Aripiprazole, brexpiprazole, and cariprazine can affect milk supply: Advice to breastfeeding mothers.

OBJECTIVE: We sought to review the effects of Dopamine Receptor Partial Agonist (DRPA) antipsychotic medications on milk supply and breastfeeding. METHOD: Narrative review of selected literature including animal and human data. RESULTS: Scant case study evidence suggests that DRPAs may lead to reduced milk supply for some. CONCLUSIONS: Women taking DRPAs should be advised of the possibility that these may affect milk supply, and reporting should be encouraged to aid future research.

A fluorescently labelled quaternary ammonium compound (NBD-DDA) to study resistance mechanisms in bacteria.

Quaternary ammonium compounds (QACs) are widely used as active agents in disinfectants, antiseptics, and preservatives. Despite being in use since the 1940s, there remain multiple open questions regarding their detailed mode-of-action and the mechanisms, including phenotypic heterogeneity, that can make bacteria less susceptible to QACs. To facilitate studies on resistance mechanisms towards QACs, we synthesized a fluorescent quaternary ammonium compound, namely N-dodecyl-N,N-dimethyl-[2-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]ethyl]azanium-iodide (NBD-DDA). NBD-DDA is readily detected by flow cytometry and fluorescence microscopy with standard GFP/FITC-settings, making it suitable for molecular and single-cell studies. As a proof-of-concept, NBD-DDA was then used to investigate resistance mechanisms which can be heterogeneous among individual bacterial cells. Our results reveal that the antimicrobial activity of NBD-DDA against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa is comparable to that of benzalkonium chloride (BAC), a widely used QAC, and benzyl-dimethyl-dodecylammonium chloride (BAC12), a mono-constituent BAC with alkyl-chain length of 12 and high structural similarity to NBD-DDA. Characteristic time-kill kinetics and increased tolerance of a BAC tolerant E. coli strain against NBD-DDA suggest that the mode of action of NBD-DDA is similar to that of BAC. As revealed by confocal laser scanning microscopy (CLSM), NBD-DDA is preferentially localized to the cell envelope of E. coli, which is a primary target of BAC and other QACs. Leveraging these findings and NBD-DDA's fluorescent properties, we show that reduced cellular accumulation is responsible for the evolved BAC tolerance in the BAC tolerant E. coli strain and that NBD-DDA is subject to efflux mediated by TolC. Overall, NBD-DDA's antimicrobial activity, its fluorescent properties, and its ease of detection render it a powerful tool to study resistance mechanisms of QACs in bacteria and highlight its potential to gain detailed insights into its mode-of-action.

Evolutionary Relationships and Range Evolution of Greenhood Orchids (Subtribe Pterostylidinae): Insights From Plastid Phylogenomics.

Australia harbours a rich and highly endemic orchid flora with over 90% of native species found nowhere else. However, little is known about the assembly and evolution of Australia's orchid flora. Here, we used a phylogenomic approach to infer evolutionary relationships, divergence times and range evolution in Pterostylidinae (Orchidoideae), the second largest subtribe in the Australian orchid flora, comprising the genera Pterostylis and Achlydosa. Phylogenetic analysis of 75 plastid genes provided well-resolved and supported phylogenies. Intrageneric relationships in Pterostylis were clarified and monophyly of eight of 10 sections supported. Achlydosa was found to not form part of Pterostylidinae and instead merits recognition at subtribal level, as Achlydosinae. Pterostylidinae were inferred to have originated in eastern Australia in the early Oligocene, coinciding with the complete separation of Australia from Antarctica and the onset of the Antarctic Circumpolar Current, which led to profound changes in the world's climate. Divergence of all major lineages occurred during the Miocene, accompanied by increased aridification and seasonality of the Australian continent, resulting in strong vegetational changes from rainforest to more open sclerophyllous vegetation. The majority of extant species were inferred to have originated in the Quaternary, from the Pleistocene onwards. The rapid climatic oscillations during the Pleistocene may have acted as important driver of speciation in Pterostylidinae. The subtribe underwent lineage diversification mainly within its ancestral range, in eastern Australia. Long-distance dispersals to southwest Australia commenced from the late Miocene onwards, after the establishment of the Nullarbor Plain, which constitutes a strong edaphic barrier to mesic plants. Range expansions from the mesic into the arid zone of eastern Australia (Eremaean region) commenced from the early Pleistocene onwards. Extant distributions of Pterostylidinae in other Australasian regions, such as New Zealand and New Caledonia, are of more recent origin, resulting from long-distance dispersals from the Pliocene onwards. Temperate eastern Australia was identified as key source area for dispersals to other Australasian regions.

