An Applicant's Residency Program Region May Influence Where They Complete Fellowship.

The primary goal of this study was to determine if an applicant's geographic region of residency was associated with where they matched for fellowship. San Francisco Match (SF Match) provided results regarding applicant data and match results from 2014-2018 for orthopaedic subspecialties except hand and shoulder and elbow. Residency programs were divided into five regions: (Northeast [NE], Southeast [SE], Midwest [MW], Southwest [SW] and West [W]). The MW region had the fewest number of fellowship positions per applicant (0.62), the W region had the most (1.7). Applicants from each region were significantly (p < 0.0001) more likely to complete fellowship in the same region where they completed residency, and there were significant (p < 0.05) differences between regions for specific subspecialties. There are imbalances in terms of the number of applicants and specific fellowship spots available in each region. This imbalance seems important considering the strong associations found between the region in which an applicant completes residency and fellowship. Level of Evidence: Level 3. (Journal of Surgical Orthopaedic Advances 30(1):030-035, 2021).

Process quality indicators for musculoskeletal injuries in the emergency department.

OBJECTIVES: Measuring quality of care for musculoskeletal injuries presenting to the ED is important given their prevalence, variations in care, the associated morbidity and financial impacts and pressure to achieve time-based performance measures. Process quality indicators (QIs) provide a quantitative method to measure the actions taken during healthcare delivery. This study aimed to develop a set of process QIs to measure the quality of care for musculoskeletal injuries in the ED. METHODS: A multiphase mixed-methods study was undertaken from 2015 to 2018, commencing with a systematic review to identify existing musculoskeletal QIs. This review, along with current evidence regarding musculoskeletal injury management in the ED, informed an expert panel who developed a preliminary set of process QIs. The preliminary set was field tested at eight EDs in Queensland, Australia, to determine the validity, reliability, feasibility and usefulness of each QI. Prospective observational data collection and retrospective chart audits were used to score the process QIs. These results were presented to the expert panel who determined a final QI set. RESULTS: A total of 633 patients were recruited and 36 process QIs included in the final set. The QIs covered important domains of pain assessment and management, history taking and physical examination, appropriateness and timeliness of imaging, fracture management, mobility, patient information and discharge considerations including safety and referrals. The best performing QIs included the use of opioid sparing analgesics and avoiding prescription of 'just in case' opioids at discharge. The poorest performing QIs included the completion of spinal red flag questioning and referrals for fragility fractures. CONCLUSION: An evidence and best practice-based set of QIs has been developed to allow EDs to assess and quantify the quality of care for musculoskeletal presentations. This will allow EDs to compare and benchmark, leading to the optimisation of care for patients.

Characterization of the structural and protein recognition properties of hybrid PNA-DNA four-way junctions.

The objective of this study is to evaluate the structure and protein recognition properties of hybrid four-way junctions (4WJs) composed of DNA and peptide nucleic acid (PNA) strands. We compare a classic immobile DNA junction, J1, vs. six PNA-DNA junctions, including a number with blunt DNA ends and multiple PNA strands. Circular dichroism (CD) analysis reveals that hybrid 4WJs are composed of helices that possess structures intermediate between A- and B-form DNA, the apparent level of A-form structure correlates with the PNA content. The structure of hybrids that contain one PNA strand is sensitive to Mg(+2). For these constructs, the apparent B-form structure and conformational stability (Tm) increase in high Mg(+2). The blunt-ended junction, b4WJ-PNA3, possesses the highest B-form CD signals and Tm (40.1 °C) values vs. all hybrids and J1. Protein recognition studies are carried out using the recombinant DNA-binding protein, HMGB1b. HMGB1b binds the blunt ended single-PNA hybrids, b4WJ-PNA1 and b4WJ-PNA3, with high affinity. HMGB1b binds the multi-PNA hybrids, 4WJ-PNA1,3 and b4WJ-PNA1,3, but does not form stable protein-nucleic acid complexes. Protein interactions with hybrid 4WJs are influenced by the ratio of A- to B-form helices: hybrids with helices composed of higher levels of B-form structure preferentially associate with HMGB1b.

Thermodynamics of prediction.

