Corrigendum to "Evaluation of 3-O-methyldopa as a biomarker for aromatic L-amino acid decarboxylase deficiency in 7 Brazilian cases" [27/100744/2021/ pages: 1-4].

[This corrects the article DOI: 10.1016/j.ymgmr.2021.100744.].

Evaluation of 3-O-methyldopa as a biomarker for aromatic L-amino acid decarboxylase deficiency in 7 Brazilian cases.

Aromatic L-amino acid decarboxylase (AADCD) deficiency is an autosomal recessive neurometabolic disorder, caused by biallelic mutations in the DDC gene, that impairs the synthesis or metabolism of neurotransmitters leading to severe motor dysfunction. The main clinical signs are oculogyric crisis, hypotonia, hypokinesia, and dystonia. The biochemical diagnosis can be performed in cerebrospinal fluid by neurotransmitter analysis, which requires an invasive lumbar puncture, and the sample needs to be shipped frozen to a reference laboratory, usually across a country border. Measurement of AADC activity in plasma is also possible, but available in a few labs globally. 3-O-methyldopa (3-OMD) is a catabolic product of L-dopa and it is elevated in patients with AADC deficiency. The quantification of 3-OMD can be performed in dried blood spots (DBS), a sample that could be shipped at room temperature. 3-OMD levels of AADCD patients and controls were quantified in DBS by liquid chromatography tandem mass spectrometry. DBS samples from 7 Brazilian patients previously diagnosed with AADCD were used to validate the 3-OMD quantification as a screening procedure for this condition. All AADCD patients had at least a four-fold increase of 3-OMD. Thus, 3-OMD seems to be a reliable marker for AADCD, with potential use also in the newborn screening of this disease.

Comparative and Functional Genomic Resource for Mechanistic Studies of Human Blood Pressure-Associated Single Nucleotide Polymorphisms.

The objective of the current study is to use comparative and functional genomic analysis to help to understand the biological mechanism mediating the effect of single nucleotide polymorphisms (SNPs) on blood pressure. We mapped 26 585 SNPs that are in linkage disequilibrium with 1071 human blood pressure-associated sentinel SNPs to 9447 syntenic regions in the mouse genome. Approximately 21.8% of the 1071 linkage disequilibrium regions are located at least 10 kb from any protein-coding gene. Approximately 300 blood pressure-associated SNPs are expression quantitative trait loci for a few dozen known blood pressure physiology genes in tissues including specific kidney regions. Blood pressure-associated sentinel SNPs are significantly enriched for expression quantitative trait loci for blood pressure physiology genes compared with randomly selected SNPs (P<0.00023, Fisher exact test). Using a newly developed deep learning method and other methods, we identified SNPs that were predicted to influence the conservation of CTCF (CCCTC-binding factor) binding across cell types, transcription factor binding, mRNA splicing, or secondary structures of RNA including long noncoding RNA. The SNPs were more likely to be located in CTCF-binding regions than what would be expected from the whole genome (P=4.90×10-7, Pearson χ2 test). One example synonymous SNP rs9337951 was predicted to influence the secondary structure of its host mRNA JCAD (junctional cadherin 5 associated) and was experimentally validated to influence JCAD protein expression. These findings provide an extensive comparative and functional genomic resource for developing experiments to test the functional significance of human blood pressure-associated SNPs in human cells and animal models.

Interobserver Reliability in Imaging-Based Fracture Union Assessment-Two Systematic Reviews.

