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Purpose: Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In addition, BMP2 is widely expressed in cells of mesenchymal origin, including bone, cartilage, skeletal and cardiac muscle, and adipose tissue. It also participates in neurodevelopment by inducing differentiation of neural stem cells. In humans, BMP2 variants result in a multiple congenital anomaly syndrome through a haploinsufficiency mechanism. We sought to expand the phenotypic spectrum and highlight phenotypes of patients harboring monoallelic missense variants in BMP2., Methods: We used retrospective chart review to examine phenotypes from an international cohort of 18 individuals and compared these with published cases. Patient-derived missense variants were modeled in zebrafish to examine their effect on the ability of bmp2b to promote embryonic ventralization., Results: The presented cases recapitulated existing descriptions of BMP2-related disorders, including craniofacial, cardiac, and skeletal anomalies and exhibit a wide phenotypic spectrum. We also identified patients with neural tube defects, structural brain anomalies, and endocrinopathies. Missense variants modeled in zebrafish resulted in loss of protein function., Conclusion: We use this expansion of reported phenotypes to suggest multidisciplinary medical monitoring and management of patients with BMP2-related skeletal dysplasia spectrum., Competing Interests: Conflict of Interest Daryl A. Scott is funded by the National Institutes of Health. Jill A. Rosenfeld and Daryl A. Scott are employed by Baylor College of Medicine. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Although evidence supports that the acne microbiome harbors a diverse range of microbes that play a vital role in the progression of acne vulgaris, the culturable microbes in the acne microbiome have not yet been largely identified. Here, we grew microbe colonies from entire acne lesions on agar plates and identified abundant Staphylococcus, Acinetobacter, and Pseudomonas species from forty selected single colonies. Staphylococcus species, including Staphylococcus epidermidis (S. epidermidis), Staphylococcus hominis (S. hominis), and Staphylococcus aureus (S. aureus), were isolated from tryptic soy broth (TSB) agar plates. However, Cutibacterium acnes (C. acnes) was predominately isolated from furazolidone-supplemented TSB agar plates. Results from gas chromatography-mass spectrometry (GC-MS) analysis revealed that, besides acetate, propionate and butyrate were the main short-chain fatty acids (SCFAs) in fermentation metabolites of C. acnes and S. epidermidis isolates, respectively. The culturable bacteria and SCFA profiles presented in this study provide a reservoir for selecting acne probiotics and developing SCFA-associated therapies against acne vulgaris., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity., Methods: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes., Results: We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1., Conclusion: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums., Competing Interests: Conflict of Interest Baylor College of Medicine and Miraca Holdings Inc have formed a joint venture with shared ownership and governance of Baylor Genetics, formerly the Baylor Miraca Genetics Laboratories, which performs chromosomal microarray analysis and clinical exome sequencing. J.L., W.Z., L.W., V.P., A.D., H.Da., L.M., F.X., W.B., P.L., and C.M.E. are employees of Baylor College of Medicine and derive support through a professional services agreement with Baylor Genetics. J.R.L. serves on the Scientific Advisory Board of the Regeneron Genetics Center and has stock ownership in 23andMe. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative delirium is a serious complication of surgery associated with prolonged hospitalisation, long-term cognitive decline, and mortality. This study aimed to determine whether targeting bispectral index (BIS) readings of 50 (light anaesthesia) was associated with a lower incidence of POD than targeting BIS readings of 35 (deep anaesthesia)., Methods: This multicentre randomised clinical trial of 655 at-risk patients undergoing major surgery from eight centres in three countries assessed delirium for 5 days postoperatively using the 3 min confusion assessment method (3D-CAM) or CAM-ICU, and cognitive screening using the Mini-Mental State Examination at baseline and discharge and the Abbreviated Mental Test score (AMTS) at 30 days and 1 yr. Patients were assigned to light or deep anaesthesia. The primary outcome was the presence of postoperative delirium on any of the first 5 postoperative days. Secondary outcomes included mortality at 1 yr, cognitive decline at discharge, cognitive impairment at 30 days and 1 yr, unplanned ICU admission, length of stay, and time in electroencephalographic burst suppression., Results: The incidence of postoperative delirium in the BIS 50 group was 19% and in the BIS 35 group was 28% (odds ratio 0.58 [95% confidence interval: 0.38-0.88]; P=0.010). At 1 yr, those in the BIS 50 group demonstrated significantly better cognitive function than those in the BIS 35 group (9% with AMTS ≤6 vs 20%; P<0.001)., Conclusions: Among patients undergoing major surgery, targeting light anaesthesia reduced the risk of postoperative delirium and cognitive impairment at 1 yr., Clinical Trial Registration: ACTRN12612000632897., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome)., Methods: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers., Results: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined., Conclusion: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