A system responding to a stochastic driving signal can be interpreted as computing, by means of its dynamics, an implicit model of the environmental variables. The system's state retains information about past environmental fluctuations, and a fraction of this information is predictive of future ones. The remaining nonpredictive information reflects model complexity that does not improve predictive power, and thus represents the ineffectiveness of the model. We expose the fundamental equivalence between this model inefficiency and thermodynamic inefficiency, measured by dissipation. Our results hold arbitrarily far from thermodynamic equilibrium and are applicable to a wide range of systems, including biomolecular machines. They highlight a profound connection between the effective use of information and efficient thermodynamic operation: any system constructed to keep memory about its environment and to operate with maximal energetic efficiency has to be predictive.

Nuclease resistance and protein recognition properties of DNA and hybrid PNA-DNA four-way junctions.

Nucleic acids possess unique biochemical features that make them ideal candidates to inhibit "difficult to target" proteins. The limited stability of nucleic acids in vivo presents a major obstacle to their development as drugs. Here, immobile four-way junctions (4WJs) are used to target the DNA-binding cytokine, High Mobility Group B1. Hybrid 4WJs composed of DNA and peptide nucleic acids (PNA) are investigated. PNA possess enhanced nuclease stability vs. DNA. 4WJs are incubated with Exonuclease III and DNase I. The nuclease assays show that 4WJs containing multiple PNAs possess significantly higher stability. Circular dichroism assays are used to probe the groove topology of 4WJs with the minor groove binder, DAPI. The CD data indicates that multi-PNA 4WJs possess altered minor groove dimensions that reduces DAPI binding affinity. Logic suggests that the minor groove of multi-PNA hybrids possess significant perturbations to the topology and local electrostatic environment that prevents proper binding/recognition by nucleases and thus enhances stability.

Conformation and protein interactions of intramolecular DNA and phosphorothioate four-way junctions.

The objectives of this study are to evaluate the structure and protein recognition features of branched DNA four-way junctions in an effort to explore the therapeutic potential of these molecules. The classic immobile DNA 4WJ, J1, is used as a matrix to design novel intramolecular junctions including natural and phosphorothioate bonds. Here we have inserted H2-type mini-hairpins into the helical termini of the arms of J1 to generate four novel intramolecular four-way junctions. Hairpins are inserted to reduce end fraying and effectively eliminate potential nuclease binding sites. We compare the structure and protein recognition features of J1 with four intramolecular four-way junctions: i-J1, i-J1(PS1), i-J1(PS2) and i-J1(PS3). Circular dichroism studies suggest that the secondary structure of each intramolecular 4WJ is composed predominantly of B-form helices. Thermal unfolding studies indicate that intramolecular four-way junctions are significantly more stable than J1. The Tm values of the hairpin four-way junctions are 25.2° to 32.2°C higher than the control, J1. With respect to protein recognition, gel shift assays reveal that the DNA-binding proteins HMGBb1 and HMGB1 bind the hairpin four-way junctions with affinity levels similar to control, J1. To evaluate nuclease resistance, four-way junctions are incubated with DNase I, exonuclease III (Exo III) and T5 exonuclease (T5 Exo). The enzymes probe nucleic acid cleavage that occurs non-specifically (DNase I) and in a 5'→3' (T5 Exo) and 3'→5' direction (Exo III). The nuclease digestion assays clearly show that the intramolecular four-way junctions possess significantly higher nuclease resistance than the control, J1.

How the Reputation of Orthopaedic Residency Programs Is Associated with Orthopaedic Fellowship Match Results.

