Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study.

Common variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Maori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

Comparison of 3-day and 7-day recall periods for food consumption reference values in foodborne disease outbreak investigations.

Investigations into an outbreak of foodborne disease attempt to identify the source of illness as quickly as possible. Population-based reference values for food consumption can assist in investigation by providing comparison data for hypothesis generation and also strengthening the evidence associated with a food product through hypothesis testing. In 2014-2015 a national phone survey was conducted in Canada to collect data on food consumption patterns using a 3- or 7-day recall period. The resulting food consumption values over the two recall periods were compared. The majority of food products did not show a significant difference in the consumption over 3 days and 7 days. However, comparison of reference values from the 3-day recall period to data from an investigation into a Salmonella Infantis outbreak was shown to support the conclusion that chicken was the source of the outbreak whereas the reference values from a 7-day recall did not support this finding. Reference values from multiple recall periods can assist in the hypothesis generation and hypothesis testing phase of foodborne outbreak investigations.

Serratia entomophila bet gene induction and the impact of glycine betaine accumulation on desiccation tolerance.

AIMS: The genes involved in choline transport and oxidation to glycine betaine in the biopesticidal bacterium Serratia entomophila were characterized, and the potential of osmoprotectants, coupled with increased NaCl concentrations, to improve the desiccation tolerance of this species was investigated. METHODS AND RESULTS: Serratia entomophila carries sequences similar to the Escherichia coli betTIBA genes encoding a choline transporter and dehydrogenase, a betaine aldehyde dehydrogenase and a regulatory protein. Disruption of betA abolished the ability of Ser. entomophila to utilize choline as a carbon source. Quantitative reverse-transcriptase PCR analysis revealed that betA transcription was reduced compared to that of the upstream genes in the operon, and that NaCl and choline induced bet gene expression. Glycine betaine and choline increased the NaCl tolerance of Ser. entomophila, and osmotically preconditioned cultures survived better than control cultures following desiccation and immediately after application to agricultural soil. CONCLUSIONS: Addition of glycine betaine and NaCl to growth medium can greatly enhance the desiccation survival of Ser. entomophila, and its initial survival in soil. SIGNIFICANCE AND IMPACT OF THE STUDY: Serratia entomophila is sensitive to desiccation and does not persist under low soil moisture conditions. Techniques described here for enhancing the desiccation survival of Ser. entomophila can be used to improve formulations of this bacterium, and allow its application under a wider range of environmental conditions.

Evaluation of the QBC Star centrifugal three-part differential haematology system.

The QBC Star haematology system includes the QBC Star centrifugal analytical analyser and the QBC Star tube system. Together, they are capable of producing a haematology profile on venous or capillary whole blood. The aim of this study is to compare full blood count (FBC) including differential white cell count performance between the QBC Star analyser and a gold standard Sysmex XE-2100 haematology analyser. The FBC performance was evaluated according to the National Committee for Clinical Laboratory Standards (NCCLS) document H20-A. Imprecision, correlation and linearity studies all showed excellent results. Overall, the haemoglobin, haematocrit, white cell count (WCC) and platelet count parameters showed excellent correlation. Mean corpuscular haemoglobin concentration (MCHC) results showed poor comparability. The white cell differential parameters showed good correlation within certain clinically significant limits. Imprecision for haemoglobin, haematocrit, WCC, MCHC and platelet count was considered acceptable. The re-read function was found to be stable over the five-hour testing period under the authors' laboratory environmental conditions. The subjective assessment by biomedical scientist staff demonstrated that the system was user friendly, required little maintenance, and no user calibration was required. Staff considered the user manual to be excellent. Overall, the QBC Star appears to be an excellent point-of-care (POC) dry haematology analyser that delivers clinically significant nine-parameter complete blood count and will make a good POC analyser for use in field hospitals, research, screening programmes, GP surgeries as well as in emergency and intensive care units. It is a health and safety-friendly analyser considering the fact that it uses dry haematology reagents instead of the bulky wet reagents that are often associated with liquid biohazard waste.

C1 fixation and classical complement pathway activation by a fragment of the Cmu4 domain of IgM.

A 56 residue fragment derived from a Waldenströme IgM protein and consisting of 24 residues of the amino-terminal portion of the Cmu4 domain disulfide bonded to 32 residues of the carboxy-terminal region of the loop has been shown to fix active C1 (C1) in a C1-fixation assay. Cleavage of the disulfide bond within the CH4 fragment resulted in a marked decrease of C1-fixing ability, although the isolated A and B fragments did retain a limited ability to fix C1. Upon incubation with normal human serum the intact CH4 fragment and equal molar amounts of the isolated A and B peptides consumed C4 suggesting that the C1-activating determinant of IgM remains intact in these three fragments. Furthermore, on a molar basis the intact or the reduced CH4 fragment consumed C4 as effectively as each of its component chains suggesting that transient binding of C1 by the individual A and B peptide chains is sufficient to activate C1. On the basis of these observations it is proposed that a classical complement fixation function, i.e. C1 binding and activation, can be localized within a region of the IgM molecule corresponding to the Cmu4 domain.

The structural basis for binding of complement by immunoglobulin M.

An insight into the structural features of human IgM that are responsible for its capacity to bind the first component of complement (C) has been obtained by examining the ability of IgM subfragments to bind active C1 (C1). The smallest two fragments found to bind C1 were the major CNBr fragment of the Fc portion of IgM and the C(H)4 fragment of the carboxy-terminal domain. The smallest fragment which fixes C1 has a disaggregated mol wt of 6,800, consists of 60 residues, and contains no carbohydrate. Structural considerations and sequence overlaps suggest that the amino-terminal side of the C(H)4 domain (24 amino acid residues) might be responsible for fixing C1.