Introduction: Hypospadias, one of the most common male genital birth defects, occurs in 1 out of every 200 male births in the United States and is increasing in prevalence globally., Objective: This study aimed to characterize the combinations of birth defects that co-occur with hypospadias more often than expected by chance, while accounting for the complex clustering patterns of congenital defects., Study Design: We analyzed cases with hypospadias and at least one additional co-occurring defect from the Texas Birth Defect Registry born between 1999 and 2014. For each combination, we calculated adjusted observed-to-expected (O/E) ratios, using Co-Occurring Defect Analysis (CODA)., Results: Among 16,442 cases with hypospadias and without known syndromes, 2,084 (12.7%) had at least one additional defect. Many of the birth defect combinations within the highest adjusted O/E ratios included cardiac, musculoskeletal, and additional urogenital defects. For example, a top combination with an adjusted O/E of 139.0 included renal agenesis and dysgenesis, reduction defects of the upper limb, and other anomalies of upper limb (including shoulder girdle). High adjusted O/E ratios were also observed in combinations that included defects outside of the urogenital developmental field. For instance, the combination with the highest O/E ratio included buphthalmos, and congenital cataract and lens anomalies (adjusted O/E ratio: 192.9). Similar results were obtained when we restricted our analyses to cases with second- or third-degree hypospadias., Discussion: Many combinations in the top results were expected (e.g., multiple urogenital defects); however, some combinations with seemingly unrelated patterns of defects may suggest the presence of some etiologic mechanisms yet to be identified., Conclusion: In summary, this study described patterns of co-occurring defect combinations with hypospadias that can inform further study and may provide insights for screening and diagnostic practices., Competing Interests: Conflict of interest None., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

There are no tools to evaluate eyebrow involvement in patients with alopecia areata. We developed and assessed the reliability of the Brigham Eyebrow Tool for Alopecia (BETA) as a quantitative evaluation of eyebrow alopecia areata. BETA uses facial landmarks of eyebrow anatomy and is calculated using surface area and density. A total of 50 eyebrow images with varying levels of hair loss were distributed to six board-certified dermatologists at three academic medical centers with standardized instructions and examples. Interrater and intrarater reliability were calculated using intraclass correlation coefficients (ICCs). BETA demonstrated high interrater (ICC = 0.88, confidence interval = 0.83-0.92 right eyebrow scores and ICC = 0.90, confidence interval = 0.85-0.94 left eyebrow scores) and intrarater (ICC = 0.90, confidence interval = 0.85-0.93 right eyebrow scores and ICC = 0.91, confidence interval = 0.87-0.94 left eyebrow scores) reliability. When measured in the same patient with varying degrees of hair loss over time, BETA demonstrated sensitivity to change. BETA is a simple and reliable objective assessment of eyebrow alopecia areata. BETA is easy-to-use and quick to calculate, making it feasible for a variety of clinical and research settings. Although developed for alopecia areata, we hope that BETA will be investigated in other etiologies of eyebrow alopecia to serve as a universal tool for monitoring disease progression, improvement, and response to treatment., (Copyright © 2020 Brigham and Women's Hospital. Published by Elsevier Inc. All rights reserved.)

Tissue engineering materials play a key role in how closely the complex architectural and functional characteristics of native healthy tissue can be replicated. Traditional natural and synthetic materials are superseded by bespoke materials that cross the boundary between these two categories. Here we present hydrogels that are derived from decellularised extracellular matrix and those that are synthesised from de novo α-helical peptides. We assess in vitro activation of murine macrophages to our hydrogels and whether these gels induce an M1-like or M2-like phenotype. This was followed by the in vivo immune macrophage response to hydrogels injected into rat partial-thickness abdominal wall defects. Over 28 days we observe an increase in mononuclear cell infiltration at the hydrogel-tissue interface without promoting a foreign body reaction and see no evidence of hydrogel encapsulation or formation of multinucleate giant cells. We also note an upregulation of myogenic differentiation markers and the expression of anti-inflammatory markers Arginase1, IL-10, and CD206, indicating pro-remodelling for all injected hydrogels. Furthermore, all hydrogels promote an anti-inflammatory environment after an initial spike in the pro-inflammatory phenotype. No difference between the injected site and the healthy tissue is observed after 28 days, indicating full integration. These materials offer great potential for future applications in regenerative medicine and towards unmet clinical needs. STATEMENT OF SIGNIFICANCE: Materials play a key role in how closely the complex architectural and functional characteristics of native healthy tissue can be replicated in tissue engineering. Here we present injectable hydrogels derived from decellularised extracellular matrix and de novo designed α-helical peptides. Over 28 days in the rat abdominal wall we observe an increase in mononuclear cell infiltration at the hydrogel-tissue interface with no foreign body reaction, no evidence of hydrogel encapsulation and no multinucleate giant cells. Our data indicate pro-remodelling and the promotion of an anti-inflammatory environment for all injected hydrogels with evidence of full integration with healthy tissue after 28 days. These unique materials offer great potential for future applications in regenerative medicine and towards designing materials for unmet clinical needs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved., Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated., Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated., Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

