing speed in HIV.

The impact of age and physical health on processing speed was investigated in 42 non-demented HIV+ individuals ranging in age from 30 to 75. We used the Medical Outcomes Study-HIV Healthy Survey (MOS-HIV) to measure self-reported physical health, neuropsychological tests to measure psychomotor and cognitive processing speed (Delis-Kaplan Executive Function System Trail Making Test, Grooved Pegboard Test, letter and category fluency), and a test of the foreperiod effect to measure reaction time under increasing attentional load. Results indicated that aging and worse physical health each independently contributed to slowing on different processing speed measures, while the interaction between aging and physical health did not contribute to processing speed. These findings highlight the importance of considering physical health separately from age when measuring cognitive function in HIV+ adults.

Global methylation in the placenta and umbilical cord blood from pregnancies with maternal gestational diabetes, preeclampsia, and obesity.

Emerging evidence indicates that maternal medical risk during pregnancy, such as gestational diabetes mellitus (GDM), preeclampsia, and obesity, predisposes the offspring to suboptimal development. However, the underlying biological/epigenetic mechanism in utero is still unknown. The current pilot study (N = 50) compared the levels of global methylation in the placenta and umbilical cord blood among women with and without each risk condition (GDM, preeclampsia, and obesity) and explored whether the levels of global methylation were associated with fetal/infant growth. Results show that global methylation levels in the placenta were lower in patients with gestational diabetes (P = .003) and preeclampsia (P = .05) but higher with obesity (P = .01). Suggestive negative associations were found between global methylation level in the placenta and infant body length and head circumference. While preliminary, it is possible that the placenta tissue, but not umbilical cord blood, may be epigenetically programmed by maternal GDM, preeclampsia, and obesity to carry out its own specific functions that influence fetal growth.

Influences of Maternal Stress during Pregnancy on the Epi/genome: Comparison of Placenta and Umbilical Cord Blood.

BACKGROUND: Maternal stress during pregnancy is one of the major adverse environmental factors in utero that is capable of influencing health outcomes of the offspring throughout life. Both genetic and epigenetic processes are susceptible to environmental insults in utero and are potential biomarkers of the experienced environment including maternal stress. METHODS: We profiled expression level of six genes in hypothalamic pituitary adrenal (HPA) axis functioning (HSD11B2, SLC6A4, NR3C1, NR3C2, CRHR1 and CRHR2), two imprinted genes (IGF2 and H19) and one neurodevelopmental gene (EGR1), from 49 pairs of placenta and umbilical cord blood (UCB) samples from a birth cohort. We also assessed global methylation levels by LUminometric Methylation Assay (LUMA) and methylation at the imprinting control region (ICR) of IGF2/H19. RESULTS: Little correlations between paired placenta and UCB were observed except H19 expression (r = 0.31, P = 0.04) and IGF2/H19 ICR methylation (r = 0.43, P = 0.01); gene expression levels were significantly higher (P < 0.001) in placenta than UCB except CRHR1 and CRHR2, which were unexpressed in placenta. Maternal stress correlated higher levels of HPA genes and lower levels of EGR1 and LUMA, but only in placenta. Positive association between maternal stress and IGF2/H19 ICR methylation was present in both placenta and UCB. CONCLUSIONS: Our findings support the notion that adverse in utero environment, as measured by antenatal maternal stress, depression and anxiety, can be observed in the epi/genome of the relevant tissues, i.e. placenta and UCBs, leading to development of molecular markers for assessing in utero adversities.

The Effects of Preeclampsia on Perinatal Risks and Infant Temperaments Among Mothers With Antenatal Depression.

