Comparing impacts of the COVID-19 pandemic on training of public health Specialty Registrars starting before or after its onset.

Objectives: To capture and compare the differences in experiences of public health Specialty Registrars who commenced training prior to the COVID-19 pandemic (pre-pandemic Registrars) and those who commenced training during the pandemic (post-pandemic Registrars). Study design: This is a mixed methods study comprising a cross-sectional survey and participatory action research. Methods: A questionnaire of 10 open and 5 closed questions exploring participants experience of training during the pandemic was sent to East Midlands Specialty Registrars. Thematic analysis and double coding were undertaken, coded based on pre- or post-pandemic Registrar status. Participatory action research was then undertaken in 2 rounds with 2 groups, based on pre/post-pandemic status to consolidate themes. Results: The survey was completed by 17 Registrars (8 pre-pandemic, and 9 post-pandemic) and 19 Registrars took part in participatory action research. The findings showed pre-pandemic Registrars noted the importance of negative impacts on their mental health whilst post-pandemic Registrars were more positive and felt well supported in their training. Conclusions: There is a stark difference in the impact of the pandemic for Registrars who started training before compared to during the pandemic. The training programme was not resilient to the impact of the pandemic. Robustness could be increased by encouraging early leadership experience and providing wellbeing support, particularly for post pandemic Registrars now and in future.

Forage fish and polycyclic aromatic compounds in the Fort McMurray oil sands area: Body burden comparisons with environmental distributions and consumption guidelines.

The Fort McMurray region in northeastern Alberta (Canada) is rich in natural sources of polycyclic aromatic compounds (PACs) from exposed bitumen beds; anthropogenic sources are being released with increased oil sands industry expansion. Here we report on investigations of PACs (47 compounds) in three species of forage fish collected during the 2012-2013 Joint Oil Sands Monitoring Program (JOSMP) fish health investigations and compare results with PAC data for sediment and water collected under JOSMP and earlier programs. PAC concentrations in sediments varied three orders in magnitude and were highest at downstream tributary mouths, which flowed through the exposed McMurray Formation, and along reaches of the Athabasca River where the formation was exposed. PAC concentrations in water were less variable but with higher concentrations near exposed bitumen beds. Forage fish exhibited the weakest spatial gradients in ΣPACs concentration, which averaged 102 ±â€¯32 ng/g in trout-perch from the Athabasca River, 125 ±â€¯22 ng/g in lake chub from the Ells River, and 278 ±â€¯267 ng/g in slimy sculpin from the Steepbank, Firebag, and Dunkirk Rivers. Low-molecular weight compounds, particularly naphthalenes and fluorenes, dominated fish PACs. Phenanthrenes occurred in greater percent composition in fish caught in areas where PAC concentrations in sediments were higher due to the proximity of bitumen sources than in other areas. Dibenzothiophene, a major component of bitumen PAC, was a minor component of fish ΣPACs. Forage fish PAC concentrations were below fish consumption guidelines established by the European Commission (2011) and for the reopening of the commercial fisheries closed by the Deepwater Horizon oil spill. PAC concentrations in forage fish were similar to concentrations observed in many other studies (fish market surveys, estuaries, and marine waters) and lower than in fish sampled from highly impacted areas (near refineries, harbors, and other industrialized areas).

Nefopam for the prevention of postoperative pain: quantitative systematic review.