OBJECTIVES: (A) To investigate the specialty of observers involved in imaging-based assessment of bone fracture union in recent orthopaedic trials and (B) to provide a general overview of observer differences (in terms of interobserver reliability) in radiologic fracture union assessment that have been reported between surgeons and radiologists. DATA SOURCES: Two separate systematic reviews (A, B) of English-, German-, and French-language articles in MEDLINE and Embase databases using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were done, with the following time frames: (A) January 2016-August 2017 and (B) through November 2017. STUDY SELECTION: (A) Clinical trials of surgical fracture treatment evaluating radiologic (non) union. (B) Interobserver studies reporting kappa-values or intraclass correlation coefficients as reliability coefficient for radiologic fracture union assessment. Inclusion criteria for both reviews were fractures of the appendicular skeleton and the use of radiographs or computed tomography. DATA EXTRACTION: Data were independently retrieved by 2 reviewers. DATA SYNTHESIS: Descriptive statistics and percentages were reported. RESULTS: (A) Forty-eight trials were included, whereof 33 (68%) did not report the observer's specialty. Six trials (13%) reported surgeon observers only, and 6 (13%) reported radiologist observers only. The median number of observers is 1 (interquartile range, 1-2). (B) Thirty-one interobserver studies were included, whereof 11 (35%) included at least 1 surgeon and 1 radiologist. Interobserver reliability varied considerably across the various fracture types studied and outcome scale used and was often unsatisfactory (kappa or intraclass correlation coefficients of <0.7). CONCLUSIONS: In most trials providing observer's characteristics, radiologic fracture union was either rated by 1 surgeon or 1 radiologist. As interobserver reliability can be unsatisfactory, we recommend surgeons and radiologists to further intensify collaboration and trials to include at least 2 observers and associated reliability statistics.

Joint Space Narrowing in Patients With Pisotriquetral Osteoarthritis.

BACKGROUND: Patients with suspected pisotriquetral osteoarthritis may show joint space narrowing. However, the extent of joint space narrowing and its deviation from the joint space width (JSW) in normal anatomy is unknown. In this pathoanatomic study, we therefore compared the JSW in the pisotriquetral joint between osteoarthritic patient wrists and healthy wrists. METHODS: We reviewed preoperative computed tomography (CT) scans of 8 wrists of patients with ulnar-sided wrist pain who underwent a pisiformectomy with confirmed pisotriquetral osteoarthritis at surgery. We also reviewed CT scans of 20 normal wrists from healthy volunteers serving as control group. Three-dimensional CT models of the pisiform and triquetrum were obtained from both affected and normal wrists, after which the minimum JSW was calculated in an automated fashion. RESULTS: In the patient group, the median (interquartile range) of the minimum JSW was 0.1 mm (0.0-0.2), and in the control group, 0.8 mm (0.3-0.9) ( P = .007). CONCLUSIONS: We showed that the pisotriquetral joint space in osteoarthritic patient wrists was significantly narrowed compared with healthy wrists. These results suggest that JSW evaluation has a potential diagnostic value in the work-up of patients with suspected pisotriquetral osteoarthritis. This is an interesting area for future clinical research, especially because no gold standard for diagnosing pisotriquetral osteoarthritis has been established yet.

Does a Comparison View Improve the Reliability of Staging Wrist Osteoarthritis?

BACKGROUND: Radiological grading of wrist osteoarthritis associated with scaphoid nonunion advanced collapse (SNAC) can be difficult. A comparison radiograph of the contralateral healthy wrist and an educational training in the various SNAC stages may improve reliability. Our purposes were to evaluate the difference in the reliability: (1) between observers who rate SNAC wrists with and without a comparison radiograph; and (2) between observers who receive training prior to ratings and those who do not. METHODS: In this cross-sectional survey study, 82 fully trained orthopedic or hand surgeons rated anteroposterior radiographs of 19 patient wrists following a scaphoid nonunion based on SNAC stages 0 to 4. Observers were randomized online in 4 groups: one group rated unilateral views without training, a second group unilateral views with training, a third group bilateral views without training, and a fourth group bilateral views with training. Training included a 1-page clarification of the SNAC stages. Interobserver agreement was calculated using kappa statistics. RESULTS: There was no significant difference between agreement between observers who rated unilateral radiographs (κ = 0.55) and who rated bilateral radiographs (κ = 0.58) ( P = .14), nor between agreement between observers who received training (κ = 0.59) and who did not (κ = 0.54) ( P = .058). CONCLUSIONS: The use of an additional comparison view and/or training does not seem to be clinically relevant in SNAC staging. There is room for improvement in the way we assess patients with SNAC wrists.