BACKGROUND: The primary goal of the present study was to determine if applicants from higher-ranking U.S. orthopaedic surgery residency programs match at a more desired position on their fellowship match-rank list compared with those applicants from lower-ranked residency programs. METHODS: San Francisco Match provided results regarding applicant data and match results from 2014 to 2018 for all orthopaedic subspecialties except the hand and the shoulder and elbow. Unmatched applicants and international medical graduates were excluded. Residency programs were divided into 5 tiers (with tier 1 being the highest-ranked residency programs and tier 5 being the lowest-ranked programs) on the basis of 2018 Doximity rankings of orthopaedic residency programs. Statistical analysis consisted of descriptive statistics, chi-square tests, and analysis of variance. RESULTS: Two thousand eight hundred and eleven applicants met inclusion criteria. Applicants from residency programs in tiers 1 and 2 applied to significantly fewer programs than those from tiers 3, 4, or 5 (p < 0.0001). Applicants from each tier were significantly more likely to attain interviews than applicants from all tiers below them (p < 0.01). Applicants from tier-1 residency programs matched at a significantly higher position on their rank list (p < 0.001) and were more desirably ranked by fellowship programs (p = 0.003) compared with all other tiers. CONCLUSIONS: Applicants from the highest-ranking residency programs apply to fewer programs, interview at a greater percentage of these programs, and are more likely to match to 1 of their top-ranking programs than applicants from lower-ranking programs. However, the association of the applicant match position with the program ranking appears to be most pronounced when it comes to fellowships selecting which applicants to interview. These findings may help future applicants when determining which programs to apply to during the match.

Musculoskeletal injury quality outcome indicators for the emergency department.

High standards of care for musculoskeletal injuries presenting to emergency departments (ED) must be maintained despite financial constraints, the model of care in place, or the pressure to reach time-based performance measures. Outcome quality indicators (QIs) provide a tangible way of assessing and improving the outcomes of health-care delivery. This study aimed to develop a set of outcome QIs for musculoskeletal injuries in the ED that are meaningful, valid, feasible to collect, simple to use for clinical quality improvement and chosen by experts in the field. The study used a multi-phase mixed methods design, commencing with a systematic review of available outcome QIs. An expert panel then developed a set of preliminary QIs based on the available scientific evidence. Prospective observational data collection was undertaken across eight EDs with subsequent retrospective chart audits, follow-up phone calls and audit of administrative databases. After statistical analysis, validated results were presented to the expert panel who discussed, refined and formally voted on a final outcome QI set. A total of 41 preliminary outcome QIs were field tested in EDs, with data collected on 633 patients. Using the field study results, the expert panel voted 11 outcome QIs into the final set. These covered effectiveness of pain management, timeliness to discharge, re-presentations to the ED and unplanned visits to health professionals in the community, missed injuries, opioids side effects and the patient experience. An evidence-based set of outcome quality indicators is now available to support clinical quality improvement of musculoskeletal injury care in the ED setting.

Affecting emergency department oxycodone discharge prescribing: An educational intervention.

OBJECTIVE: To describe the impact of an educational intervention for ED prescribers on discharge oxycodone prescribing both for the number of oxycodone prescriptions per 1000 discharged patients, and the number of tablets per prescription. Secondary outcomes included the quality of general practitioner communication. METHODS: An interrupted time series assessment was conducted in the ED of a tertiary referral hospital to establish the pre-intervention, peri-intervention and post-intervention prescribing profile of ED medical practitioners. Prescriber numbers were used to obtain drug data for all oxycodone-containing prescriptions from the Queensland Health Medicines Regulation and Quality Unit database. The intervention included education sessions, a staff information email, posters within the ED, and a patient brochure. It was conducted with relevant nurses, pharmacists and prescribing doctors. RESULTS: In the pre-intervention period, 656/17 371 (38 per 1000) discharged patients were prescribed oxycodone, compared to 180/5938 (30 per 1000) during the intervention, and 602/20 505 (29 per 1000) post-intervention. This equated to a decrease of 8 per 1000 (95% CI 5-12 per 1000) and a 22% (95% CI 13-31%) relative prescribing reduction. The mean total number of tablets of oxycodone per prescription decreased from 16.7 (SD 16.5) pre-intervention, to 12.7 (SD 6.0) peri-intervention, to 10.7 (SD 5.2) post-intervention. After the intervention, there was an increase in discharge communications to general practitioners by 15.4% (95% CI 9.7-21.1%). CONCLUSIONS: An ED prescriber-targeted intervention reduced overall prescribing of oxycodone and improved communication at discharge. The prescribing intervention is one strategy that may be used by ED medical staff to improve patient safety and opioid stewardship in Australia.

Interactions of recombinant HMGB proteins with branched RNA substrates.