Nefopam, a centrally acting analgesic, has been used in the surgical setting in many countries since the mid-1970s. However, clinical trials provide contflicting results for its analgesic potency. We performed a systematic search (multiple databases, bibliographies, any language, to January 2008) for randomized, placebo-controlled trials of nefopam for the prevention of postoperative pain. Data were combined using classic methods of meta-analyses and were expressed as weighted mean difference (WMD), relative risk (RR), and number needed to treat/harm (NNT/H) with 95% confidence interval (CI). Nine trials (847 adult patients, 359 received nefopam) were included. Nefopam (cumulative doses, 20-160 mg) was given orally or i.v., as single or multiple doses, or as a continuous infusion. Compared with placebo, cumulative 24 h morphine consumption was decreased with nefopam: WMD -13 mg (95% CI -17.9 to -8.15). Pain intensity at 24 h was also decreased: on a 100 mm visual analogue scale, WMD -11.5 mm (95% CI -15.1 to -7.85). The incidence of tachycardia was increased with nefopam (RR 3.12, 95% CI 1.11-8.79; NNH 7), as was the incidence of sweating (RR 4.92, 95% CI 2.0-12.1; NNH 13). There is limited evidence from the published literature that nefopam may be a useful non-opioid analgesic in surgical patients. The analgesic potency seems to be similar to non-steroidal anti-inflammatory drugs. However, dose responsiveness and adverse effect profile remain unclear, and the role of nefopam as part of multimodal analgesia needs to be established. Data in children are lacking.

Development of a novel automated screening method for detection of FVIII Inhibitors.

INTRODUCTION: Factor VIII activity is routinely determined by measuring the activated partial thromboplastin time (aPTT) of a patient plasma sample and determining percent activity from a standard curve. To maximize the detection of a clotting factor inhibitor, a subjective assessment of parallelism of a patient curve compared with a standard curve is performed. We developed and validated an automated objective method to assess parallelism as a rapid screening tool for detection of an inhibitor to factor VIII during routine FVIII assays. METHODS: We performed FVIII assays on a subset of FVIII-deficient patients with hemophilia A with and without inhibitors. Utilizing a ratio of the slopes from parallelism curves obtained by an independent Microsoft excel program in patients compared with a normal standard curve, we determined a cutoff ratio predictive for presence of an inhibitor. RESULTS: A cutoff ratio of patient to control slopes of <0.45 for the detection of an inhibitor to FVIII was 100% sensitive and 91.6% specific, with a positive predictive value of 92.3% and a negative predictive value of 100%. CONCLUSION: Utilizing a ratio of the slopes from parallelism curves in patients with and without an inhibitor, we developed and validated a rapid, automated, and objective method to assess parallelism as an added screening tool for detection of an inhibitor to factor VIII during routine FVIII assays on a STAGO-based coagulation platform. This simple automated method has the potential to detect inhibitors to other clotting factors.

The differential lysis of phosphoester bonds by nuclease P1.

The hydrolysis by nuclease P1 of the 16 common deoxydinucleoside monophosphates was examined. The rates of hydrolysis of phosphodiester bond differ by more than two orders of magnitude; dinucleotide monophosphates of the type d(TpN) being most resistant and d(GpN) being next most resistant. The profiles of a mixture of the 16 common dinucleoside monophosphates and of DNA after partial hydrolysis by nuclease P1 and simultaneous treatment with acid phosphatase were compared. The resultant profiles are very similar, except for the appearance of 5-methyldeoxycytidine in the latter. Similar profiles are also obtained from a mixture of dinucleoside monophosphates and from DNA exposed to ionizing radiation beforehand. The 8-hydroxyguanine lesion and a formamido remnant of thymine appear in both profiles as a modified nucleoside and as modified dinucleoside monophosphate respectively. These results suggest that certain radiation induced DNA lesions can be selectively postlabelled based on their resistance to hydrolysis by nuclease P1. The nature of the nuclease P1-substrate interaction is discussed.

Elevated mercury concentrations in fish in lakes in the Mackenzie River Basin: the role of physical, chemical, and biological factors.