Is there a trend in CT scanning scaphoid nonunions for deformity assessment?-A systematic review.

PURPOSE: The effect of scaphoid nonunion deformity on wrist function is uncertain due to the lack of reliable imaging tools. Advanced three-dimensional (3-D) computed tomography (CT)-based imaging techniques may improve deformity assessment by using a mirrored image of the contralateral intact wrist as anatomic reference. The implementation of such techniques depends on the extent to which conventional CT is currently used in standard practice. The purpose of this systematic review of medical literature was to analyze the trend in CT scanning scaphoid nonunions, either unilaterally or bilaterally. MATERIALS AND METHODS: Using Medline and Embase databases, two independent reviewers searched for original full-length clinical articles describing series with at least five patients focusing on reconstructive surgery of scaphoid nonunions with bone grafting and/or fixation, from the years 2000-2015. We excluded reports focusing on only nonunions suspected for avascular necrosis and/or treated with vascularized bone grafting, as their workup often includes magnetic resonance imaging. For data analysis, we evaluated the use of CT scans and distinguished between uni- and bilateral, and pre- and postoperative scans. RESULTS: Seventy-seven articles were included of which 16 were published between 2000 and 2005, 19 between 2006 and 2010, and 42 between 2011 and 2015. For these consecutive intervals, the rates of articles describing the use of pre- and postoperative CT scans increased from 13%, to 16%, to 31%, and from 25%, to 32%, to 52%, respectively. Hereof, only two (3%) articles described the use of bilateral CT scans. CONCLUSION: There is an evident trend in performing unilateral CT scans before and after reconstructive surgery of a scaphoid nonunion. To improve assessment of scaphoid nonunion deformity using 3-D CT-based imaging techniques, we recommend scanning the contralateral wrist as well.

Observer Variability in Evaluating Pisotriquetral Osteoarthritis using Pisotriquetral View.

A pisotriquetral (semilateral) view of the wrist may improve the assessment of pisotriquetral osteoarthritis (OA), but its reliability and reproducibility are unclear. The purpose of this cross-sectional observer study was to investigate (1) the inter- and intraobserver agreement of evaluating pisotriquetral OA using pisotriquetral views with a special focus on sclerosis, joint space width (JSW) narrowing and osteophyte formation, and (2) the incidence of these latter radiographic features in patients suspected for pisotriquetral OA. Five independent observers rated independently at two different occasions 27 pisotriquetral views from patients treated for ulnar-sided wrist pain suspected for pisotriquetral OA requiring a pisiform resection. The agreement was calculated using kappa statistic. Agreement between observers ranged from 0.38 (fair) to 0.56 (moderate). Average intraobserver agreement ranged from 0.43 (moderate) to 0.52 (moderate). In 36% of the ratings, JSW narrowing was observed, followed by osteophyte formation (30%) and sclerosis (28%). Observers found it especially difficult to detect JSW narrowing. Despite the availability of a pisotriquetral view to enhance visualization of the pisotriquetral joint, assessment of the specific features indicating pisotriquetral OA leads to only fair-to-moderate agreement. This limits the applicability of a radiographic assessment. A rationale for a more reliable radiologic approach in assessing the level of pisotriquetral OA is needed, which may require the use of more advanced imaging techniques.

Estimating Scaphoid Lengths Using Anatomical Measurements in the Wrist.