The high mobility group protein HMGB1 is a highly abundant chromosomal protein known to interact preferentially with DNA that is branched, bent or otherwise structurally altered. Biologically the protein is thought to facilitate promoter attachment by transcription factors. Recently, however, HMGB1 has been shown to have biological roles beyond that of an architectural DNA-binding protein. Here we investigate the binding interactions of recombinant HMGB1 proteins with two branched RNA's E. coli 5S rRNA and the group I intron ribozyme from Azoarcus pre-tRNA(Ile). Using competitive electrophoretic mobility and circular dichroism binding assays, we show that HMGB proteins bind both substrates with high affinity. We also report that a recombinant rat HMGB protein, rHMGB1b, inhibits RNA cleavage by the ribozyme. These results raise the possibility that HMGB proteins possess structure dependent RNA binding activity and can modulate RNA processing as well as transcription.

The Hippocampus and Cortex Together Generate the Scalp EEG Ictal Discharge in Temporal Lobe Epilepsy.

PURPOSE: The scalp EEG ictal discharge in temporal lobe epilepsy is reportedly visible only after the intracranial discharge becomes well synchronized and present over 10 to 30 cm of cortex. We investigated the role of the hippocampal formation in the generation of the scalp EEG ictal discharge. METHODS: Intracranial EEG video monitors were recorded using simultaneous scalp, stereotaxic depth, and subdural strip electrodes in 19 subjects with temporal lobe epilepsy. The location, frequency, morphology, and timing of the initial ictal discharge, and subsequent ictal patterns, were examined in hippocampal formation, medial paleocortex, and lateral temporal neocortex electrocorticographic and scalp temporal EEG recordings. RESULTS: In every subject, a scalp ictal discharge was visible only after the intracranial ictal discharge had spread to involve the whole temporal lobe (hippocampal formation, medial paleocortex, and lateral temporal neocortex). Beta/gamma frequency and decremental electrocorticographic ictal discharges were never visualized in the EEG. The scalp EEG ictal discharge frequency was 2.4 to 10 Hz and appeared a median of 18 seconds after a faster frequency electrocorticographic initial ictal discharge, once the intracranial discharge slowed to an alpha, theta, or delta frequency. CONCLUSIONS: In temporal lobe epilepsy, an ictal pattern is not readily visible in the scalp EEG until the intracranial ictal discharge is ≤10 Hz and has propagated from its site of onset to involve the hippocampus, medial paleocortex, and lateral temporal neocortex.

Ethnographic analysis on the use of the electronic medical record for clinical handoff.

The objective of this study was to understand the social elements of clinical and organizational interactions of the key stakeholders in the specific context of an electronic dashboard used by the emergency department (ED) and inpatient medicine teams at the time of clinical referral and handover. An electronic handover function is utilised at the ED-inpatient interface at this institution and has given clinicians the ability to better communicate, monitor the department and strive to improve patient safety in streamline the delivery of care in the acute phase. This study uses an ethnographic qualitative research design incorporating semistructured interviews, participant observation on the ED floor and fieldwork notes. The setting for this research was in the ED at a tertiary University affiliated hospital. Triangulation was used to combine information obtained from multiple sources and information from fieldwork and interviews refined into useable chunks culminating in a thematic analysis. Thematic analysis yielded five central themes that reflected how the clinical staff utilised this IT system and why it had become embedded in the culture of clinical referral and handover. Efficient time management for improved patient flow was demonstrated, value added communication (at the interpersonal level), the building trust at the ED-inpatient interface, the maintenance of mutual respect across medical cultures and an overall enhancement of the quality of ED communication (in terms of the information available). A robust electronic handover process, resulted in an integrated approach to patient care by removing barriers to admission for medical inpatients, admitted via ED. The value proposition for patients was a more complete information transfer, both within the ED and between departments.

Supporting data for the characterization of PNA-DNA four-way junctions.

Holliday or DNA four-way junctions (4WJs) are cruciform/bent structures composed of four DNA duplexes. 4WJs are key intermediates in homologous genetic recombination and double-strand break repair. To investigate 4WJs in vitro, junctions are assembled using four asymmetric DNA strands. The presence of four asymmetric strands about the junction branch point eliminates branch migration, and effectively immobilizes the resulting 4WJ. The purpose of these experiments is to show that immobile 4WJs composed of DNA and peptide nucleic acids (PNAs) can be distinguished from contaminating labile nucleic acid structures. These data compare the electrophoretic mobility of hybrid PNA-DNA junctions vs. i) a classic immobile DNA 4WJ, J1 and ii) contaminating nucleic acid structures.