Cognitive recovery after anaesthesia and surgery is a concern for older adults, their families, and caregivers. Reports of patients who were 'never the same' prompted a scientific inquiry into the nature of what patients have experienced. In June 2018, the ASA Brain Health Initiative held a summit to discuss the state of the science on perioperative cognition, and to create an implementation plan for patients and providers leveraging the current evidence. This group included representatives from the AARP (formerly the American Association of Retired Persons), American College of Surgeons, American Heart Association, and Alzheimer's Association Perioperative Cognition and Delirium Professional Interest Area. This paper summarises the state of the relevant clinical science, including risk factors, identification and diagnosis, prognosis, disparities, outcomes, and treatment of perioperative neurocognitive disorders. Finally, we discuss gaps in current knowledge with suggestions for future directions and opportunities for clinical and translational projects., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970&#95;2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors., Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study., Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970&#95;2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970&#95;2972del., Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Tissue necrosis is a form of cell death common in advanced and aggressive solid tumors, and is associated with areas of intratumoral chronic ischemia. The histopathology of necrotic regions appear as a scaffold of cellular membrane remnants, reflective of the hypoxia and cell degradation events associated with this cellular death pathway. Changes in the glycosylation of cell surface proteins is another common feature of cancer progression. Using a recently developed mass spectrometry imaging approach to evaluate N-linked glycan distributions in human formalin-fixed clinical cancer tissues, differences in the glycan structures of regions of tumor, stroma and necrosis were evaluated. While the structural glycan classes detected in the tumor and stromal regions are typically classified as high mannose or branched glycans, the glycans found in necrotic regions displayed limited branching, contained sialic acid modifications and lack fucose modifications. While this phenomenon was initially classified in breast cancer tissues, it has been also seen in cervical, thyroid and liver cancer samples. These changes in glycosylation within the necrotic regions could provide further mechanistic insight to necrotic changes in cancer tissue and provide new research directions for identifying prognostic markers of necrosis.

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Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder)., (Copyright © 2018 Jointly by the British Journal of Anaesthesia, American Society of Anesthesiologists Inc, Wolters Kluwer Health Inc, International Anesthestic Research Society, Canadian Anesthesiologist’s Society, Acta Anaesthesiologica Scandinavica Foundation, and IOS Press., Jointly by the British Journal of Anaesthesia, American Society of Anesthesiologists Inc, International Anesthesia Research Society, Canadian Anesthesiologist’s Society, Acta Anaesthesiologica Scandinavica Foundation, and IOS Press. Published by Elsevier Ltd.. All rights reserved.)

The transcriptional program that regulates the differentiation of endothelial precursor cells into a highly organized vascular network is still poorly understood. Here we explore the role of SOX7 during this process, performing a detailed analysis of the vascular defects resulting from either a complete deficiency in Sox7 expression or from the conditional deletion of Sox7 in FLK1-expressing cells. We analysed the consequence of Sox7 deficiency from E7.5 onward to determine from which stage of development the effect of Sox7 deficiency can be observed. We show that while Sox7 is expressed at the onset of endothelial specification from mesoderm, Sox7 deficiency does not impact the emergence of the first endothelial progenitors. However, by E8.5, clear signs of defective vascular development are already observed with the presence of highly unorganised endothelial cords rather than distinct paired dorsal aorta. By E10.5, both Sox7 complete knockout and FLK1-specific deletion of Sox7 lead to widespread vascular defects. In contrast, while SOX7 is expressed in the earliest specified blood progenitors, the VAV-specific deletion of Sox7 does not affect the hematopoietic system. Together, our data reveal the unique role of SOX7 in vasculogenesis and angiogenesis during embryonic development., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT)., Methods: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs)., Results: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development., Conclusion: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

