Reliability of Hip Strength Assessment in Young Active People with Hip Dysplasia: An Examination in Student Circus Artists.

BACKGROUND: Developmental dysplasia of the hip (DDH) is common in performing artists and other young active individuals and involves abnormalities in bony morphology of the acetabulum and proximal femur that can negatively impact walking biomechanics, muscular strength, quality of life, and sleep. Rehabilitation for hip-related conditions should target known modifiable impairments such as hip muscle strength, though a reliable method of assessment in this population remains unclear. OBJECTIVE: To determine the inter- and intra-rater reliability of hip muscle strength assessments using handheld dynamometry (HHD) in young active circus artists with DDH. METHODS: Reliability of hip strength in all planes was assessed using HHD in 21 adult performing circus arts students (mean age 21.3 yrs [3.2]; 13 M, 5 F, 3 NB) with symptomatic radiologically and clinically diagnosed hip dysplasia. The reliability of average peak force and absolute peak force were expressed for each position tested. Reliability was assessed using intraclass correlation coefficients (ICC) with standard error of measurement (SEM) and minimal detectable change (MDC) values calculated to improve clinical interpretability. RESULTS: Good to excellent inter-rater reliability resulted for all hip muscle strength testing positions, ICC=0.88 (95%CI 0.70 to 0.95) to ICC=0.97 (0.92 to 0.99), except average peak hip flexion strength, ICC=0.71 (0.28 to 0.88). Absolute peak hip abduction, ICC=0.77 (0.16 to 0.94), and adduction strength, ICC=0.72 (-0.55 to 0.92), demonstrated the lowest intra-rater reliability. Transverse plane strength measures (rotation) produced the lowest SEM and MDC values followed by the frontal plane (abduction/adduction) and sagittal plane (flexion/extension). CONCLUSION: HHD is an appropriate and reliable method to assess hip muscle strength in circus artists with DDH.

The Impact of the COVID-19 Pandemic on the Number of Adolescents/Young Adults Seeking Eating Disorder-Related Care.

PURPOSE: The COVID-19 pandemic has led to the development and worsening of eating disorder (ED) symptoms in adolescents and young adults. In order to examine COVID-19-related trends in ED care-seeking at our institution. METHODS: We used interrupted time series regression to examine pre- and postpandemic monthly summary data of the following: (1) ED-related inpatient admissions for medical stabilization; (2) ED-related hospital bed-days; (3) completed outpatient ED assessments; and (4) ED outpatient care-related inquiries at a children's hospital in Boston, MA. RESULTS: Inpatient admissions, hospital bed-days, and outpatient care-related inquiries increased on average over time postpandemic compared to stable volume over time prepandemic (p < .01). Outpatient assessments decreased precipitously initially following COVID-19-related limitations, and rose quickly back to baseline. CONCLUSION: These results indicate increased need for ED-related care during the pandemic. Bolstering resources to meet the needs of these vulnerable patients is critical as the effects of the pandemic continue to be felt.

Flexibility and mobility of SARS-CoV-2-related protein structures.

The worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity. For example, for the SARS-CoV-2 spike protein-using its complete homo-trimer configuration with 2905 residues-our method identifies a large-scale opening and closing of the S1 subunit through movement of the S[Formula: see text] domain. We compute the full structural information of this process, allowing for docking studies with possible drug structures. In a dedicated database, we present similarly detailed results for the further, nearly 300, thus far resolved SARS-CoV-2-related protein structures in the PDB.

Validation of the Manchester spoken language development scale (MSLDS).