During the mid-1990s and through the early 2000s, researchers determined that elevated mercury concentrations were a common occurrence in predatory fish in many lakes in the Mackenzie River Basin (MRB), located in northern Canada. Here we present the results of studies investigating factors contributing to higher mercury concentrations in fish in many of these lakes. Twenty-two percent of lake trout, 33% of northern pike, and 50% of walleye populations had mean mercury concentrations >0.5 microg/g, the guideline for the commercial sale of fish. Higher mercury concentrations were strongly associated with the relatively old age of MRB predatory fish; mean age ranged from 7.6 to 24.9 years for the three species. In contrast, none of the lake trout sampled in eight lakes further south in northern Saskatchewan and Alberta had mean mercury concentrations >0.5 microg/g; fish also were younger (mean age 6 years for the 8 lakes). Mercury concentrations in MRB fish generally increased with fish length, age, and trophic feeding although the nature of these relationships varied with the lake. Mean length was a good predictor of mean mercury concentrations in walleye populations across the study lakes but not for whitefish, lake trout, and pike; age was a good predictor for lake trout and walleye. Mercury concentrations in water and invertebrates were similar to those observed in more southerly regions where fish do not have elevated mercury concentrations. Mercury concentrations tended to be higher in fish in smaller vs. larger lakes and as a probable consequence of higher summer epilimnion temperatures, which favour a higher net methylation rate, and higher mercury and methyl mercury concentrations in water which enter these lakes from the watershed. Increasing fishing pressures on MRB lakes may be a means of reducing mean fish age, improving growth rates, and decreasing mercury body burdens. Increased global warming may result in higher mercury concentrations in fish through increased water temperatures, a longer ice free season, and increased release of stored mercury from the watershed into these lakes.

A history of total mercury in edible muscle of fish from lakes in northern Canada.

Subsistence fishing has been an important source of food for Native People in northern Canada since prehistoric time. Measurements of the levels of mercury in edible muscle of northern fish have been undertaken for over three decades in efforts to evaluate the risks of consuming northern fish. This report summarizes the data obtained from 7974 fish of 25 species from sites distributed from the Yukon to Labrador. The most abundant species were lake trout, lake whitefish, arctic char, walleye, northern pike and burbot. The question being asked was essentially "Are the fish safe to eat?" The results were used to support decisions on fishing and consumption of fish. They were sorted in several ways, into concentration ranges corresponding to human consumption guidelines, into political jurisdictions and into types of bedrock geology. Overall walleye, northern pike and lake trout, usually exceeded the subsistence consumption guideline of 0.2 microg g-1 total mercury and often exceeded the higher guideline of 0.5 microg g-1 total mercury for commercial sales of fish. Mercury in burbot, another facultative predator, was often lower but several still exceeding a guideline. Arctic char collections were mostly from anadromous populations and these had very low levels of mercury, presumably reflecting marine food sources. Lake whitefish were among the cleanest fish examined with 69 of 81 collections falling in the lowest range. Most collections were from sites in sedimentary rock. However a few sites were in metamorphic, intrusive or volcanic rocks and these, taken together, tended to have a higher proportion of sites in the higher ranges of mercury. These results indicate a widespread problem with mercury in subsistence fisheries for predator species of fish with the problem being most problematic for Nunavut.

N-type Ca2+ channels in cultured rat sphenopalatine ganglion neurons: an immunohistochemical and electrophysiological study.

Results from pharmacological studies have suggested that presynaptic N-type Ca2+ channels play an important role in regulating neuronal Ca2+ influx and transmitter nitric oxide (NO) release in isolated cerebral arteries. However, the presence of N-type Ca2+ channels in cerebral perivascular nerves has not been directly demonstrated. As a major source of cerebral perivascular NOergic innervation is the sphenopalatine ganglion (SPG), adult rat SPGs were cultured and examined by whole-cell patch-clamp technique. One week after growing in the culture medium, significant neurite outgrowth from the SPG neuronal cells was observed. Both soma and neurites of these cells were immunoreactive for N-type Ca2+ channels, transmitter-synthesizing enzymes (choline acetyltransferase and NO synthase), and several neuropeptides (vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, substance P, and pituitary adenylate cyclase-activating peptide-38) that had been found in cerebral perivascular nerves in whole-mount vascular preparations. In current-clamp recordings, injection of a small depolarizing current caused action potential firing. In voltage-clamp recordings, the fast inward currents were blocked by tetrodotoxin and outward currents by tetraethylammonium, which is typical for neurons. Most Ca2+ currents isolated by blockade of sodium and potassium currents were blocked by omega-conotoxin, indicating that N-type Ca2+ channels are the dominant voltage-dependent Ca2+ channels regulating Ca2+ influx during membrane depolarization of SPG neurons. The ability to culture postganglionic SPG neurons provides an opportunity to directly study the electrophysiological and pharmacological properties of these neurons.

