Reference Protocol to Assess Analytical Performance of Higher Order Structural Analysis Measurements: Results from an Interlaboratory Comparison.

Measurements of protein higher order structure (HOS) provide important information on stability, potency, efficacy, immunogenicity, and biosimilarity of biopharmaceuticals, with a significant number of techniques and methods available to perform these measurements. The comparison of the analytical performance of HOS methods and the standardization of the results is, however, not a trivial task, due to the lack of reference protocols and reference measurement procedures. Here, we developed a protocol to structurally alter and compare samples of somatropin, a recombinant biotherapeutic, and describe the results obtained by using a number of techniques, methods and in different laboratories. This, with the final aim to provide tools and generate a pool of data to compare and benchmark analytical platforms and define method sensitivity to structural changes. Changes in somatropin HOS, induced by the presence of zinc at increasing concentrations, were observed, both globally and at more localized resolution, across many of the methods utilized in this study and with different sensitivities, suggesting the suitability of the protocol to improve understanding of inter- and cross-platform measurement comparability and assess analytical performance as appropriate.

[Face protective patches do not reduce facial pressure ulcers in a simulated model of non-invasive ventilation]. / Uso de parches protectores faciales no reduce la presión facial en un modelo simulado de ventilación mecánica no invasiva.

Noninvasive ventilation (NIV) frequently involves the development of facial pressure ulcers (FPU). Its prevention considers the empirical use of protective patches between skin and mask, in order to reduce the pressure exerted by it. OBJECTIVES: To evaluate the effect of protective patches on the pressure exerted by the facial mask, and its impact on the programmed ventilatory parameters. METHOD: Bilevel NIV simulated model using full face mask in phantom with a physiological airway (ALS PRO +) in supine position. Forehead, chin and cheekbones pressure were measured using 3 types of standard protective patches versus a control group using pressure sensors (Interlinks Electronics®). The values obtained with the protective patches-mask model were evaluated in the programmed variables maximum inspiratory flow (MIF)), expired tidal volume (Vte) and positive inspiratory pressure (IPAP), with Trilogy 100 ventilator, Respironics®. The programming and recording of the variables was carried out in 8 opportunities in each group by independent operators. RESULTS: There was no decrease in facial pressure with any of the protective patches compared to the control group. Moltopren increased facial pressure at all support points (p < 0.001), increased leakage, it decreased MIF, Vte and IPAP (p < 0.001). Hydrocolloid patches increased facial pressure only in the left cheekbone, increased leakage and decreased MIF. Polyurethane patches did not produce changes in facial pressure or ventilatory variables. CONCLUSION: The use of protective patches of moltopren, hydrocolloid and polyurethane transparent did not contribute to the decrease of the facial pressure. A deleterious effect of the moltopren and hydrocolloid patches was observed on the administration of ventilatory variables, concluding that the non-use of the protective patches allowed a better administration of the programmed parameters.

[High flow nasal cannula in infants: Experience in a critical patient unit]. / Cánula nasal de alto flujo en lactantes: experiencia en una unidad de paciente crítico.

INTRODUCTION: The high flow nasal cannula (HFNC) is a method of respiratory support that is increasingly being used in paediatrics due to its results and safety. OBJECTIVE: To determine the efficacy of HFNC, as well as to evaluate the factors related to its failure and complications associated with its use in infants. PATIENTS AND METHOD: An analysis was performed on the demographic, clinical, blood gas, and radiological data, as well as the complications of patients connected to a HFNC in a critical care unit between June 2012 and September 2014. A comparison was made between the patients who failed and those who responded to HFNC. A failure was considered as the need for further respiratory support during the first 48hours of connection. The Kolmogorov Smirnov, Mann-Whitney U, chi squared and the Exact Fisher test were used, as well as correlations and a binary logistic regression model for P≤.05. RESULTS: The study included 109 patients, with a median age and weight: 1 month (0.2-20 months) and 3.7kg (2-10kg); 95 percentile: 3.7 months and 5.7kg, respectively. The most frequent diagnosis and radiological pattern was bronchiolitis (53.2%) and interstitial infiltration (56%). Around 70.6% responded. There was a significant difference between failure and response in the diagnosis (P=.013), radiography (P=018), connection context (P<.0001), pCO2 (median 40.7mmHg [15.4-67 mmHg] versus 47.3mmHg [28.6-71.3mmHg], P=.004) and hours on HFNC (median 60.75hrs [5-621.5 hrs] versus 10.5hrs [1-29 hrs], P<.0001). The OR of the PCO2 ≥ 55mmHg for failure was 2.97 (95% CI; 1.08-8.17; P=.035). No patient died and no complications were recorded. CONCLUSION: The percentage success observed was similar to that published. In this sample, the failure of HFNC was only associated with an initial pCO2 ≥ 55mmHg. On there being no complications reported as regards it use, it is considered safe, although a randomised, controlled, multicentre study is required to compare and contrast these results.