Introduction: Standardized outcome measures are importantfor accurately monitoring the language development of pre-lingually deaf children receiving auditory implants. Current commonly used outcome measures are time-consuming,limiting the practicality of regular testing. To address these limitations, the Manchester Spoken Language Development Scale (MSLDS) was developed as a quick and easily applicable interim measurement. This is an 11-point scale designed to provide a streamlined overview of a child's expressive language development. This study describes the MSLDS, evaluates its ease of use and inter-rater reliability, and outlines its application in the paediatric auditory implant population. Methods: Sixteen speech therapists and teachers for the deaf reviewed videos of paediatric cochlear implant assessmentsand rehabilitation sessions at a UK auditory implant centre. Twenty-five videos from fourteen children were used in this validation study. Reviewers were asked to evaluate a child's language development using the MSLDS by assigning a score for each video and to evaluate the ease of use of the scale. Each video wasrated by three different reviewers. Results: MSLDS scores showed a high degree of consistency between raters for each child. 8/25 (32%) videos demonstrated perfect agreement on the MSLDS. In 15/25 (60%) videos, there was a one-point difference between MSLDS scores. The remaining 2/25 (8%) videos varied by 2 points. Statistical analysis demonstrated an intra-class correlation coefficient (ICC) of 0.987, indicating a high level of agreement between users of the scale. Qualitative feedback from the raters suggested further modifications which have been incorporated into the scale. Conclusion: The high inter-rater agreement reflects the potential for the MSLDS to be a reliable tool for monitoring language development in the paediatric auditory implant population.

'Something in the way she moves': The functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI).

Protein disulfide isomerase (PDI) has diverse functions in the endoplasmic reticulum as catalyst of redox transfer, disulfide isomerization and oxidative protein folding, as molecular chaperone and in multi-subunit complexes. It interacts with an extraordinarily wide range of substrate and partner proteins, but there is only limited structural information on these interactions. Extensive evidence on the flexibility of PDI in solution is not matched by any detailed picture of the scope of its motion. A new rapid method for simulating the motion of large proteins provides detailed molecular trajectories for PDI demonstrating extensive changes in the relative orientation of its four domains, great variation in the distances between key sites and internal motion within the core ligand-binding domain. The review shows that these simulations are consistent with experimental evidence and provide insight into the functional capabilities conferred by the extensive flexible motion of PDI.

Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.

BACKGROUND: Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca(2+)-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly(204)Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals. RESULTS: In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca(2+) binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca(2+) during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder. CONCLUSIONS: We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca(2+) binding during biosynthesis.

A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents.

BACKGROUND: Anorexia nervosa (AN) is a serious disorder incurring high costs due to hospitalization. International treatments vary, with prolonged hospitalizations in Europe and shorter hospitalizations in the USA. Uncontrolled studies suggest that longer initial hospitalizations that normalize weight produce better outcomes and fewer admissions than shorter hospitalizations with lower discharge weights. This study aimed to compare the effectiveness of hospitalization for weight restoration (WR) to medical stabilization (MS) in adolescent AN. METHOD: We performed a randomized controlled trial (RCT) with 82 adolescents, aged 12-18 years, with a DSM-IV diagnosis of AN and medical instability, admitted to two pediatric units in Australia. Participants were randomized to shorter hospitalization for MS or longer hospitalization for WR to 90% expected body weight (EBW) for gender, age and height, both followed by 20 sessions of out-patient, manualized family-based treatment (FBT). RESULTS: The primary outcome was the number of hospital days, following initial admission, at the 12-month follow-up. Secondary outcomes were the total number of hospital days used up to 12 months and full remission, defined as healthy weight (>95% EBW) and a global Eating Disorder Examination (EDE) score within 1 standard deviation (s.d.) of published means. There was no significant difference between groups in hospital days following initial admission. There were significantly more total hospital days used and post-protocol FBT sessions in the WR group. There were no moderators of primary outcome but participants with higher eating psychopathology and compulsive features reported better clinical outcomes in the MS group. CONCLUSIONS: Outcomes are similar with hospitalizations for MS or WR when combined with FBT. Cost savings would result from combining shorter hospitalization with FBT.

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway.

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10(-5) M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding - differential affinity, rapid ligand exchange and conformational flexibility.

The Bristol Radiology Report Assessment Tool (BRRAT): developing a workplace-based assessment tool for radiology reporting skills.