Midazolam inhibits long-term potentiation through modulation of GABAA receptors.

Benzodiazepine drugs (BZ) are used for anxiety, insomnia, and seizures. They worsen memory, especially in large doses, but the mechanism of this action is uncertain. In micromolar concentrations, benzodiazepines have been shown to reduce long-term potentiation (LTP), which could be a cellular basis for their amnesic action. We have found that the LTP-inhibiting effects of BZ occur in the nanomolar concentrations attained in humans, and that this effect occurs through modulation of GABAA receptor function. We recorded extracellular synaptic input/output (I/O) curves for population spikes (PS) and EPSPs in rat hippocampal slices before and after induction of LTP. LTP increased maximal PS and EPSPs and shifted I/O curves for PS and EPSPs to the left, reflecting increased synaptic responsiveness after LTP. Curves relating EPSPs to PS were also shifted, so that after LTP larger PS were elicited for the same size EPSP (E-S potentiation). Midazolam (0.5 microM) markedly inhibited the left-shift in PS I/O curves due to E-S potentiation but did not significantly affect other parameters. 8-Phenyltheophylline (10 microM), an adenosine receptor antagonist, did not prevent midazolam inhibition of LTP. Bicuculline, a GABAA receptor antagonist, caused a dose-dependent antagonism of midazolam's LTP inhibition. Our results suggest that benzodiazepines reduce LTP primarily through reduction of E-S potentiation, and that this effect occurs through modulation of GABAA receptor function. This could in part account for the ability of benzodiazepines to disturb new memory formation.

Lithium enhances neuronal muscarinic excitation by presynaptic facilitation.

The mechanisms underlying the psychotropic actions of lithium are not established, but modulation of endogenous brain neurotransmitter systems is likely to be important. Several interactions of lithium with muscarinic responses have been reported, including a marked potentiation of seizures produced by muscarinic agonists. Because the mechanism by which lithium augments muscarinic seizures may be related to the mechanism by which it produces its psychotropic effects, we have studied the interaction of lithium and muscarinic agonists in vitro. Using rat hippocampal slices, we found that a muscarinic agonist, pilocarpine, increased postsynaptic neuronal excitability, but simultaneously decreased synaptic transmission because of presynaptic inhibition. Lithium did not alter pilocarpine's postsynaptic excitatory actions, but reversed its presynaptic inhibitory action, leading to markedly increased action potential firing. These presynaptic effects are not caused by alterations in presynaptic action potential shape or reliability of conduction, and do not involve pertussis toxin-sensitive G proteins. Activation of protein kinase C with phorbol-12,13-dibutyrate, or inhibition with H-7 and sphingosine, did not affect muscarinic presynaptic inhibition, but abolished lithium's ability to enhance synaptic transmission, suggesting that this effect of lithium involves protein kinase C. We propose that presynaptic facilitation accounts for lithium's potentiation of muscarinic seizures. Since these effects occur with concentrations of lithium used clinically, similar presynaptic effects in endogenous brain neurotransmitter systems may be important for lithium's psychotropic actions.

Photographic grading in the retinopathy of prematurity cryotherapy trial.

We report a system for photographic grading of the posterior fundus features of retinopathy of prematurity and correlation of such features with potential future visual function. The severity of temporal vessel traction, retinal fold, macular ectopia, retinal detachment, retrolental mass, blood vessel attenuation, retinal pigment epithelial scarring, and cataract was assessed by review of photographs at the Fundus Photograph Reading Center, Portland, Ore, according to a scheme designed to avoid bias or knowledge of treatment status. Reliability for all features was in the fair to excellent range (kappa greater than .40), except for blood vessel attenuation (kappa = .18), which was not a factor in the final outcome determination. The grading scheme provided the basis for the 3-month conclusions of the multicenter trial of cryotherapy for retinopathy of prematurity. This system will have further application in the 12-month Cryotherapy for Retinopathy of Prematurity Study conclusions and in future long-term correlation with visual acuity as the trial patients mature.

