Choosing event‐driven and daily HIV pre‐exposure prophylaxis – data from two European PrEP demonstration projects among men who have sex with men

IntroductionDaily and event‐driven PrEP are both efficacious in reducing the risk for HIV infection. However, the practice of event‐driven PrEP (edPrEP) is less well studied, in particular when provided as an alternative to daily PrEP. We studied regimen preferences and switches, and sexually transmitted infection (STI) incidence.MethodsWe analysed pooled data from two prospective cohort studies among MSM: Be‐PrEP‐ared, Belgium and AMPrEP, the Netherlands. In both projects, participants could choose between daily and edPrEP at three‐monthly study visits, when they were also screened for sexually transmitted infections including hepatitis C (HCV). We assessed the proportion choosing each regimen, and the determinants of choosing edPrEP at baseline. Additionally, we compared the incidence rates (IRs) of HCV, syphilis and chlamydia or gonorrhoea between regimens using Poisson regression. The study period was from 3 August 2015 until 24 September 2018.Results and discussionWe included 571 MSM, of whom 148 (25.9%) chose edPrEP at baseline. 31.7% of participants switched regimen at least once. After 28 months, 23.5% used edPrEP. Older participants (adjusted odds ratio (aOR) = 1.38 per 10 years, 95% confidence interval (CI) = 1.15 to 1.64) and those unemployed (aOR = 1.68, 95% CI = 1.03 to 1.75) were more likely to initially choose edPrEP. IR of HCV and syphilis did not differ between regimens, but the IR of chlamydia/gonorrhoea was higher among daily users (adjusted incidence rate ratio = 1.61, 95% CI = 1.35 to 1.94).ConclusionsA quarter of participants chose edPrEP at baseline and at 28 months this proportion was similar. Although the IR of HCV and syphilis were similar in the two regimens, the lower incidence of chlamydia and gonorrhoea among edPrEP users may suggest that less frequent STI testing of this group could be considered.     

Learning-related coordination of striatal and hippocampal theta rhythms during acquisition of a procedural maze task

The striatum and hippocampus are conventionally viewed as complementary learning and memory systems, with the hippocampus specialized for fact-based episodic memory and the striatum for procedural learning and memory. Here we directly tested whether these two systems exhibit independent or coordinated activity patterns during procedural learning. We trained rats on a conditional T-maze task requiring navigational and cue-based associative learning. We recorded local field potential (LFP) activity with tetrodes chronically implanted in the caudoputamen and the CA1 field of the dorsal hippocampus during 6-25 days of training. We show that simultaneously recorded striatal and hippocampal theta rhythms are modulated differently as the rats learned to perform the T-maze task but nevertheless become highly coherent during the choice period of the maze runs in rats that successfully learned the task. Moreover, in the rats that acquired the task, the phase of the striatal-hippocampal theta coherence was modified toward a consistent antiphase relationship, and these changes occurred in proportion to the levels of learning achieved. We suggest that rhythmic oscillations, including theta-band activity, could influence not only neural processing in cortico-basal ganglia circuits but also dynamic interactions between basal ganglia-based and hippocampus-based forebrain circuits during the acquisition and performance of learned behaviors. Experience-dependent changes in coordination of oscillatory activity across brain structures thus may parallel the well known plasticity of spike activity that occurs as a function of experience.     

Subchronic infusion of the product of inflammation prostaglandin J2 models sporadic Parkinson's disease in mice

Background  

Chronic neuroinflammation is implicated in Parkinson's disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a disorder that exhibits accumulation of ubiquitinated proteins in neuronal inclusions (Lewy bodies). The role of J2 prostaglandins in promoting PD neurodegeneration has not been investigated under in vivo conditions.     

Hospital variation in transfusion and infection after cardiac surgery: a cohort study

Background  

Transfusion practices in hospitalised patients are being re-evaluated, in part due to studies indicating adverse effects in patients receiving large quantities of stored blood. Concomitant with this re-examination have been reports showing variability in the use of specific blood components. This investigation was designed to assess hospital variation in blood use and outcomes in cardiac surgery patients.     

DFNB74, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 12q14.2-q15

Autosomal recessive nonsyndromic hearing impairment (ARNSHI) segregating in three unrelated, large consanguineous Pakistani families (PKDF528, PKDF859 and PKDF326) is linked to markers on chromosome 12q14.2-q15. This novel locus is designated DFNB74 . Maximum two-point limit of detection (LOD) scores of 5.6, 5.7 and 2.6 were estimated for markers D 12 S 313, D 12 S 83 and D 12 S 75 at θ = 0 for recessive deafness segregating in these three families. Haplotype analyses identified a critical linkage interval of 5.35 cM (5.36 Mb) defined by D 12 S 329 at 74.58 cM and D 12 S 313 at 79.93 cM. DFNB74 is the second ARNSHI locus mapped to chromosome 12, but the physical intervals do not overlap with one another. A locus contributing to the early onset, rapidly progressing hearing loss of A/J mice ( ahl4 , age-related hearing loss 4) was reported to map to chromosome 10 in a region of conserved synteny to DFNB74 , suggesting that ahl4 and DFNB74 may be due to mutations of the same gene in these two species.     