AIM: To review the development of a workplace-based assessment tool to assess the quality of written radiology reports and assess its reliability, feasibility, and validity. MATERIALS AND METHODS: A comprehensive literature review and rigorous Delphi study enabled the development of the Bristol Radiology Report Assessment Tool (BRRAT), which consists of 19 questions and a global assessment score. Three assessors applied the assessment tool to 240 radiology reports provided by 24 radiology trainees. RESULTS: The reliability coefficient for the 19 questions was 0.79 and the equivalent coefficient for the global assessment scores was 0.67. Generalizability coefficients demonstrate that higher numbers of assessors and assessments are needed to reach acceptable levels of reliability for summative assessments due to assessor subjectivity. CONCLUSION: The study methodology gives good validity and strong foundation in best-practice. The assessment tool developed for radiology reporting is reliable and most suited to formative assessments.

The value of traditional vital signs, shock index, and age-based markers in predicting trauma mortality.

BACKGROUND: Systolic blood pressure (SBP), heart rate (HR), and respiratory rate are poor predictors of trauma outcome. We postulate that HR/SBP (shock index [SI]) and novel new markers SI × age (SIA), SBP / age (BPAI), maximum HR (220 - age) - HR (minpulse [MP]), and HR / maximum HR (pulse max index [PMI]) are better predictors of 48-hour mortality compared with traditional vital signs. METHODS: Data were extracted from the Trauma Audit and Research Network database. Exclusions included any head or spine injury and prehospital intubation or cardiac arrest. Area under receiver operator characteristic curve (AUROC) was determined for 48-hour mortality for all variables and age. A threshold for each marker was derived using the specificity (rule-in) cutoffs at both 90% and 95% from the receiver operator characteristic curve. Positive likelihood ratios were described for each marker's derived threshold. RESULTS: Vital signs, markers, and age were all significantly associated with 48-hour mortality (p < 0.001). HR, SBP, and respiratory rate fared worst overall (AUROC = 0.69, 0.66, and 0.66, respectively). SIA, MP, PMI, BPAI, and SI were significantly (p < 0.05) better than age at predicting 48-hour mortality (AUROC = 0.79, 0.77, 0.77, 0.74, 0.73, and 0.68, respectively; AUROC for age = 0.68). Thresholds derived for these five markers were values 55 or greater, 44 or less, 70% or greater, 1.5 or less, and 0.9 or greater, respectively, each with a specificity of 95% for 48-hour mortality (positive likelihood ratios were 8.4, 6.1, 6.7, 6.6, and 7.5, respectively). The likelihood of death in 48 hours was 8.4 times more likely if SIA was greater than 55 than if it was lower. CONCLUSION: Older age seems to be significantly associated with early mortality. Newer markers, especially those combining traditional vital signs with age (SIA, BPAI, MP, and PMI), may contribute to better trauma triage of patients with blunt injuries than traditional vital signs. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III.

High-resolution NMR studies of structure and dynamics of human ERp27 indicate extensive interdomain flexibility.

ERp27 (endoplasmic reticulum protein 27.7 kDa) is a homologue of PDI (protein disulfide-isomerase) localized to the endoplasmic reticulum. ERp27 is predicted to consist of two thioredoxin-fold domains homologous with the non-catalytic b and b' domains of PDI. The structure in solution of the N-terminal b-like domain of ERp27 was solved using high-resolution NMR data. The structure confirms that it has the thioredoxin fold and that ERp27 is a member of the PDI family. (15)N-NMR relaxation data were obtained and ModelFree analysis highlighted limited exchange contributions and slow internal motions, and indicated that the domain has an average order parameter S(2) of 0.79. Comparison of the single-domain structure determined in the present study with the equivalent domain within full-length ERp27, determined independently by X-ray diffraction, indicated very close agreement. The domain interface inferred from NMR data in solution was much more extensive than that observed in the X-ray structure, suggesting that the domains flex independently and that crystallization selects one specific interdomain orientation. This led us to apply a new rapid method to simulate the flexibility of the full-length protein, establishing that the domains show considerable freedom to flex (tilt and twist) about the interdomain linker, consistent with the NMR data.