Analysis of DNA damage at the dinucleoside monophosphate level: application to the formamido lesion.

The dinucleoside monophosphates d(TpG), d(TpC), and d(TpT) were X-irradiated in oxygenated solution. In each case the modification of the dinucleoside in which the thymine base is degraded to a formamido remnant was observed as a principal product. The hydrolysis of the phosphoester bond of formamido-modified dinucleosides is much slower than that of the corresponding unmodified dinucleosides. This effect is also observable in the hydrolysis of irradiated DNA, where hydrolysis by nuclease P1 (plus acid phosphatase) generates the modified dinucleosides d(TFpN), TF being the modified thymidine. The total yield of the formamido lesion in all its forms, d(TFpN), exceeds the yield of any other base modification.

Radiation-induced formation of a crosslink between base moieties of deoxyguanosine and thymidine in deoxygenated solutions of d(CpGpTpA).

A new type of tandem base lesion has been observed in d(CpGpTpA) X-irradiated in aqueous solution. The lesion is attributed to the formation of a covalent bond between the C8 carbon atom of guanine and the methyl carbon atom of thymine. This tandem base lesion is formed in the absence of oxygen. It is the main product produced by ionizing radiation under these conditions.

Cholinergic-nitrergic transmitter mechanisms in the cerebral circulation.

Cerebral blood vessels from several species are innervated by vasodilator nerves. Acetylcholine (ACh) released from parasympathetic cholinergic nerves was first suggested to be the transmitter for vasodilation. Results from pharmacological studies in isolated cerebral arterial ring preparations, however, have demonstrated that nitric oxide (NO) but not ACh mediates the major component of neurogenic vasodilation. More recently, ACh and NO have been shown to co-release from the same cholinergic-nitrergic nerves, and that ACh acts as a presynaptic transmitter in modulating NO release. In this communication, evidence for the neuronal origin of NO and possible role of ACh in modulating NO release in large cerebral arteries at the base of the brain will be discussed.

Failure to obtain follow-up testing for gestational diabetic patients in a rural population.

OBJECTIVE: To determine physician and patient compliance rates for diabetes testing in patients with previous gestational diabetes. METHODS: Questionnaires regarding follow-up testing and personal health history were sent to 66 patients with previous gestational diabetes who did not have diabetes when they participated in a follow-up study conducted 5 years earlier. A 2-hour glucose tolerance test (GTT) was offered to those whose last test was done more than 1 year previously. RESULTS: All 66 individuals returned the questionnaire and 20 (30.3%) reported having received a yearly 2-hour GTT. Of the remaining 46, 19 had been tested at least once in the previous 5 years, but 27 had not been tested. Of the patients who had been tested at least once in the 5-year period, their physicians initiated testing 61.5% of the time and the patients initiated the remainder. There were no significant differences between physician specialty and rate or appropriateness of the testing. Of 39 individuals who had been tested at least once in the 5-year period, eight had diabetes and four were glucose intolerant. Of 12 individuals who had not been tested in the past year and agreed to be tested in 1995, four had diabetes and two had glucose intolerance. CONCLUSION: Although physicians and their gestational diabetic patients knew the risks of diabetes development, compliance with follow-up testing was poor and the risk of developing diabetes high.

Electrophysiology of embryonic, adult and aged rat hippocampal neurons in serum-free culture.