PURPOSE: In reconstructive surgery of scaphoid nonunions with humpback deformity, some surgeons recommend restoration of the normal scaphoid length whereas others overexpand the normal length to ensure carpal realignment and prevent late collapse. To be able to define overexpansion and investigate which levels of overexpansion yield optimal clinical results, a precise method for estimating the original scaphoid length is required. The purpose of this anatomic study was to investigate the precision of estimating normal scaphoid lengths based on intact adjacent bone dimensions, compared with using the contralateral scaphoid length. METHODS: From bilateral computed tomographic scans of 28 healthy wrist pairs, 3-dimensional virtual bone models were created. The left and right scaphoid lengths were determined at the central axis. The capitate length at the central axis and the distal radius width served to derive an ipsilateral scaphoid length estimate. Estimation precision for individual cases was based on the 95% range (±1.96 × SD) of the observed differences between the actual and estimated lengths. RESULTS: On average, the capitate length was 10% smaller than the scaphoid length; the radius width was 9% larger. Consequently, we averaged the capitate length and radius width for ipsilateral estimations. The average difference between the scaphoid length and the latter ipsilateral estimate was 0.1 mm. The average contralateral scaphoid length difference was also 0.1 mm. Estimation precisions, however, were ±2.2 and ±1.4 mm, respectively. CONCLUSIONS: Scaphoid length estimation based on the contralateral scaphoid is more precise than the estimating scaphoid length using the ipsilateral radius and capitate. CLINICAL RELEVANCE: Scaphoid overexpansion can be ensured if the restored length is at least 1.4 mm longer than the contralateral length. This may be valuable information when establishing a target length for reconstruction and investigating the consequences of scaphoid overexpansion on clinical function, such as range of motion, which are currently unknown.

Validation of the contralateral side as reference for selecting radial head implant sizes.

PURPOSE: In arthroplasty of comminuted radial head fractures, the contralateral radial head diameter can be used as reference for implant selection. However, potential bilateral asymmetry may result in a mismatch of the implant with the native bone. Therefore, our purpose was to evaluate anatomical right-to-left differences of radial head diameters. We also compared conventional two-dimensional (2D) with three-dimensional (3D) measurements. METHODS: We used bilateral CT-scans from 25 intact proximal radius pairs of right-handed adult subjects to obtain 50 3D radial head models. After contralateral matching, diameters were calculated using a 3D-based method using an automated circle-fit in standardized cross-sections at the widest level midway through the radial head. The 3D-based diameters were compared to orthogonal line measurements in standard axial CT-slices. RESULTS: Three-dimensional analysis yielded a radial head diameter of 23.0 ± 1.7 mm. The dominant right side was significantly wider, with right-to-left differences of 0.2 ± 0.4 mm, with a maximum of 0.9 mm. The 2D-based diameter was 22.9 ± 1.7 mm, which was 0.1 ± 0.3 mm smaller compared to corresponding 3D-based diameter. CONCLUSIONS: In healthy radial heads, the diameter was biased to the dominant right side, but individual differences were not larger than 1 mm. Compared to implant designs, in which diameter increments are usually 2 mm, this right-bias is not clinically relevant, as it would not affect implant selection. Therefore, the contralateral side can be considered a suitable reference. In clinical practice, the surgeon could estimate this diameter using standard axial CT slices, since its difference with the 3D-based evaluation was also relatively small compared to implant sizing increments.

Factors Associated with Patient Delay in Scaphoid Nonunions.

Delay in seeking medical attention by patients, ─so-called patient delay, contributes to the relative high rate of delayed diagnosis and treatment in scaphoid nonunion cases. In this retrospective study we investigated the incidence of patients with a patient delay exceeding 6 months, thus by definition having an established nonunion. In addition to this, we investigated demographic, injury and patient related factors associated with this patient delay in scaphoid nonunion patients. We included 101 patients with established scaphoid nonunions treated surgically at our specialized hand surgery unit. Information regarding demographic and injury characteristics, and subjective patient related factors was obtained from medical records and a questionnaire-based survey. Sixty-four patients (63 %) responded to our survey. A quarter (25 %) of the patients showed a delay of more than 6 months. Demographic and injury characteristics were not related to this delay. In contrast to this, not attributing post-injury symptoms to a fracture but to e.g. a sprain instead, showed to be an independent predictor of patient delay. We report a high incidence of patients with an established scaphoid nonunion who delayed seeking medical attention. As there appears to be no demographic or injury characteristics associated with this patient delay, future developments of strategies to reduce patient delay should be targeted on all patients with a suspected scaphoid injury.

Three-Dimensional Assessment of Bilateral Symmetry of the Scaphoid: An Anatomic Study.