Non-classical helix-stabilizing interactions: C-H...O H-bonding between Phe and Glu side chains in alpha-helical peptides.

The classical picture of H-bonds has evolved considerably. In contrast to earlier expectations, C-H...O H-bonds are now known to be prevalent in both small organic and large biological systems. However, there are few reports on the energetic contribution of C-H...O H-bonds in protein or polypeptide systems and we do not know whether such interactions are stabilizing. Here we investigate C-H...O H-bonding interactions between Phe and Glu side chains by determining their effects on the helicity of model alpha-helical peptides using a combination of CD and NMR spectroscopy. The results suggest that Glu/Phe C-H...O H-bonding interactions stabilize helical structure, but only in the orientation Glu --> Phe (N --> C). Each Glu --> Phe (N --> C) interaction can contribute approximately -0.5 kcal mol(-1) to the stability of helical peptide. In the reverse orientation, Phe --> Glu (N --> C) appears to contribute negligibly. pH titrations provide further evidence for the existence of C-H...O H-bonds. The C-H...O H-bonding interactions in these peptides are insensitive to the screening effect of added neutral salt. Our results provide quantitative energetic information on C-H...O H-bonds that should be useful for empirical force-field calibration.

Imaging Brain Dynamics Using Independent Component Analysis.

The analysis of electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings is important both for basic brain research and for medical diagnosis and treatment. Independent component analysis (ICA) is an effective method for removing artifacts and separating sources of the brain signals from these recordings. A similar approach is proving useful for analyzing functional magnetic resonance brain imaging (fMRI) data. In this paper, we outline the assumptions underlying ICA and demonstrate its application to a variety of electrical and hemodynamic recordings from the human brain.

Interaction of HMG proteins and H1 with hybrid PNA-DNA junctions.

The objective of this study was to evaluate the effects of inserting peptide nucleic acid (PNA) sequences into the protein-binding surface of an immobilized four-way junction (4WJ). Here we compare the classic immobile DNA junction, J1, with two PNA containing hybrid junctions (4WJ-PNA1 and 4WJ-PNA3 ). The protein interactions of each 4WJ were evaluated using recombinant high mobility group proteins from rat (HMGB1b and HMGB1b/R26A) and human histone H1. In vitro studies show that both HMG and H1 proteins display high binding affinity toward 4WJ's. A 4WJ can access different conformations depending on ionic environment, most simply interpreted by a two-state equilibrium between: (i) an open-x state favored by absence of Mg(2+), low salt, and protein binding, and (ii) a compact stacked-x state favored by Mg(2+). 4WJ-PNA3, like J1, shifts readily from an open to stacked conformation in the presence of Mg(+2), while 4WJ-PNA1 does not. Circular dichroism spectra indicate that HMGB1b recognizes each of the hybrid junctions. H1, however, displays a strong preference for J1 relative to the hybrids. More extensive binding analysis revealed that HMGB1b binds J1 and 4WJ-PNA3 with nearly identical affinity (K(D)s) and 4WJ-PNA1 with two-fold lower affinity. Thus both the sequence/location of the PNA sequence and the protein determine the structural and protein recognition properties of 4WJs.

Reversible posterior leukoencephalopathy syndrome: a case presentation.

Reversible posterior leukoencephalopathy syndrome (RPLS) is encountered in many subspecialty areas of medical practice but is seen relatively infrequently by the neurodiagnostic technologist. There are several different names for this condition including: reversible posterior leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, posterior reversible encephalopathy syndrome, and hypertensive encephalopathy. A brief review of RPLS and the case presentation of a woman who developed eclampsia, temporary blindness, and recurrent seizures captured by EEG/video monitoring are presented in this paper EEG samples and brain magnetic resonance imaging (MRI) changes related to RPLS are highlighted.