A persistent neurological deficit, such as paraplegia or paraparesis, secondary to spinal cord injury remains one of the most feared complications of surgery on the descending thoracic or abdominal aorta. This is despite sophisticated advances in imaging and the use of less invasive endovascular procedures. Extensive fenestrated endovascular aortic graft prostheses still carry a risk of spinal cord injury of up to 10%; thus, this risk should be identified and strategies implemented to protect the spinal cord and maintain perfusion. The patients at highest risk are those undergoing extensive thoracic aortic stenting including thoracic, abdominal, and pelvic vessels. Although many techniques are available, lumbar cerebrospinal fluid drainage remains the most frequent intervention, along with maintenance of perfusion pressure and possibly staged procedures to allow collateral vessel stabilization. Many questions remain regarding other technical aspects, spinal cord monitoring and cooling, pharmacological protection, and the optimal duration of interventions into the postoperative period., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Since general anaesthesia invariably accompanies surgery, the contribution of each to the development of postoperative cognitive dysfunction (POCD) has been difficult to identify., Methods: A prospective randomized controlled trial was undertaken in elderly patients undergoing extracorporeal shock wave lithotripsy (ESWL). Between 2005 and 2011, 2706 individuals were screened to recruit 100 eligible patients. Patients were randomly assigned to receive general or spinal anaesthesia alone. A battery of eight neuropsychological tests was administered before operation and at 7 days and 3 months after operation. The reliable change index was used to calculate the incidence of POCD. Intention-to-treat analysis was used to compare rates of POCD., Results: Futility analysis led to stopping of the trial after recruitment of 100 patients. Fifty patients were randomly assigned to general anaesthesia, and 48 patients to spinal anaesthesia without sedation or postoperative opioids. At 3 months, POCD was detected in 6.8% [95% confidence interval (CI): 1.4-18.7%] of patients in the general anaesthesia group and 19.6% (95% CI: 9.4-33.9%) in the spinal group (P=0.07). At 7 days after operation, the incidence of POCD was 4.1% (95% CI: 0.5-14%) in the general anaesthesia group and 11.9% (95% CI: 4.0-26.6%) in the spinal group (P=0.16)., Conclusions: We found no significant difference in the rates of POCD when comparing general anaesthesia with spinal anaesthesia, suggesting that the surgical or procedural process itself may contribute to the development of POCD., Clinical Trial Registration: Australian Clinical Trials Registry number ACTRN12605000150640., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Left heart catheterisation with coronary angiography (CA) may lead to cognitive dysfunction, as a result of neurological injury. The aim was to assess the incidence of cognitive dysfunction in elderly patients three months after CA and investigate any association between cognitive dysfunction and microembolic count during CA., Methods: This was a prospective observational study with a control cohort. Cognitive testing was undertaken at baseline and at 3 months using a battery of 8 neuropsychological tests. Subjects comprised 51 CA patients, aged ≥ 50 years, with normal baseline cognition, and 31 community control participants. Microemboli were measured by Transcranial Doppler throughout the procedure. All patients underwent trans-femoral CA with aortography and ventriculography. Cognitive dysfunction was defined in an individual when their reliable change index score was less than -1.96 on 2 or more tests and/or their combined z score was less than -1.96. Microembolic count was assessed by off-line manual counting and automatic software was also used to count and differentiate gaseous from solid microemboli., Results: Cognitive dysfunction was identified in 15.7% of patients at 3 months. Microemboli were detected in all patients, predominantly during aortography and ventriculography. The median total embolic count was 365 (IQR 192, 574), the majority being gaseous (84%). There was no multivariable association between cognitive dysfunction at 3 months and microembolic count., Conclusions: This study demonstrated that cognitive dysfunction following CA is not associated with microembolic load. Cognitive dysfunction occurs in 15.7% of patients at 3 months. This is reassuring for the proceduralist and suggests that other perioperative elements are involved., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the effect of study identification methods and network size on the relative effectiveness and cost-effectiveness of recommended pharmacological venous thromboembolic events (VTEs) prophylaxis for adult patients undergoing elective total knee replacement surgery in the United Kingdom., Methods: A stepwise literature search specifically designed to identify indirect evidence was conducted to extend the original clinical review from the latest National Institute for Health and Care Excellence (NICE) VTE technology appraisal. Different network sizes or network orders, based on the successive searches, informed three network meta-analyses (NMAs), which were compared with a replicated base case. The resulting comparative estimates were inputted in an economic model to investigate the effect of network size on cost-effectiveness probabilities., Results: Searches increased the number of indirect comparisons between VTE interventions, progressively widening the relevant network of studies for NMA. Precision around mean relative treatment effects was increased as the network was extended from the base case to first-order NMA, but further extensions had limited effect. Cost-effectiveness analysis results were largely insensitive to variation in clinical inputs from the different NMA orders., Conclusions: No standard methodology is currently recommended by NICE to identify the most relevant network of studies for NMA. Our study showed that optimizing the identification of studies for NMA can extend the evidence base for analysis and reduce the uncertainty in relative effectiveness estimates. Although in our example network extensions did not affect the acceptability of available treatments in VTE prevention based on cost-effectiveness results, it may in other applications., (Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard of hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health-care services are provided in a linguistically and culturally sensitive manner. This guideline offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.

Postoperative cognitive dysfunction (POCD) was originally thought to be associated with cardiac surgery, but has since been associated with non-cardiac surgery and even sedation for non-invasive procedures such as coronary angiography. The focus of POCD has thus shifted from the type of surgery or anaesthetic to patient susceptibility. The realisation that cognitive impairment, such as mild cognitive impairment (MCI - the prodrome for Alzheimer's disease (AD)), may already exist in many elderly patients who incidentally present for surgery beckons anaesthesia to align cognitive research with that of AD in order to draw valid parallels between the two disciplines. Long-term studies are required to understand if POCD is merely a transient phenomenon, or if it is the harbinger of long-term cognitive deterioration which may lead eventually to dementia. In this regard, the use of CSF analysis to diagnose AD many years before symptoms appear may identify susceptible individuals. Furthermore, animal studies indicate that volatile anaesthestics may augment the pathological processes of AD by affecting amyloid-beta processing. Identification of a link between surgery/anaesthesia, POCD, MCI, and AD would create a unique opportunity to fast-track the development of clinical or pharmacological preventive strategies that would benefit a significant proportion of the population., (2011 Elsevier Ltd. All rights reserved.)

Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta-analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis. This report from the International Society for Pharmacoeconomics and Outcomes Research Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on technical aspects of conducting network meta-analyses (our use of this term includes most methods that involve meta-analysis in the context of a network of evidence). We start with a discussion of strategies for developing networks of evidence. Next we briefly review assumptions of network meta-analysis. Then we focus on the statistical analysis of the data: objectives, models (fixed-effects and random-effects), frequentist versus Bayesian approaches, and model validation. A checklist highlights key components of network meta-analysis, and substantial examples illustrate indirect treatment comparisons (both frequentist and Bayesian approaches) and network meta-analysis. A further section discusses eight key areas for future research., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: The relationship of aortic atheroma to postoperative cognitive dysfunction (POCD), a common complication of coronary artery bypass graft surgery, has not been resolved. We undertook assessment of aortic atheroma using intraoperative ultrasonography and related the degree of aortic atheroma to POCD., Methods: Aortic atheroma was assessed using intraoperative transesophageal and epiaortic echocardiography in 311 patients who underwent coronary artery bypass graft surgery. Atheroma was graded from 0 (normal or minimal) to 3 (mobile or rough) in each of four quadrants of the proximal ascending to proximal descending thoracic aorta. Atheroma burden was defined as the atheroma score divided by the total possible score for that patient. Patients also completed a neuropsychological battery consisting of eight tests taken the week before surgery and at 1 week and 3 and 12 months afterward. Decreased cognitive function for each test was defined as an individual decrease of at least 1 standard deviation of the group baseline mean for that test, and POCD was defined as a decrease in two or more tests., Results: The atheroma burden (%) was greater in the patients with POCD. The difference was greatest at 1 week (10.4+/-14.7 versus 4.4+/-9.0, p=0.0002) and diminished progressively at 3 months (8.9+/-14.1 versus 5.4+/-10.1, p=0.06) and 12 months (6.6+/-12.0 versus 5.6+/-10.2, p=0.56). Multivariable analysis showed that atheroma burden strongly predicted POCD at 1 week., Conclusions: Aortic atheroma burden predicts POCD at 1 week but has less impact on POCD as time progresses. Atheroma burden is highly correlated with age and may be a good predictor of early POCD., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Decreased cognitive function associated with coronary artery bypass graft surgery is common. These deficits may be similar to the cognitive dysfunction seen in the spectrum of mild cognitive impairment to Alzheimer's disease, which are believed to result from the accumulation of amyloid beta (Abeta) peptide in the brain. We measured cognition both before and after coronary artery bypass graft surgery and assayed Abeta levels to investigate whether the cognitive dysfunction of cardiac surgery was associated with Abeta levels., Methods: The plasma of 332 patients, who had undergone neuropsychological testing before and 3 and 12 months after coronary artery bypass graft surgery, was analyzed for Abeta(42) and Abeta(40). Patients were classified as having preexisting cognitive impairment if cognitive function was decreased in two or more tests compared with a healthy control group, and postoperative cognitive dysfunction was defined as a decline in two or more tests compared with the group mean baseline score., Results: Preexisting cognitive impairment was present in 117 patients (35.2%), and postoperative cognitive dysfunction was present in 40 (12%) at 3 months and 41 (13%) at 12 months after surgery. Both plasma Abeta(42) and Abeta(40) levels assessed before the surgery were significantly lower in patients who later had postoperative cognitive dysfunction at 3 months., Conclusions: Decreased preoperative plasma levels of Abeta(42) and Abeta(40) in patients who exhibit postoperative cognitive dysfunction at 3 months suggest that postoperative cognitive dysfunction at this time may share a common mechanism with mild cognitive impairment and Alzheimer's disease. This process may be exacerbated by anesthesia.

Objective: To demonstrate the importance of considering all relevant indirect data in a network meta-analysis of treatments for non-small-cell lung cancer (NSCLC)., Methods: A recent National Institute for Health and Clinical Excellence appraisal focussed on the indirect comparison of docetaxel with erlotinib in second-line treatment of NSCLC based on trials including a common comparator. We compared the results of this analysis to a network meta-analysis including other trials that formed a network of evidence. We also examined the importance of allowing for the correlations between the estimated treatment effects that can arise when analysing such networks., Results: The analysis of the restricted network including only trials of docetaxel and erlotinib linked via the common placebo comparator produced an estimated mean hazard ratio (HR) for erlotinib compared with docetaxel of 1.55 (95% confidence interval [CI] 0.72-2.97). In contrast, the network meta-analysis produced an estimated HR for erlotinib compared with docetaxel of 0.83 (95% CI 0.65-1.06). Analyzing the wider network improved the precision of estimated treatment effects, altered their rankings and also allowed further treatments to be compared. Some of the estimated treatment effects from the wider network were highly correlated., Conclusions: This empirical example shows the importance of considering all potentially relevant data when comparing treatments. Care should therefore be taken to consider all relevant information, including correlations induced by the network of trial data, when comparing treatments.