Barriers and Challenges in Performing Pharmacokinetic Studies to Inform Dosing in the Neonatal Population.

A number of barriers and challenges must be overcome in order to conduct the pharmacokinetic studies that are urgently needed to inform the selection and dosing of medication in neonates. However, overcoming these barriers can be difficult. This review outlines the common barriers researchers are confronted with, including issues with ethics approval and consent, study design for pharmacokinetic studies and the ability to measure the drug concentrations in the blood samples obtained. Strategies to overcome these challenges are also proposed.

Links between depressive symptoms and unmet health and social care needs among older prisoners.

BACKGROUND: absolute numbers of older prisoners and their proportion of the total prison population are increasing. They have multiple health and social care needs that are prominent on entry into prison. No previous studies have identified older prisoners' health and social care needs at this crucial point. OBJECTIVE: to examine unmet health and social care needs among older men entering prison and their links with depressive symptoms. METHODS: a cross-sectional survey across nine prisons in the North of England was completed. One hundred male prisoners aged between 60 and 81 were interviewed, using the Camberwell Assessment of Need-Forensic short version (CANFOR-S) and Geriatric Depression Scale-Short Form (GDS-15). Descriptive statistics were generated and χ(2) tests performed. RESULTS: participants reported high levels of unmet needs as measured with the CANFOR-S, notably in the domains of knowledge about their condition and treatment (38%); psychological distress (34%); daytime activities (29%); benefits (28%); food (22%) and physical health (21%). The mean total number of unmet needs was 2.74, with a median of 2.0. More than half the sample (56%, 95% CI 45-66%) exhibited clinical signs of depression. A significant association between depressive symptomology and an unmet physical health need, as measured by the CANFOR-S, was detected (χ(2) = 6.76, df = 1, P < 0.01). CONCLUSIONS: high levels of depressive symptoms were experienced by older prisoners on entry into prison. Personalised health and social care needs assessment and discrete depression screening are required on prison entry to facilitate effective management of unmet needs.

Using Continuing Professional Development with Portfolio in a Pharmaceutics Course.

The introduction of Continuing Professional Development (CPD) to encourage individual life-long learning as a way of maintaining professional competency in pharmacy has faced resistance. To investigate ways to address this barrier we included CPD with portfolio in a university Pharmaceutics course. Underpinning knowledge for the course was delivered using a flipped classroom approach and students used the CPD model to address clinical scenarios presented in a simulated pharmacy setting. Students produced portfolio items for the different case scenarios and submitted these for assessment. This provided the opportunity for students to carry out repeated application of the CPD cycle and, in so doing, develop skills in critical thinking for self-reflection and self-evaluation. This course was designed to encourage the development of higher level learning skills for future self-directed learning. Thirty six students submitted a completed portfolio. Twenty nine students achieved a result of >70%, five students scored between 57%-69%, one student obtained a mark of 50% and one student failed. The end of course survey revealed that while students found portfolio development challenging (40%), they also reported that it was effective for self-learning (54%). Differentiating between the concepts "reflection" and "evaluation" in CPD was problematic for some students and the use of clearer, simpler language should be used to explain these processes in future CPD work.

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future.

Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.

Female reproductive tract pain: targets, challenges, and outcomes.

Pain from the female reproductive tract (FRT) is a significant clinical problem for which there are few effective therapies. The complex neuroanatomy of pelvic organs not only makes diagnosis of pelvic pain disorders difficult but represents a challenge to development of targeted therapies. A number of potential therapeutic targets have been identified on sensory neurons supplying the FRT but our knowledge on the basic neurophysiology of these neurons is limited compared with other viscera. Until this is addressed we can only guess if the new experimental therapies proposed for somatic, gastrointestinal, or bladder pain will translate to the FRT. Once suitable therapeutic targets become clear, the next challenge is drug delivery. The FRT represents a promising system for topical drug delivery that could be tailored to act locally or systemically depending on formulation. Development of these therapies and their delivery systems will need to be done in concert with more robust in vivo and in vitro models of FRT pain.