Increased ictal discharge frequency and neocortex gliosis in lateral temporal lobe epilepsy.

PURPOSE: Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis has both a scalp EEG initial ictal discharge frequency, which is faster, and also an intracranial EEG onset site that is more restricted to the hippocampus, than lateral TLE without hippocampal sclerosis. This study was performed to determine if lateral TLE patients have either intracranial EEG neocortical initial ictal frequencies or measures of lateral neocortex (LNC) histopathology that differ from patients whose seizures start in medial or multiple temporal lobe areas. METHODS: Thirty-six TLE patients undergoing ictal depth and subdural strip electrode recordings were studied to determine the initial ictal discharge site (epileptogenic zone) within the temporal lobe and neocortical ictal frequency. In 25 patients, the number of reactive astrocytes in the neocortex and other measures of pathologic assessment of LNC were assessed. RESULTS: The initial neocortical ictal frequency was significantly faster when the initial ictal discharge was in the LNC ± medial paleocortex than either when it was in the hippocampus ± medial paleocortex or when it occurred simultaneously over the entire temporal lobe. Intracortical and Chaslin gliosis were both significantly greater when the initial ictal discharge was limited to the LNC than when it was in the hippocampus and/or medial paleocortex. CONCLUSIONS: Temporal lobe seizures originating in neocortex had a faster initial neocortical ictal frequency than seizures arising either medially in the hippocampus or widely over the whole temporal lobe. Epileptogenic zones limited to temporal neocortex were associated with greater intraneocortical and Chaslin gliosis compared with zones confined to medial structures.

Treatment of recalcitrant, multiply operated tibial nonunions with the RIA graft and rh-BMP2 using intramedullary nails.

Nonunions of the tibia continue to present some of the most difficult challenges in orthopaedic fracture care. Whether the consequence of the initial presenting injury, co-morbidity or subsequent attempts at fixation, the biological environment is often compromised. Compounding this problem is a lack of consensus on the best approach to addressing nonunited tibia fractures, placing them at risk for multiple, and sometimes ill-informed attempts at nonunion repair. We present nine cases of recalcitrant tibial nonunions which had previously undergone 4 or more attempts at repair treated with a protocol using RIA graft, rh-BMP2 and intramedullary nail fixation.

RD114 envelope proteins provide an effective and versatile approach to pseudotype lentiviral vectors.

Lentiviral vectors derived from the HIV-1 genome offer great promise for gene therapy due to their ability to transduce non-dividing cells and sustain long-term expression of transgenes. The majority of current lentiviral vectors are pseudotyped with the vesicular stomatitis viral envelope (VSV-G). VSV-G equips lentiviral vectors with a broad host cell tropism and increased stability. Increased particle stability enables viral supernatants to be concentrated by high-speed centrifugation to enhance their infectivity. Despite its efficacy, VSV-G is cytotoxic - a feature that prohibits the development of stable cell lines that constitutively express this envelope. Therefore, non-toxic envelope proteins are being investigated. RD114 is an attractive alternative because it also provides increased particle stability and its receptor is widely expressed on hematopoietic stem cells (HSCs). In this study, the packaging efficiency of three envelope proteins, RD114, RDpro and VSV-G, were evaluated with two lentiviral vectors (TRIP GFP and HPV-402). RDpro is an RD114-HIV chimera designed to pseudotype lentiviral vectors more efficiently. In transient systems, VSV-G generated titers of 10(8) and 10(7) viral particles/mL for TRIP GFP and HPV-402. RDpro possessed titers of 10(7) and 10(6), while RD114 titers were one log lower for each vector. Despite having relatively lower titers, RD114 proteins are less toxic; this was demonstrated in the extension of transient transfection reactions from 48 to 96 h. VSV-G transfections are generally limited to 48 h. In regard to gene therapy applications, we show that RDpro supernatants efficiently transduce peripheral blood HSCs. The versatility of RD114 envelopes was again demonstrated by using a 'mixed' expression system; composed of stably expressed RD114 envelope proteins to pseudotype lentiviral vectors generated in trans (titer range 10(3)-10(5)). Our data show that RD114 envelope proteins are effective and versatile constructs that could prove to be essential components of therapeutic lentiviral gene transfer systems.