IMPORTANCE: Preeclampsia and depression are two most prevalent disorders known to affect pregnant women and unborn infant. However, few studies have prospectively examined the adverse influence of the in-utero exposures to the two disorders on the optimal development in their offspring, including mortality, adverse birth outcomes, and infant temperament styles. OBJECTIVES: (1) To examine whether exposures to preeclampsia and antenatal depression were associated with developmental indices of offspring at birth and temperament at 3 months; and (2) To evaluate how preeclampsia and antenatal depression associated with offspring temperamental style. DESIGN: Prospective cohort study with regular assessment of mother's blood pressure at each prenatal visit: offspring were followed till 3 months. SETTING: Two prenatal clinics, New York City, USA. PARTICIPANTS: A cohort of 233 pregnant women was followed throughout pregnancy. Of those, 141 provided ratings of infant temperament at three months. EXPOSURES: Diagnostic outcome of maternal depression by clinical interviewers blind to preeclampsia status, were ascertained using the Structured Clinical Interview for DSM-IV Axis I Disorders. The development of preeclampsia, defined by the onset of hypertension (> 140/90 mm HG) after 20 weeks' gestation, accompanied by 300 mg of protein, monitored via electronic medical records. MAIN OUTCOME MEASURES: Birth outcomes were assessed via standardized ratings at delivery. Infant temperament was reported by the mother at three months, using 91-item IBQ-R (Infant Behavioral Questionnaire-Revised). RESULTS: Preeclampsia was associated with an over 5-fold increased risk for fetal/infant mortality, a 3- to 7-fold increased risk for poorer birth outcomes, and flatter affect and distress in infants. Furthermore, infants born to preeclamptic mothers with co-occurring depression displayed lower levels of smile/laughter, high-intensity pleasure seeking behavior, perceptual sensitivity, and approach behavior. CONCLUSION: Preeclampsia was associated with a few difficult temperament styles in the first three months after birth. Moreover, its negative impact was amplified by mother's antenatal depression. Our findings regarding additive risk for negative infant outcomes in babies exposed to preeclampsia and antenatal depression suggests that the development of early detection programs to identify and monitor women who are at heightened risk for these conditions can potentially have a positive influence on long-term infant neurobehavioral development.

Assessing the Impact of Parental Depressive Symptoms on Offspring Temperament and Development in Infancy.

The study prospectively followed 135 women during their pregnancy and their offspring till 6 months of age, to examine the roles of maternal and paternal depression during pregnancy on offspring neurobehavioral development as measured by their early temperament. Maternal and paternal depression statuses were ascertained during the third trimester, and infant temperament was evaluated at 6 months, via mothers self-report. Multivariable general linear model was used to assess 1) the main effects of maternal and paternal depression on infant temperament and 2) the interaction effect between maternal and paternal depression on infant temperament. Results show that maternal depression, but not paternal depression, was directly associated with greater neurobehavioral impairment in offspring as evident by more difficult temperament, including lower Smiling and Laughter (p= .006), lower Soothability (p= .02), elevated Sadness (p= .04) and lower Vocal Reactivity (p= .001). Moreover, only in the presence of maternal depression, was paternal depression significantly associated with signs of offspring neurobehavioral impairment, including lower Smiling and Laughter (p= .01) lower High Pleasure Seeking (p= .03), lower Soothability (p= .05), lower Cuddliness (p= .05) and lower Vocal Reactivity (p< .0001). These findings suggest that maternal, but not paternal, depression was directly associated with infant neurobehavioral impairment. Significant interaction effect suggests that in the presence of maternal depression, paternal depression amplifies its negative valence on infant neurobehavioral development. Providing intervention services not only for depressed mothers but also their partners during pregnancy may prove to be an effective prevention strategy for suboptimal neurobehavioral development in offspring.

Gray matter volumes and cognitive ability in the epileptogenic brain malformation of periventricular nodular heterotopia.

Periventricular nodular heterotopia (PNH) is a brain malformation clinically characterized by the triad of epilepsy, normal intelligence, and dyslexia. We investigated the structure-function relationship between cerebral volumes and cognitive ability in this disorder by studying 12 subjects with PNH and 6 controls using volumetric analysis of high-resolution anatomical MRI and neuropsychological testing. Total cerebral volumes and specific brain compartment volumes (gray matter, white matter, and cerebrospinal fluid) in subjects with PNH were comparable to those in controls. There was a negative correlation between heterotopic gray matter volume and cortical gray matter volume. Cerebral and cortical volumes in PNH did not correlate with Full Scale IQ, unlike in normal individuals. Our findings support the idea that heterotopic nodules contain misplaced neurons that would normally have migrated to the cortex, and suggest that structural correlates of normal cognitive ability may be different in the setting of neuronal migration failure.