Impact of the COVID-19 Pandemic on Outcomes for Patients with Lung Cancer Receiving Curative-intent Radiotherapy in the UK.

AIMS: Previous work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre's usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19-27). We present the impact of these changes on patient outcomes. MATERIALS AND METHODS: The COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression. RESULTS: Patient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I-II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661). CONCLUSION: This study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations.

Searching for better X-ray and γ-ray photodetectors: structure-composition properties of the TlPb2Br5-x I x quaternary system.

Developing X-ray and γ-ray detectors with stable operation at ambient temperature and high energy resolution is an open challenge. Here, we present an approach to search for new detector materials, combining binary photodetector compounds. More specifically, we explore quaternary TlPb2Br5-x I x compositions, relying on materials synergy between TlBr, TlI, and PbI2 photodetectors. We discover a broad solid solution in the TlPb2Br5-'TlPb2I5' section, which can be derived from a new quaternary compound, TlPb2BrI4, by partial substitution of Br by I atoms on the 4c site or by replacement of I by Br atoms on the 16l site. We carry out a thorough crystallographic analysis of the new TlPb2BrI4 compound and prepare a high-quality standardized structure file. We also complete the phase diagram of the TlPb2Br5-'TlPb2I5' section, based on 21 alloys. Furthermore, we synthesize a series of high quality centimeter-sized TlPb2Br5-x I x single crystals (x = 2, 2.5, 3, 3.5, 4, 4.5) by the Bridgman-Stockbarger method and study their structure and properties using a combination of experimental techniques (X-ray diffraction, X-ray photoelectron spectroscopy, and absorption spectroscopy) and theoretical calculations.

Changes in the Management of Patients having Radical Radiotherapy for Lung Cancer during the First Wave of the COVID-19 Pandemic in the UK.

AIMS: In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020. MATERIALS AND METHODS: Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression. RESULTS: In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease. CONCLUSIONS: The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes.

HDAC inhibitor-based therapies and haematological malignancy.

Reversible acetylation mediated by histone deacetylase (HDAC) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumour cells. Since HDAC inhibition prompts tumour cells to enter apoptosis, small-molecule HDAC inhibitors have been developed as a new class of mechanism-based anticancer agent, many of which have entered clinical trials. While the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumour types undergo a favourable response, in particular haematological malignancies. Vorinostat (suberoylanilide hydroxamic acid) has been approved for treating cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. Here, we discuss developments in our understanding of molecular events that underlie the anticancer effects of HDAC inhibitors and relate this information to the emerging clinical picture for the application of HDAC inhibitors in haematological malignancies.

Epstein-Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFbeta signaling pathways.

The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumors where it plays an essential role in the maintenance, replication and transcription of the EBV genome. Transcriptional profiling of EBNA1-expressing carcinoma cells demonstrated that EBNA1 also influences the expression of a range of cellular genes including those involved in translation, transcription and cell signaling. Of particular interest was the ability of EBNA1 to enhance expression of STAT1 and sensitize cells to interferon-induced STAT1 activation with resultant enhancement of major histocompatibility complex expression. A negative effect of EBNA1 on the expression of TGFbeta1-responsive betaig-h3 and PAI-1 genes was confirmed at the protein level in EBV-infected carcinoma cells. This effect resulted from the ability of EBNA1 to repress TGFbeta1-induced transcription via a reduction in the interaction of SMAD2 with SMAD4. More detailed analysis revealed that EBNA1 induces a lower steady-state level of SMAD2 protein as a consequence of increased protein turnover. These data show that EBNA1 can influence cellular gene transcription resulting in effects that may contribute to the development of EBV-associated tumors.

Women and minorities in orthopaedic residency programs.

Women and underrepresented minorities make up smaller proportions of orthopaedic residency programs than their numbers in medical school would predict, according to our evaluation of self-reported orthopaedic residency data from 1998 and 2001, as well as information on medical students published in 2002. Based on race, ethnicity, and sex, comparisons were made between students entering and graduating from medical school and those in orthopaedic residency programs. With few exceptions, the percentages of women and underrepresented minorities were statistically significantly lower among those training in orthopaedic residency programs compared with those same groups entering and graduating from medical school. The percentage of women and minorities in orthopaedic residency programs remained constant between 1998 and 2001. Further study is necessary to determine whether fewer students of color and women apply to orthopaedic residency programs because of lack of interest, lack of appropriate mentoring and role models, or other factors.

