Organochlorine accumulation by sentinel mallards at the Winston-Thomas sewage treatment plant, Bloomington, Indiana

Farm-raised 12-month-old female mallards (Anas platyrhynchos) were released at the Winston-Thomas sewage treatment plant, Bloomington, Indiana. Five mallards were sacrificed at the start of the study and at approximately 10-day intervals through day 100. Concentrations of polychlorinated biphenyls (PCBs) in carcasses increased linearly with time of exposure and exceeded 16 g/g wet weight by day 100; PCBs in breast muscle exceeded 3.9 g/g by day 100. These PCB values are among the highest recorded for wild or sentinel waterfowl. PCB concentrations in breast muscle (26–523 g/g lipid weight) were 50–1,000 times greater than human consumption guidelines for edible poultry in Canada (0.5 g/g lipid weight) and 9–176 times greater than consumption guidelines for edible poultry in the United States (3.0 g/g lipid weight). Additionally, PCB concentrations in carcass and breast muscle exceeded the threshold of the Great Lakes Sport Fish Consumption Advisory do not eat category (1.9 g/g wet weight) by day 20 and day 50, respectively. Hepatic cytochrome P450-associated monooxygenases including BROD (benzyloxyresorufin-O-dealkylase), EROD (ethoxyresorufin-O-dealkylase), and PROD (pentoxyresorufin-O-dealkylase) were induced over 5-fold compared to reference mallards. BROD, EROD, and PROD were each significantly correlated to total PCBs and to the toxicity of selected PCB congeners, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin.     

Is Gd-DTPA required for routine cranial MR imaging?

Gadopentetate dimeglumine (gadolinium diethylenetriaminepentaacetic acid [DTPA]) was administered prospectively to 500 consecutive children and adults referred for routine cranial magnetic resonance (MR) imaging over a 4-month period. Pre- and postcontrast images were blindly and independently interpreted by two experienced neuroradiologists. Specific criteria were provided to the readers to define objectively when contrast material enhancement (or lack thereof) would be considered "radiologically helpful." Contrast-enhancing lesions were observed in 99 cases (20%). In only 15 cases (3%) did Gd-DTPA permit detection of lesions not also apparent on the precontrast studies. Contrast enhancement was considered radiologically helpful in 74 of the 99 cases. Lack of enhancement was considered helpful in 112 of the 500 cases (22%). Factors that may indicate increased usefulness of Gd-DTPA include increased patient age, definite lesion seen at computed tomography or precontrast MR imaging, prior craniotomy for tumor, and clinically documented systemic or central nervous system disease. Gd-DTPA should probably be used routinely for cranial MR imaging in most patients, except, perhaps, children and young adults with normal precontrast images.     

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Accumulating evidence suggests that selective M₄ muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M₄ activators were unsuccessful because of the lack of M₄ mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M₄ positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M₄ on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M₄-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M₄ modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M₄ PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.     

High levels of dd‐cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury

The clinical importance of subclinical, early T cell–mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor‐derived cell‐free DNA (dd‐cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd‐cfDNA. Forty‐two patients had elevated dd‐cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd‐cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] ?16.22% to ?1.39%) (?3.50 mL/min/1.73 m² IQR ?8.00 to ?1.00) vs 0% (?4.92%, 4.76%) in low dd‐cfDNA patients (P = .004), de novo donor‐specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd‐cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy.     

A systematic review and meta-analysis of complications following the posterior and lateral surgical approaches to total hip arthroplasty

IntroductionTotal hip arthroplasty is one of the most commonly performed orthopaedic procedures. Despite this, medical evidence to inform the choice of surgical approach is lacking. Currently in the UK, the two most frequently performed approaches to the hip are the posterior and the direct lateral.MethodsThis systematic review was performed according to Cochrane guidelines following an extensive search for prospective controlled trials published in any language before January 2014. Of the 728 records identified from searches, 6 prospective studies (including 3 randomised controlled trials) involving 517 participants provided data towards this review.FindingsCompared with the lateral approach, the posterior approach conferred a significant reduction in the risk of Trendelenburg gait (odds ratio [OR]: 0.31, p=0.0002) and stem malposition (OR: 0.24, p=0.02), and a non-significant reduction in dislocation (OR: 0.37, p=0.16) and heterotopic ossification (OR: 0.41, p=0.13). Neither approach conferred a functional advantage. We draw attention to the paucity of evidence and the need for a further randomised trial.     

Inconsistent reporting of minimally invasive surgery errors

Introduction

Minimally invasive surgery (MIS) is a complex task requiring dexterity and high level cognitive function. Unlike surgical ‘never events’, potentially important (and frequent) manual or cognitive slips (‘technical errors’) are underresearched. Little is known about the occurrence of routine errors in MIS, their relationship to patient outcome, and whether they are reported accurately and/or consistently.

Methods

An electronic survey was sent to all members of the Association of Surgeons of Great Britain and Ireland, gathering demographic information, experience and reporting of MIS errors, and a rating of factors affecting error prevalence.

Results

Of 249 responses, 203 completed more than 80% of the questions regarding the surgery they had performed in the preceding 12 months. Of these, 47% reported a significant error in their own performance and 75% were aware of a colleague experiencing error. Technical skill, knowledge, situational awareness and decision making were all identified as particularly important for avoiding errors in MIS. Reporting of errors was variable: 15% did not necessarily report an intraoperative error to a patient while 50% did not consistently report at an institutional level. Critically, 12% of surgeons were unaware of the procedure for reporting a technical error and 59% felt guidance is needed. Overall, 40% believed a confidential reporting system would increase their likelihood of reporting an error.

Conclusion

These data indicate inconsistent reporting of operative errors, and highlight the need to better understand how and why technical errors occur in MIS. A confidential ‘no blame’ reporting system might help improve patient outcomes and avoid a closed culture that can undermine public confidence.