A dissociation between anterograde and retrograde amnesia after treatment with electroconvulsive therapy: a naturalistic investigation.

OBJECTIVE: The aim of the present study is to investigate the cumulative effects of a clinically determined course of electroconvulsive therapy (ECT) on anterograde and retrograde amnesia. In this study, mood and memory were examined in the context of a protocol driven by therapeutic response, rather than by preordained research criteria. METHODS: Twenty-two patients with major depressive disorder and 18 nondepressed controls were taught a series of faces and names before the initiation of ECT, and their retention of this information was examined after the end of treatment. Anterograde (ie, new learning) and retrograde memory (ie, recall of information learned before ECT) were assessed. Eleven ECT patients underwent unilateral (UL) stimulation, and 11 had a combination of UL and bilateral stimulation. Major depressive disorder patients and nondepressed controls participants were matched according to baseline memory abilities. Unilateral and unilateral/bilateral (UB) ECT patients were matched according to baseline depression and memory abilities. RESULTS: Treatment with ECT resulted in a dissociation between anterograde and retrograde memory; after treatment, major depressive disorder patients demonstrated significant retrograde amnesia, whereas there was no change in their anterograde memory. Unilateral and UB ECT patients performed equally well on tasks of anterograde memory. Contrary to our expectation, UB ECT was not associated with greater retrograde memory loss than was UL ECT treatment. However, a trend toward a group difference was present on 1 memory measure. CONCLUSIONS: Results of the study suggest that a clinical course of ECT is associated with isolated impairment for information learned before treatment (ie, retrograde memory), whereas there was no effect of ECT on posttreatment learning abilities (ie, anterograde memory).

Evaluation of dynamic mass redistribution technology for pharmacological studies of recombinant and endogenously expressed g protein-coupled receptors.

The Epic cell assay technology (Corning Inc., Corning, NY) uses a resonant waveguide grating optical biosensor to measure cellular response to ligands manifested through dynamic mass redistribution (DMR) of cellular contents. The DMR measurement is a noninvasive, label-free assay that can be used to assess the pharmacological properties of compounds. In this study, a panel of 12 compounds was evaluated against two G protein-coupled receptor (GPCR) targets in recombinant expressed cell lines using the Corning Epic system in 384-well microplates. The evaluation was performed in a double-blinded fashion such that the identity and properties of both the GPCR targets and compounds were unknown to the researchers at the time of the study. Analysis of the DMR response from cell stimulation was used to identify compounds that functioned as agonists or antagonists and to evaluate the associated efficacy and potency. DMR results were shown to have good agreement with data obtained from cyclic AMP and calcium flux assays for compounds evaluated. A further analysis was performed and successfully identified the signaling pathways that the two GPCRs activated. In addition, the DMR measurement was able to detect responses from an endogenous receptor in these cells. The Epic DMR technology provides a generic platform amenable to pharmacological evaluation of cellular responses to GPCR activation in a label-free live cell assay format.

"I know what I like": stability of aesthetic preference in Alzheimer's patients.

Two studies explored the stability of art preference in patients with Alzheimer's disease and age-matched control participants. Preferences for three different styles of paintings, displayed on art postcards, were examined over two sessions. Preference for specific paintings differed among individuals but AD and non-AD groups maintained about the same stability in terms of preference judgments across two weeks, even though the AD patients did not have explicit memory for the paintings. We conclude that aesthetic responses can be preserved in the face of cognitive decline. This should encourage caregivers and family to engage in arts appreciation activities with patients, and reinforces the validity of a preference response as a dependent measure in testing paradigms.