Cherenkov light production from the α-emitting decay chains of 223Ra, 212Pb, and 149Tb for Cherenkov Luminescence Imaging.

Cherenkov Luminescence Imaging (CLI) is a new method to image radioactive therapeutic and diagnostic agents, primarily in preclinical studies. This study used Geant4 and Python to generate the predicted Cherenkov light production as a function of time for a set of isotopic chains of interest for targeted alpha therapy: 223Ra, 212Pb, and 149Tb. All are shown to produce substantial Cherenkov light, though time delays between initial decays and the production of Cherenkov light requires caution in interpreting CLI.

A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin.

Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Aminocamptothecin (9-AC) is a water-insoluble derivative of camptothecin which has demonstrated impressive antitumor activity in preclinical models. While two other water-soluble derivatives, CPT-11 and topotecan, have successfully completed Phase I and Phase II testing, biochemical and tissue culture studies suggest that camptothecin analogues differ in characteristics which may be important in determining antitumor activity. We performed a Phase I trial of 9-AC to determine the pharmacokinetics, dose-limiting toxicity, and maximum tolerated dose of this agent when administered as a 72-h continuous i.v. infusion. Thirty-one patients with resistant solid cancers received 5-60 microgram/m2/h 9-AC for 72 h, repeated at 3-week intervals. The drug was administered in a vehicle containing dimethylacetamide, polyethylene glycol, and phosphoric acid. Blood samples were collected and the lactone (closed ring) form of 9-AC was quantitated. The maximum tolerated dose of 9-AC was determined to be 45 microgram/m2/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematological toxicities. Minimal responses were seen in patients with gastric, colon, and non-small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was observed, pooled data were fit to a two-compartment model, with a terminal half-life of 36 h. Analyses of topoisomerase protein levels in peripheral blood cells indicated decreases in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.

Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency.

Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of 22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5-42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI.

The snapping scapula in association with the thoracic outlet syndrome.

Thirteen of 100 patients treated for thoracic outlet syndrome by first-rib resection postoperatively developed an associated painful superior angle of the scapula, or snapping scapula syndrome. The scapula angle was painful in 15 scapulas and the pain persisted in these 13 patients. Resection of the superior angle of the scapula was performed on 9 patients (11 snapping scapulas) with complete relief of symptoms. We propose that snapping scapula syndrome be considered a causative factor for apparent failure of thoracic outlet surgery.

Ability of clinical isolates of group A streptococci to adhere to and invade HEp-2 epithelial cells.

Individual strains of group A streptococci (GAS) differ in virulence, but the reasons for these differences are incompletely understood. To determine if the ability of GAS to cause invasive disease corresponded with their capacity to adhere to or invade epithelial cells, 63 clinical isolates of GAS (40 from patients with systemic infection and 23 from superficial disease) were examined in quantitative assays of bacterial adhesion to and invasion of HEp-2 cells, a continuous line of human pharyngeal epithelial cells. The results showed that individual isolates of GAS varied considerably in their ability to adhere to and penetrate HEp-2 cells. However, on the whole, strains from patients with invasive disease adhered to cells in numbers c.1.5 greater than those from superficial infection. Paradoxically, strains from patients with invasive disease invaded HEp-2 cells to a significantly lesser extent than those from superficial sites, with a two-fold difference in invasion index (defined as the percentage of cell-associated bacteria located intracellularly). To determine if these differences were caused by differences in the production of hyaluronic acid capsule or M protein by the two groups of bacteria, the adherence and invasive capacities of bacteria carrying defined mutations in the genes for these factors were examined. Although M6-protein-deficient [corrected] bacteria were less adherent to HEp-2 cells than the wild-type, neither the hyaluronic acid capsule nor the M protein had a significant influence on the ability of GAS to adhere to or invade HEp-2 cells. The results of this study demonstrate that there are biological differences between GAS isolates associated with invasive and superficial diseases and that these differences can be demonstrated by an assay of bacterial adherence to and invasion of HEp-2 epithelial cells.

Results of upper plexus thoracic outlet syndrome operation.

A review of 181 patients with thoracic outlet syndrome treated in our clinic revealed that 22 (12%) showed symptoms of compression of the distal median nerve only. Although there are several distinct anatomic abnormalities involving the upper brachial plexus, a first rib resection using the transaxillary approach was found to relieve these patients' symptoms as well as it did in those who exhibited the classic findings of ulnar nerve paresthesias. A comparison of the patients' outcomes showed no appreciable differences in the results obtained in those with distal median nerve compression symptoms only, lower plexus involvement, or combined upper and lower plexus symptoms.