Methods were recently developed for culturing neurons from adult rat hippocampus using the serum-free medium Neurobasal with B27 supplement. To determine whether adult cultured neurons have normal electrical properties, we studied cultures from rats of three age groups: (1) embryonic; (2) 10-11 months old and (3) 35-36 months old. Neurons had a polarized morphology with a large branching apical dendrite and small basal dendrites. Mean resting potentials were similar in the three age groups. All neurons had nonlinear current-voltage relationships, indicating the presence of voltage-sensitive ion channels. Most neurons had a voltage-sensitive inward current followed by a sustained voltage-sensitive outward current. Tetrodotoxin blocked the inward current, which is likely to be a sodium current. The sustained outward current, which is likely to be a potassium current, reversed at -71 mV. Most neurons exhibited anomalous rectification. Calcium currents were present in both embryonic and adult neurons. Embryonic neurons would sometimes fire multiple action potentials but adult neurons fired only single action potentials. Our results indicate that both embryonic and adult cultured neurons retain a clearly neuronal electrophysiological phenotype in Neurobasal/B27 serum-free medium.

Decreased GABA and increased glutamate receptor-mediated activity on inferior colliculus neurons in vitro are associated with susceptibility to ethanol withdrawal seizures.

Cessation of ethanol administration in ethanol-dependent rats results in an ethanol withdrawal (ETX) syndrome, including audiogenic seizures (AGS). The inferior colliculus (IC) is the initiation site for AGS, and membrane properties of IC neurons exhibit hyperexcitability during ETX. Previous studies observed that ETX alters GABA and glutamate neurotransmission in certain brain sites. The present study evaluated synaptic properties and actions of GABA or glutamate antagonists during ETX in IC dorsal cortex (ICd) neurons in brain slices from rats treated with ethanol intragastrically 3 times daily for 4 days. A significant increase of spontaneous action potentials (APs) was observed during ETX. The width, area and rise time of excitatory postsynaptic potentials (EPSPs) evoked by stimulation in the commissure of IC were significantly elevated during ETX. A fast EPSP was sensitive to block by the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and a slow EPSP was sensitive to the NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP5). However, during ETX the concentration of CNQX or AP5 needed to block these EPSPs was elevated significantly. Inhibitory postsynaptic potentials (IPSPs) in ICd neurons evoked in both normal and ETX rats were blocked by the GABA(A) antagonist, bicuculline. However, IPSPs during ETX displayed a significantly greater sensitivity to bicuculline. These data indicate that decreased GABA(A)-mediated inhibition and increased glutamate-mediated excitability in IC may both be critical mechanisms of AGS initiation during ETX, which is similar to observations in a genetic form of AGS. The common changes in IC neurotransmission in these AGS forms may be general mechanisms subserving AGS and other forms of auditory system pathophysiology in which the IC is implicated.

Inferior colliculus neuronal membrane and synaptic properties in genetically epilepsy-prone rats.

Previous studies using single-unit recording techniques have shown that the inferior colliculus is critical for audiogenic seizure initiation in genetically epilepsy-prone rats (GEPR). In order to investigate cellular abnormalities that may be important in causing audiogenic seizure susceptibility, intracellular recordings were made from neurons of inferior colliculus dorsal cortex (ICd) in a GEPR variety that exhibits severe audiogenic seizures (GEPR-9). GEPR neuronal membrane and synaptic properties were compared to those of normal Sprague-Dawley rats (SD), the strain from which GEPR were derived. We found six electrophysiological differences between GEPR and normal SD ICd neurons, all of which could promote seizures in GEPR. (1) Input resistance was higher in GEPR than in normal ICd neurons. (2) Threshold for repetitive action potential firing was closer to resting membrane potential in GEPR ICd neurons. (3) GEPR neurons showed faster repetitive spike firing than normal SD neurons. (4) Anode break spikes occurred at the offset of a hyperpolarizing pulse more often in GEPR than in normal SD neurons. (5) Stimulation of the commissure of the inferior colliculus caused synaptic paired pulse inhibition in normal ICd neurons, but paired pulse facilitation was always observed in GEPR neurons. (6) In GEPR, a large epileptiform depolarizing event could be elicited by strong electrical stimulation of the commissure of the inferior colliculus. In normal SD rats, similar epileptiform activity was seen only after application of bicuculline or NMDA. Our results suggest that both abnormal neuronal membrane properties and altered synaptic transmission are likely to contribute to seizure predisposition and audiogenic seizure initiation in GEPR.