Functional magnetic resonance: biomarkers of response in breast cancer

Functional magnetic resonance (MR) encompasses a spectrum of techniques that depict physiological and molecular processes before morphological changes are visible on conventional imaging. As understanding of the pathophysiological and biomolecular processes involved in breast malignancies evolves, newer functional MR techniques can be employed that define early predictive and surrogate biomarkers for monitoring response to chemotherapy. Neoadjuvant chemotherapy is increasingly used in women with primary breast malignancies to down-stage the tumour and enable successful breast conservation surgery. It also plays a role in the treatment of undetected micrometastases. Cardinal physiological features of tumours that occur as a result of interactions between cancer cells, stromal cells and secreted factors and cytokines and how they change with treatment provide the opportunity to detect changes in the tumour microenvironment prior to any morphological change. Through sequential imaging, tumour response can be assessed and non-responders can be identified early to enable alternative therapies to be considered. This review summarises the functional magnetic resonance biomarkers of response in patients with breast cancer that are currently available and under development. We describe the current state of each biomarker and explore their potential clinical uses and limitations in assessing treatment response. With the aid of selected interesting cases, biomarkers related to dynamic contrast-enhanced MRI, diffusion-weighted MRI, T2*/BOLD and MR spectroscopy are described and illustrated. The potential of newer approaches, such as MR elastography, are also reviewed.     

Optimal habits can develop spontaneously through sensitivity to local cost

Habits and rituals are expressed universally across animal species. These behaviors are advantageous in allowing sequential behaviors to be performed without cognitive overload, and appear to rely on neural circuits that are relatively benign but vulnerable to takeover by extreme contexts, neuropsychiatric sequelae, and processes leading to addiction. Reinforcement learning (RL) is thought to underlie the formation of optimal habits. However, this theoretic formulation has principally been tested experimentally in simple stimulus-response tasks with relatively few available responses. We asked whether RL could also account for the emergence of habitual action sequences in realistically complex situations in which no repetitive stimulus-response links were present and in which many response options were present. We exposed naïve macaque monkeys to such experimental conditions by introducing a unique free saccade scan task. Despite the highly uncertain conditions and no instruction, the monkeys developed a succession of stereotypical, self-chosen saccade sequence patterns. Remarkably, these continued to morph for months, long after session-averaged reward and cost (eye movement distance) reached asymptote. Prima facie, these continued behavioral changes appeared to challenge RL. However, trial-by-trial analysis showed that pattern changes on adjacent trials were predicted by lowered cost, and RL simulations that reduced the cost reproduced the monkeys’ behavior. Ultimately, the patterns settled into stereotypical saccade sequences that minimized the cost of obtaining the reward on average. These findings suggest that brain mechanisms underlying the emergence of habits, and perhaps unwanted repetitive behaviors in clinical disorders, could follow RL algorithms capturing extremely local explore/exploit tradeoffs.     

Mechanisms of U46619-induced contraction of rat pulmonary arteries in the presence and absence of the endothelium

Background and purpose:

Thromboxane A₂ and endothelial dysfunction are implicated in the development of pulmonary hypertension. The receptor-transduction pathway for U46619 (9,11-dideoxy-9α, 11α-methanoepoxy prostaglandin F_2α)-induced contraction was examined in endothelium-intact (E+) and denuded (E−) rat pulmonary artery rings.

Experimental approach:

Artery rings were mounted on a wire myograph under a tension of 7–7.5 mN at 37°C and gassed with 95% O₂/5% CO₂. Isometric recording was made by using Powerlab data collection and Chart 5 software.

Key results:

Both E+ and E− contractile responses were sensitive to Rho-kinase inhibition and the chloride channel blocker NPPB [5-nitro-2-(3-phenylpropylamino)benzoic acid]. The E+ response was sensitive to the store-operated calcium channel blockers SKF-96365 {1-[B-[3-(4-methoxyphenyl)propoxy]-4-methoxy-phenethyl]-1H-imidazole hydrochloride} and 2-APB (2-amino ethoxy diphenylborate) (75–100 µmol·L⁻¹). The E− response was sensitive to 2-APB (10–30 µmol·L⁻¹), a putative IP₃ receptor antagonist, and the calcium and chloride channel blockers nifedipine, DIDS (4,4′-diisothiocyanostilbene-2,2′-disulphonic acid) and niflumic acid but was insensitive to SKF-96365. Inhibiting K_V with 4-AP in E+ rings exposed a contraction sensitive to nifedipine, DIDS and niflumic acid, whereas inhibiting BK_Ca exposed a contraction sensitive to mibefradil, DIDS and niflumic acid. This indicates that removal of the endothelium allows the TP receptor to inhibit K_V, which may involve coupling to phospholipase C, because inhibition of phospholipase C with {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075","term_text":"U73122"}}U73122 (1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-y]amino]hexyl]– 1H-pyrrole-2,5-dione) switched the E− pathway to the E+ pathway.

Conclusions and implications:

The results from this study indicate that distinct transduction pathways can be employed by the TP receptor to produce contraction and that the endothelium is able to influence the coupling of the TP receptor.British Journal of Pharmacology (2009) 157, 581–596; doi:10.1111/j.1476-5381.2008.00084.x; published online 22 April 2009This article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009