Using in-clerkship tests to identify students with insufficient knowledge and assessing the effect of counseling on final examination performance.

PURPOSE: To determine whether in-clerkship tests identify students with insufficient knowledge and whether counseling affects final examination pass rates. METHOD: The authors reviewed students' mean scores from two internal medicine clerkship tests at the Wright State University School of Medicine from February 1993 to July 1996. To determine the sensitivity and specificity of the tests for identifying students with insufficient knowledge, they compared students in the lowest quartile of clerkship test results with those who scored 290 or less on the end-of-clerkship National Board of Medical Examiners' (NBME) subject examination in medicine. The authors also compared the final examination pass rates of counseled and non-counseled students. RESULTS: Twenty-five students scored 290 or less on the NBME subject examination. Of those, 17 had low mean clerkship test scores (sensitivity of 68%). The specificity of a low mean clerkship test score was 81%. Counseling did not improve final examination pass rates. CONCLUSION: In-clerkship tests can identify students who are at risk of failing an end-of-clerkship examination. Because counseling may be insufficient to raise final examination pass rates, further study into the appropriate clerkship intervention for low-achievement students is needed.

Internal medicine residents' perceptions of the balance between service and education in their night-call activities.

PURPOSE: To quantify the workload of residents on night call and to determine the residents' perceptions of the balance between service and education in their night-call activities. METHOD: Twenty-two internal medicine residents--nine first-year residents and 13 senior residents (i.e., in their second, third, or fourth year)--kept logs of their night-call activities for two periods of 16 days each in 1991-92, at a 772-bed teaching hospital affiliated with Wright State University School of Medicine. The residents used the following five-point scale to rate each activity: 1, strictly service; 3, even balance; 5, strictly education. They also recorded the total times spent on various activities. Data were analyzed by using the independent and paired t-tests. RESULTS: Ninety-eight percent of the logs were returned. The first-year and senior residents did not differ significantly in times spent on logged events. Both the first-year and the senior residents perceived many night-call activities to be weighted toward education, especially those involving evaluation of acutely ill patients being considered for hospital admission (overall mean rating of 3.3). There was no striking difference between the first-year and senior residents' perceptions of the balance between service and education in their activities. CONCLUSION: The residents' perceptions of the relationship between service and education indicate that there was an even balance between the two. The educational aspects of night-call duties can and should remain an integral part of residents' training.

Impact of advanced trauma life support training on early trauma management.

To assess the impact of ATLS education on early trauma management, charts of patients with an ISS of 14 or greater were reviewed for a 1 year period before and after ATLS training of emergency room trauma care providers. There were 50 patients in the before ATLS group, with a mean age of 41.6 years and an ISS of 29.8, and 71 patients in the after ATLS group, with a mean age of 40.6 years and an ISS of 30.6. Of those parameters evaluated as measures of early assessment, only rectal examination was found to be performed significantly more frequently after ATLS training. The mortality rates of 26 percent before ATLS and 20 percent after ATLS were not significantly different. In evaluating assessment and management parameters in the patients who died, no airway management errors were found in the after ATLS group; however, there were more missed injuries in this group. We have concluded that ATLS instruction failed to produce a quantifiable improvement in patient assessment or outcome. Further studies directed at assessing the retention rate for ATLS education and determining the impact on clinical performance are needed.

Double-crush nerve compression in thoracic-outlet syndrome.

We studied 165 cases of thoracic-outlet syndrome in 142 patients in whom resection of the first rib had been performed. In seventy-three cases (44 per cent), there was compression of a nerve distally, as shown by electromyography and conduction studies. The most common secondary compression was carpal tunnel syndrome (forty-one cases). Thirteen patients needed an operation at three sites or more. Our results show that proximal compression of a nerve lessens its ability to withstand more distal compression. Once the diagnosis of thoracic-outlet syndrome has been made, the possibility of an additional distal compression neuropathy should be investigated.

Rotator cuff tears associated with os acromiale.

We studied the cases of eight patients, one with bilateral involvement, who had a rotator cuff tear and an associated lesion delineated roentgenographically - a separate fragment of the acromion that we believe to be an ununited ossification center of the acromion (os acromiale). In reviewing the literature, we found no mention of an association between a rotator cuff tear and os acromiale. It is highly unlikely that such an association is coincidental because it appears that in our patients abnormal motion existed through the site of fibrous union of the acromion and may have contributed to the impingement of the acromion on the rotator cuff. Repair of the rotator cuff with removal of the loose fragment of acromion was done in the six patients who had operative treatment.