Assisting oxidative protein folding: how do protein disulphide-isomerases couple conformational and chemical processes in protein folding?

Oxidative folding is the simultaneous process of forming disulphide bonds and native structure in proteins. Pathways of oxidative folding are highly diverse and in eukaryotes are catalysed by protein disulphide isomerases (PDIs). PDI consists of four thioredoxin-like domains, two of which contain active sites responsible for disulphide interchange reactions. The four domains are arranged in a horseshoe shape with the two active sites facing each other at the opening of the horseshoe. An extended hydrophobic surface at the bottom of the horseshoe is responsible for non-covalent, hydrophobic interactions with the folding protein. This binding site is capable of distinguishing between fully-folded and partially- or un-folded proteins. PDI is not only a catalyst of the formation of disulphide bonds, but also catalyses folding steps which involve significant conformational change in the folding protein. This review brings together the latest catalytic and structural data aimed at understanding how this is achieved.

The radiology report--are we getting the message across?

The radiology report is the primary method of communication between radiologist and referrer. Despite this, radiologists receive very little formal training regarding the structure of the radiology report and also its importance as a medico-legal document. We present a review of radiology reporting, highlighting the importance of report structure and language with the purpose of helping radiologists improve the clarity, brevity, pertinence, and readability of reports. We encourage radiologists to avoid hedging and strive to improve communication with referring clinicians.

Multiphase multidetector CT in the diagnosis of haemobilia: a potentially catastrophic ruptured hepatic artery aneurysm complicating the treatment of a patient with locally advanced rectal cancer.

Acute haemobilia is an unusual and potentially catastrophic cause of gastrointestinal bleeding. We describe such a case presenting as a rare complication of a hepatic artery aneurysm following the development and successful treatment of subacute bacterial endocarditis during a radical downstaging chemoradiotherapy regime for locally advanced rectal cancer. We suggest that multiphase multidetector-row CT can have an important role in the diagnosis of acute haemobilia and discuss imaging findings associated with the condition. This case raises awareness of benign conditions mimicking malignancy in oncological patients and reinforces the importance of reviewing historical imaging.

Plasticity of human protein disulfide isomerase: evidence for mobility around the X-linker region and its functional significance.

Protein disulfide isomerase (PDI), which consists of multiple domains arranged as abb'xa'c, is a key enzyme responsible for oxidative folding in the endoplasmic reticulum. In this work we focus on the conformational plasticity of this enzyme. Proteolysis of native human PDI (hPDI) by several proteases consistently targets sites in the C-terminal half of the molecule (x-linker and a' domain) leaving large fragments in which the N terminus is intact. Fluorescence studies on the W111F/W390F mutant of full-length PDI show that its fluorescence is dominated by Trp-347 in the x-linker which acts as an intrinsic reporter and indicates that this linker can move between "capped" and "uncapped" conformations in which it either occupies or exposes the major ligand binding site on the b' domain of hPDI. Studies with a range of constructs and mutants using intrinsic fluorescence, collision quenching, and extrinsic probe fluorescence (1-anilino-8-naphthalene sulfonate) show that the presence of the a' domain in full-length hPDI moderates the ability of the x-linker to generate the capped conformation (compared with shorter fragments) but does not abolish it. Hence, unlike yeast PDI, the major conformational plasticity of full-length hPDI concerns the mobility of the a' domain "arm" relative to the bb' "trunk" mediated by the x-linker. The chaperone and enzymatic activities of these constructs and mutants are consistent with the interpretation that the reversible interaction of the x-linker with the ligand binding site mediates access of protein substrates to this site.

Power and empowerment: fostering effective collaboration in meeting the needs of orphans and vulnerable children.