A prospective study of the efficacy of routine decontamination for gastrointestinal endoscopes and the risk factors for failure.

BACKGROUND: Patient-ready endoscopes were monitored over an 80-week period to determine the efficacy of decontamination procedures in a busy endoscopy center. Decontamination failure was related to patient and procedural parameters. METHODS: Samples from patient-ready endoscopes were cultured aerobically and anaerobically and subjected to polymerase chain reaction (PCR) to detect hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV. PCR to detect coliforms from 109 culture negative washes was used as a surrogate marker for biofilm in endoscopes. PCR was used to detect the presence of Helicobactor pylori in endoscopes used on infected patients. Procedural information such as biopsy retrieval, endoscope number, diagnosis, attending personnel, and decontamination system procedures was collected. RESULTS: Gastroscopes (n = 1,376) and colonoscopes (n = 987) were equally contaminated (1.8% vs 1.9%, respectively) with low numbers of organisms commonly isolated from the nasopharynx and/or feces. Only 1 wash contained viral nucleic acid (HCV). There was a significant correlation (P < .001) between the number of times a patient-ready endoscope was contaminated and its frequency of use. Colonoscopes used on patients with gastrointestinal disease were significantly more likely to remain contaminated through the decontamination process (P < .05). All other patient, staff, and decontamination system parameters remained not statistically significant. Coliform DNA was detected in 40% of culture-negative washes collected from patient-ready endoscopes, suggesting the presence of biofilm. No H pylori DNA was detected. CONCLUSION: Recommended decontamination procedures do not entirely eliminate persistence of low numbers of organisms on a few endoscopes, but this is unlikely to cause serious consequences in patients. Bacterial biofilm is difficult to remove and may explain this low-level persistence.

Sequential histomorphometric analysis of the growth plate following irradiation with and without radioprotection.

BACKGROUND: The availability of radioprotectant drugs that selectively protect normal cells but not tumor cells has rekindled interest in the effects of irradiation on the growth plate. The purpose of the present study was to quantitatively examine the sequential histomorphometric effects of irradiation and pretreatment with a free radical scavenger radioprotectant, amifostine, on the growth plate over time. METHODS: Sixty four-week-old male Sprague-Dawley rats were randomized into five groups of twelve animals that were to be killed at 0.5, one, two, three, or four weeks after irradiation. One-half of the animals also received amifostine (100 mg/kg) prior to irradiation. In all animals, the right knee was treated with a single 17.5-Gy dose of radiation. End points were assessed with quantitative histomorphometric analysis of the growth plate, BrdU labeling for evidence of proliferation, evaluation of chondroclast cellularity, and determination of growth rates by means of oxytetracycline labeling. RESULTS: The mean lengths of the femur, tibia, and hind limb continued to increase at each time-interval following treatment, but by one week the mean limb length was 4% less on the irradiated side than on the control side, and this difference remained significant for four weeks (p < 0.05). The proximal tibial growth rate decreased during the first week to 18% of the control level. Nevertheless, growth continued even at the earliest time-periods, began to return toward normal at two weeks, and ultimately returned to at least 80% of normal by four weeks after irradiation. The area fraction of matrix in the hypertrophic zone increased initially and returned to control levels at three and four weeks. The administration of the radioprotectant resulted in significant increases in growth, growth rate, growth plate height, hypertrophic zonal height, and chondroclast profiles compared with the values for limbs in which irradiation had not been preceded by treatment with amifostine. CONCLUSIONS: We found an initially profound but transient direct inhibitory effect of irradiation on growth plate chondrocytes. Recovery of growth plate function after irradiation corresponded temporally with the appearance of newly formed islands of proliferating chondrocytes. Accumulation of matrix led to a transient increase in overall growth plate height, which was most pronounced in the hypertrophic zone. This was due, in part, to the sensitivity of chondroclasts to irradiation. The radioprotectant amifostine reduced these effects on growth rate, growth plate height, matrix accumulation, and limb length.