Objective: To examine the reliability of work-related activity coding for injury-related hospitalisations in Australia., Method: A random sample of 4,373 injury-related hospital separations from 1 July 2002 to 30 June 2004 were obtained from a stratified random sample of 50 hospitals across four states in Australia. From this sample, cases were identified as work-related if they contained an ICD-10-AM work-related activity code (U73) allocated by either: (i) the original coder; (ii) an independent auditor, blinded to the original code; or (iii) a research assistant, blinded to both the original and auditor codes, who reviewed narrative text extracted from the medical record. The concordance of activity coding and number of cases identified as work-related using each method were compared., Results: Of the 4,373 cases sampled, 318 cases were identified as being work-related using any of the three methods for identification. The original coder identified 217 and the auditor identified 266 work-related cases (68.2% and 83.6% of the total cases identified, respectively). Around 10% of cases were only identified through the text description review. The original coder and auditor agreed on the assignment of work-relatedness for 68.9% of cases., Conclusions and Implications: The best estimates of the frequency of hospital admissions for occupational injury underestimate the burden by around 32%. This is a substantial underestimate that has major implications for public policy, and highlights the need for further work on improving the quality and completeness of routine, administrative data sources for a more complete identification of work-related injuries.

Background: Pain after craniotomy is often under-treated. Opiates carry distinct disadvantages. Non-steroidal anti-inflammatory drugs have an anti-platelet action and carry a bleeding risk. Cyclo-oxygenase 2 inhibitors such as parecoxib are not associated with a bleeding risk and would be welcome analgesics if shown to be effective., Methods: In a prospective double-blind, randomized, placebo-controlled study, we investigated the analgesic effect of a single dose of parecoxib 40 mg given at dural closure in 82 patients undergoing elective craniotomies. Remifentanil was used intraoperatively, and i.v. morphine was titrated to the requirement in the post-anaesthetic unit. On the ward, i.m. morphine 5 mg as required and regular acetaminophen was prescribed. Morphine use and visual analogue pain scores were recorded at 1, 6, 12, and 24 h after surgery., Results: Parecoxib reduced pain scores at 6 h and morphine use at 6 and 12 h after operation. However, overall, it had only minimal impact on postoperative analgesia. We found a wide variability in analgesic requirements where 11% of patients required no opioids and 16% required more than 15 mg i.v. morphine 1 h after the surgery., Conclusions: We found only limited evidence to support parecoxib as an analgesic after craniotomy.

Background: The plasma protein apolipoprotein E (APOE) is a risk factor for degenerative cognitive decline manifested by mild cognitive impairment and later by Alzheimer's disease. Patients undergoing coronary artery bypass grafting (CABG) are known to have a high prevalence of preexisting cognitive impairment and postoperative cognitive dysfunction. Because both mild cognitive impairment and Alzheimer's disease generally occur in elderly individuals, the age group that commonly present for CABG, we investigated if the APOE epsilon4 allele was associated with patients manifesting preexisting cognitive impairment and postoperative cognitive dysfunction., Methods: The DNA of 282 patients who had undergone neuropsychologic testing before and 3 and 12 months after CABG was analyzed for APOE genotype. Patients were classified as having preexisting cognitive impairment if cognitive function was decreased in two or more tests compared with a healthy control group. Postoperative cognitive dysfunction was defined as a decrease in two or more tests compared with the group mean baseline score., Results: The APOE epsilon4 allele was found in 83 (29.4%) patients. Although preexisting cognitive impairment was present in 105 (37.2%) and postoperative cognitive dysfunction in 33 (12%) and 31 (11%) at 3 and 12 months postoperatively, there was no relationship with the presence of the APOE epsilon4 allele or any of the six genotypes., Conclusions: Preexisting cognitive impairment and postoperative cognitive dysfunction are not associated with APOE epsilon4 genotype, suggesting that cognitive impairment both before and after CABG may not be associated with degenerative cognitive decline.

Objectives: To compare methods of tobacco use profiling in patients undergoing maintenance treatment for periodontitis., Methods: The smoking status of 108 subjects attending a university-based specialist periodontics clinic was assessed by examination of referring records, patient-completed questionnaires, clinician-administered interviews and by salivary cotinine and expired-air carbon monoxide (ECO) measurement., Results: Ten percent of the detected smokers (salivary cotinine>14.2ngml(-1)) reported to be non-smokers in the clinician-administered interview. 4.2% of the smokers detected by ECO analysis (ECO>8ppm) reported to be non-smokers in the clinician-administered interview. Systematic under reporting of tobacco use was also apparent in patient-completed questionnaires from the periodontics clinic and, to a larger degree, in the referring clinic records when compared to the clinician-administered interview., Conclusions: By biochemically analyzing recent cigarette smoke exposure, our data show that clinician assessment is the most accurate means by which to obtain anamnestic data concerning tobacco use. ECO analysis using portable CO monitors is inexpensive and simple with no requirement for laboratory support. The combination of ECO measurement and clinician-administered tobacco use interview represents a clinically applicable method to improve the detection of an important, periodontally susceptible population-regular smokers who deny smoking.