Preoperative 3D CT imaging techniques provide displacement analysis of the distal scaphoid fragment in 3D space, using the matched opposite scaphoid as reference. Its accuracy depends on the presence of anatomical bilateral symmetry, which has not been investigated yet using similar techniques. Our purpose was to investigate symmetry by comparing the relative positions of distal and proximal poles between sides. We used bilateral CT scans of 19 adult healthy volunteers to obtain 3D scaphoid models. Left proximal and distal poles were matched to corresponding mirrored right sides. The left-to-right positional differences between poles were quantified in terms of three translational and three rotational parameters. The mean (SD) of ulnar, dorsal, and distal translational differences of distal poles relative to proximal poles was 0.1 (0.6); 0.4 (1.2); 0.2 (0.6) mm and that of palmar rotation, ulnar deviation, and pronation differences was -1.1 (4.9); -1.5 (3.3); 1.0 (3.7)°, respectively. These differences did not significantly differ from zero and thus were not biased to left or right side. We proved that, on average, the articular surfaces of scaphoid poles were symmetrically aligned in 3D space. This suggests that the contralateral scaphoid can serve as reference in corrective surgery. No level of evidence is available.

Quantifying scaphoid malalignment based upon height-to-length ratios obtained by 3-dimensional computed tomography.

PURPOSE: To determine if 3-dimensional height-to-length (H/L) measurements including coronal plane assessment will improve malalignment detection of scaphoid fractures and to determine if more waist than proximal pole nonunions are malaligned. METHODS: Computed tomography scans of uninjured wrists (n = 74) were used to obtain 3-dimensional models of healthy scaphoids. These models were used to determine 95% normal ranges of the H/L ratio in standard sagittal and coronal planes in an automated fashion. Subsequently, the H/L ratios of fibrous nonunions (n = 26) were compared with these normal ranges and were classified as either aligned or malaligned. RESULTS: The mean normal H/L ratio in the sagittal plane was 0.61 (range, 0.54-0.69) and in the coronal plane 0.42 (range, 0.36-0.48). The mean H/L ratios of the nonunions differed from those of the healthy scaphoids in these planes: 0.65 and 0.48, respectively. Based on sagittal plane evaluation of all nonunions, 46% exceeded the normal H/L range versus 54% based on combining sagittal and coronal plane measurements. More waist nonunions (71%) than proximal pole nonunions (22%) exceed the normal H/L range. CONCLUSIONS: Evaluation of the H/L ratio in the coronal plane provided valuable additional information for the detection of scaphoid deformities. More malaligned cases were found for waist nonunions than for proximal pole nonunions. CLINICAL RELEVANCE: This method may be a helpful diagnostic tool to detect malalignment and to choose between in situ fixation or reconstruction.

Medical student attitudes to the autopsy and its utility in medical education: a brief qualitative study at one UK medical school.

Attending postmortems enables students to learn anatomy and pathology within a clinical context, provides insights into effects of treatment and introduces the reality that patients die. Rates of clinical autopsies have declined and medical schools have cut obligatory autopsy sessions from their curricula making it difficult to assess medical student perceptions of, and attitudes towards, the educational value of autopsy. Our aim was to investigate these perceptions by designing a brief qualitative study comprising nominal technique and focus group discussions with Cambridge Graduate Course students, all of whom had attended autopsies. Three general themes emerged from the focus group discussions: the value of autopsy as a teaching tool and ways the experience could be improved, the initial impact of the mortuary and the autopsy itself, and the "emerging patient"-an emotional continuum running from cadaver to autopsy subject and living patient. Educational benefits of autopsy-based teaching included greater understanding of anatomy and physiology, greater appreciation of the role of other health care professionals and an enhanced appreciation of psycho-social aspects of medical practice. Students suggested improvements for ameliorating the difficult emotional consequences of attendance. We conclude that autopsy-based teaching represents a low-cost teaching technique which is highly valued by students and has application to many diverse medical specialties and skills. However, careful preparation and organization of sessions is required to maximize potential educational benefits and reduce any negative emotional impact.