In sub-Saharan Africa, HIV/AIDS has resulted in a rapidly growing population of orphans and vulnerable children (OVC). These OVC have strained the traditional safety net provided by extended families to its breaking point. Increasingly, community-based initiatives are emerging to fill the gap. However, relatively little is known about these efforts and their effectiveness. This article looks at one such initiative in rural Tanzania, and explores the relationship between local communities that seek to empower themselves to address the needs of their OVC and external organisations that have the resources and power to help them. This case study describes the successful effort of a community to build a Centre housing its orphans, and the subsequent closure of that Centre despite its evident success, because of a conflict between internal and external interests. This case study is used as the basis of a broader discussion on how those with power, and communities seeking empowerment, are complexly intertwined.

Automated summaries of serious adverse events in the hepatitis C antiviral long-term treatment against cirrhosis trial.

BACKGROUND: Even though adverse event (AE) collection and official accounting are mandatory for clinical trials, there are limited detailed guidelines specifying how to summarize the event for reporting in a timely and expeditious manner. This article details the AE and serious adverse event (SAE) reporting summary developed for a large multi-center National Institutes of Health (NIH)-sponsored clinical trial. PURPOSE: To review and analyze the large volume of AE data reported by 10 sites (806 SAEs and 19,034 AEs from August 2000 to May 2007) the automated SAE summary was developed. It was designed to ensure timeliness and clarity in the complex process of AE review and reporting. METHODS: The AE and SAE case report forms (CRFs) as well as the automated SAE summary were developed within a database management system developed by the Data Coordinating Center (DCC) which allowed for web-based data entry at the DCC and 10 sites and offered immediate overall and site-specific reports accessible by the DCC, site, and NIH project staff. RESULTS: The automated SAE summary pulled data from multiple CRFs to create a succinct and informative summary and allowed for prompt and easy reporting to the regulatory agencies. The summary was adaptable to the needs of reviewers because of the availability of multiple search options.

Enhanced hydrogen and 1,3-propanediol production from glycerol by fermentation using mixed cultures.

The conversion of glycerol into high value products, such as hydrogen gas and 1,3-propanediol (PD), was examined using anaerobic fermentation with heat-treated mixed cultures. Glycerol fermentation produced 0.28 mol-H(2)/mol-glycerol (72 mL-H(2)/g-COD) and 0.69 mol-PD/mol-glycerol. Glucose fermentation using the same mixed cultures produced more hydrogen gas (1.06 mol-H(2)/mol-glucose) but no PD. Changing the source of inoculum affected gas production likely due to prior acclimation of bacteria to this type of substrate. Fermentation of the glycerol produced from biodiesel fuel production (70% glycerol content) produced 0.31 mol-H(2)/mol-glycerol (43 mL H(2)/g-COD) and 0.59 mol-PD/mol-glycerol. These are the highest yields yet reported for both hydrogen and 1,3-propanediol production from pure glycerol and the glycerol byproduct from biodiesel fuel production by fermentation using mixed cultures. These results demonstrate that production of biodiesel can be combined with production of hydrogen and 1,3-propanediol for maximum utilization of resources and minimization of waste.

Mapping of the ligand-binding site on the b' domain of human PDI: interaction with peptide ligands and the x-linker region.

PDI (protein disulfide-isomerase) catalyses the formation of native disulfide bonds of secretory proteins in the endoplasmic reticulum. PDI consists of four thioredoxin-like domains, of which two contain redox-active catalytic sites (a and a'), and two do not (b and b'). The b' domain is primarily responsible for substrate binding, although the nature and specificity of the substrate-binding site is still poorly understood. In the present study, we show that the b' domain of human PDI is in conformational exchange, but that its structure is stabilized by the addition of peptide ligands or by binding the x-linker region. The location of the ligand-binding site in b' was mapped by NMR chemical shift perturbation and found to consist primarily of residues from the core beta-sheet and alpha-helices 1 and 3. This site is where the x-linker region binds in the X-ray structure of b'x and we show that peptide ligands can compete with x binding at this site. The finding that x binds in the principal ligand-binding site of b' further supports the hypothesis that x functions to gate access to this site and so modulates PDI activity.