Background: The validity and reliability of high-stakes examinations such as those used by national, regional and state or provincial dental boards are under intense scrutiny by candidates, dental schools, dental educators, dental associations, and state or provincial dental boards., Methods: The authors followed the progress of 1,063 candidates from nonaccredited dental programs who began the National Dental Examining Board of Canada's (NDEB) clinical examinations between January 1996 and November 1999 through the administration of the examination's final component in December 2003 examine the utility and validity of the patient-based component of the examination process., Results: The results showed that the first three components of the examination were effective in screening out candidates who were not adequately prepared to take the patient-based component. Only 12 (1.1 percent) of the candidates failed the maximum allowed three attempts to pass the patient-based component., Conclusions: The results demonstrated that the patient-based component did not contribute to the overall examination validity or decision making and did not prevent candidates from obtaining certification., Practice Implications: Owing to this lack of utility, the associated costs and ethical concerns, NDEB eliminated the patient-based component of the examination and replaced it with the requirement to complete an accredited, qualifying/degree completion dental program followed by completion of NDEB's written and objective structured clinical examination components.

Background: The assessment of postoperative cognitive dysfunction after coronary artery bypass graft surgery is made with the repeated administration of cognitive tests. This classification is vulnerable to error, and it has been suggested that increasing the number of tests in a battery while maintaining constant inclusion criteria for postoperative cognitive dysfunction increases the rate of false positive classification of deterioration. The current study tested this by applying a constant rule for cognitive dysfunction using combinations of two to seven cognitive tests., Methods: Two hundred and four coronary artery bypass graft patients (surgical) and 90 healthy nonsurgical controls aged 55 years or older completed a battery of cognitive tests at baseline (preoperative) and 1 week later (postoperative). In both groups, postoperative cognitive dysfunction was classified using all unique combinations of two to seven cognitive tests when performance deteriorated on two or more tests by at least the value of the baseline standard deviation., Results: The average incidence of cognitive dysfunction progressively increased in both groups as the number of cognitive tests increased from two (surgical: 13.3%; control: 3.1%) to seven tests (surgical: 49.4%; control: 41.1%)., Conclusions: Increasing the number of tests used to classify postoperative cognitive dysfunction appears to increase the sensitivity to change in the coronary artery bypass graft group. However, accompanying false positive classifications suggest that this improved sensitivity reflected increased error. Future rules for postoperative cognitive dysfunction need to account for this error and include a control group.

Objectives: To evaluate the cost-effectiveness and budget impact of a new heat wrap therapy for low back pain compared to paracetamol and ibuprofen from the perspective of the UK National Health Service (NHS)., Methods: We evaluated cost-effectiveness using data from a phase III trial comparing the three therapies in 371 patients aged 18 to 55 years presenting with acute uncomplicated low back pain. The primary effectiveness measure used was successful treatment, defined as both clinically meaningful pain relief and clinically meaningful reduction in disability. We conducted a simple evaluation using NHS prescription costs and a modeled extrapolation including the costs of further treatment and consultations for patients treated unsuccessfully or with adverse events. Uncertainty was addressed using nonparametric bootstrapping and sensitivity analyses., Results: Successful treatment was reported by 57% of patients treated with heat wrap therapy, 26% treated with paracetamol and 18% treated with ibuprofen (P < 0.05 for heat wrap vs. both other groups). NHS prescription cost per patient was estimated to be 1.35 pounds Sterling for heat wrap therapy, 0.26 pounds Sterling for paracetamol, and 0.28 pounds Sterling for ibuprofen and cost per successful treatment was 3.52 pounds Sterling for heat wrap therapy compared to paracetamol, and 2.72 pounds Sterling compared to ibuprofen. In the modeled extrapolation, NHS cost per patient was 27.77 pounds Sterling for heat wrap therapy, 34.20 pounds Sterling for paracetamol, and 36.04 pounds Sterling for ibuprofen. Sensitivity analyses indicated that the findings were robust to plausible changes in data and assumptions., Conclusions: Economic evaluation of this study suggests that the NHS cost of introducing heat wrap therapy in place of oral analgesics would be modest and heat wrap therapy might potentially reduce the total cost of managing episodes of lower back pain.

Background: Postoperative cognitive decline is a common complication after coronary artery bypass graft (CABG) surgery. Postoperative cognitive decline is defined on the basis of change in cognitive function detected with repeated assessments using neuropsychological tests. Therefore improvement in neuropsychological testing instruments may increase our understanding of postoperative cognitive decline., Methods: Fifty patients undergoing CABG surgery completed both a conventional and a computerized battery of tests before and 6 days after CABG surgery. Fifty age- and education-matched controls completed the same test batteries 6 days apart. The reliability and the sensitivity to postoperative cognitive decline were computed for each battery., Results: Both test batteries detected postoperative cognitive decline 6 days after CABG surgery. For the computerized battery, the reliability of the reaction times (intraclass correlation 0.89-0.92) was greater than for any test from the conventional battery (intraclass correlation 0.56-0.71), although accuracy measures were less reliable (intraclass correlation 0.61-0.89). The computerized battery detected all the cases of POCD identified by the conventional test battery and also five cases that were classified as normal by the conventional tests., Conclusion: Computerized tests are suitable for measuring cognitive change after CABG surgery and may detect change in a greater proportion of patients 6 days after CABG surgery than conventional neuropsychological tests.

The fluorescent dye 2',7'-bis-(2-carboxyethyl)-5(and-6)-carboxyfluorescein (BCECF) has been widely used as an indicator of cytosolic pH. Here we report that BCECF localizes to hydrogenosomes (hydrogen-generating organelles found in several phylogenetically separate groups of anaerobic protists) in Trichomonas vaginalis, where it was observable by fluorescence microscopy. Its cellular location was confirmed by treatment of BCECF-loaded cells with diaminobenzidine and hydrogen peroxide together with UV illumination. This produced an osmiophilic precipitate in the matrix of hydrogenosomes, observable by electron microscopy. Use of a short (7.5 min) loading period, loading on ice, use of concentrations of BCECF (acetoxymethyl ester) down to 10 nM, and inclusion of the anion channel blockers probenicid or sulfinpyrazone, or the K+/H+ ionophore nigericin in the loading buffer all failed to prevent hydrogenosomal accumulation of BCECF. This uptake was best observed when intact cells were loaded with the ester form of BCECF, but could also be seen using free BCECF following either incubation with ruptured cells or electroporation of intact cells. Hydrogenosomal BCECF loading was also obtained with washed cell lysates, without cytoplasm or metabolic substrates. We tested a range of other fluorogenic dyes designed for cytosolic labeling, and found that the calcium indicator fura-2 (acetoxymethyl ester) and the cell viability marker fluorescein diacetate also labeled hydrogenosomes. The results illustrate a novel use for BCECF as a fluorescent marker for hydrogenosomes (the first such marker), but present a warning against the indiscriminate use of fluorogenic ester dyes to measure properties of the cytosol in hydrogenosome-containing organisms - the dyes may also be indicating the properties of the hydrogenosome.

Ropivacaine is a new local anaesthetic with advantages that suggest an important role in the provision of postoperative analgesia. The main aim of this study was to investigate the dose-response relationship of extradural infusion of ropivacaine. We studied 36 ASA I-III patients undergoing upper abdominal surgery during general anaesthesia and extradural block (catheter insertion at T6-9) using 0.5% ropivacaine in a randomized, double-blind study. After surgery nine patients each received an extradural infusion of either ropivacaine 0.1%, 0.2%, 0.3% or saline at a rate of 10 ml h-1 for 21 h. All patients had access to i.v. morphine via a PCA device. The ropivacaine groups consumed significantly less morphine over the 21-h infusion period than the saline group (medians: saline 75 mg; 0.1% ropivacaine 32 mg; 0.2% ropivacaine 39 mg; 0.3% ropivacaine 13 mg) (P < 0.05). Pain (VAS scores) at rest was significantly lower in all ropivacaine groups than in the saline group after 4 h of infusion (medians: saline 45 mm; 0.1% ropivacaine 15 mm; 0.2% ropivacaine 12 mm; 0.3% ropivacaine 0 mm). Pain on coughing was significantly less in all ropivacaine groups than in the saline group after 4 h infusion (medians: saline 67 mm; 0.1% ropivacaine 44 mm; 0.2% ropivacaine 33 mm; 0.3% ropivacaine 0 mm) and for 0.2% and 0.3% ropivacaine at later times. Motor block was negligible throughout the infusion. Patient satisfaction was higher in the 0.2% and 0.3% ropivacaine groups than in the two other groups.

Activities of phenylalanine ammonia-lyase (PAL) and tyrosine ammonia-lyase (TAL) were assessed at each stage of a three-step purification of PAL. Assays were performed by high-performance liquid chromatographic (HPLC) separation and ultraviolet detection of reaction products. Use of HPLC permitted assay of low activities of PAL and TAL for periods up to approximately four and two days, respectively. HPLC also facilitated the accurate quantitation of the product of the TAL reaction, trans-p-coumaric acid, which was observed to isomerize readily under experimental conditions. PAL and TAL were associated throughout the purification procedure, with TAL activity at 0.6-1.3% of PAL activity. It was concluded that, contrary to previous reports, TAL and PAL activities are mediated by the same enzyme, or else by chromatographically very similar enzymes.