Phenotypic changes and the fate of digestive enzymes during induction of amber disease in larvae of the New Zealand grass grub (Costelytra zealandica).

Amber disease of the New Zealand grass grub Costelytra zealandica (Coleoptera: Scarabaeidae) is caused by ingestion of pADAP plasmid carrying isolates of Serratia entomophila or Serratia proteamaculans (Enterobacteriaceae) and causes infected larvae to cease feeding and clear their midgut to a pale amber colour where midgut serine protease activities are virtually eliminated. Using bacterial strains and mutants expressing combinations of the anti-feeding (afp) and gut clearance (sep) gene clusters from pADAP, we manipulated the disease phenotype and demonstrated directly the relationship between gene clusters, phenotype and loss of enzyme activity. Treatment with afp-expressing strains caused cessation of feeding without gut clearance where midgut protease activity was maintained at levels similar to that of healthy larvae. Treatment with strains expressing sep-genes caused gut clearance followed by a virtual elimination of trypsin and chymotrypsin titre in the midgut indicating both the loss of pre-existing enzyme from the lumen and a failure to replenish enzyme levels in this region by secretion from the epithelium. Monitoring of enzymatic activity through the alimentary tract during expression of disease showed that loss of serine protease activity in the midgut was matched by a surge of protease activity in the hindgut and frass pellets, indicating a flushing and elimination of the midgut contents. The blocking of enzyme secretion through amber disease appears to be selective as leucine aminopeptidase and alpha-amylase were still detected in the midgut of diseased larvae.

Serine proteases identified from a Costelytra zealandica (White) (Coleoptera: Scarabaeidae) midgut EST library and their expression through insect development.

Costelytra zealandica larvae are pests of New Zealand pastures causing damage by feeding on the roots of grasses and clovers. The major larval protein digestive enzymes are serine proteases (SPs), which are targets for disruption in pest control. An expressed sequence tag (EST) library from healthy, third instar larval midgut tissue was constructed and analysed to determine the composition and regulation of proteases in the C. zealandica larval midgut. Gene mining identified three trypsin-like and 11 chymotrypsin-like SPs spread among four major subgroups. Representative SPs were examined by quantitative PCR and enzyme activity assayed across developmental stages. The serine protease genes examined were expressed throughout feeding stages and downregulated in nonfeeding stages. The study will improve targeting of protease inhibitors and bacterial disruptors of SP synthesis.

Boron-Doped C24 Fullerenes for Alkyl Functionalization or Potential Polymerization.

Replacing a single carbon atom in C24 with a boron atom allows the functionalization of one additional carbon atom. Such a process involves little energy cost with regard to the structure of the fullerene. Two such replacements are required if the fullerenes are to act as "pearls on a string". This work shows trends for increasingly higher levels of carbon replacement with boron as well as hydrogenation, methylation, and ethylation of a subsequent carbon atom in such a boron-doped small fullerene. Additionally, dimers are shown to be stable, and the linking ethyl groups actually stabilize the overall structure more than when the ethyl groups are on the surface of the structure and are not serving as linkers. Such stringed fullerenes would certainly have applications to materials science if polymers could be made from these stringed pearls and would be suitable for neutron radiation shielding in spacecraft or spacesuits.

A comparative analysis of the C1-binding ability of fragments derived from complement-fixing and noncomplement-fixing IgM proteins.

The purpose of this study was to examine the molecular parameters necessary for initiation of complement fixation by IgM proteins. To determine why some IgM molecules are capable of complement fixation while others are not, several different Waldenström IgM proteins were examined for their ability to fix total hemolytic complement in the CH(50) assay. Subsequently, the C1 fixing ability of a 56-residue fragment derived from the Cmu4 domain of each of these IgM molecules was studied with C1 fixation assay. One of the three Waldenström IgM proteins (Gr) used in the present study was found unable to consume complement in a CH(50) assay when tested at the same concentration as the two complement-consuming IgM molecules (Dau and Bus). However, when the 56-residue C(H)4 fragment from the Cmu4 domain of each IgM molecule was tested for C1-fixing ability, all three were found to bind C1. On the basis of these observations, it is proposed that a C1 binding site exists within the Cmu4 domain of both complement-fixing and noncomplement-fixing IgM molecules. Presumably, the latter molecules are unable to interact in their native state with C1 in the manner required for initiation of the classical complement pathway, possibly due to the configurational inaccessibility of the entire C1 binding site.

Structure and gene cluster of a tyvelose-containing O-polysaccharide of an entomopathogenic bacterium Yersinia entomophaga MH96T related to Yersinia pseudotuberculosis.

An O-polysaccharide was isolated from the lipopolysaccharide of an entomopathogenic bacterium Yersinia entomophaga MH96T by mild acid hydrolysis and studied by 2D NMR spectroscopy. The following structure of the branched tetrasaccharide repeating unit of the polysaccharide was established: where Tyv indicates 3,6-dideoxy-d-arabino-hexose (tyvelose). The structure established is consistent with the gene content of the O-antigen gene cluster. The O-polysaccharide structure and gene cluster of Y. entomophaga are related to those of some Y. pseudotuberculosis serotypes.

Association of US Centers for Medicare and Medicaid Services Hospital 30-Day Risk-Standardized Readmission Metric With Care Quality and Outcomes After Acute Myocardial Infarction: Findings From the National Cardiovascular Data Registry/Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines.

Importance: The US Centers for Medicare and Medicaid Services Hospital Readmissions Reduction Program penalizes hospitals with higher-than-expected risk-adjusted 30-day readmission rates (excess readmission ratio [ERR] > 1) after acute myocardial infarction (MI). However, the association of ERR with MI care processes and outcomes are not well established. Objective: To evaluate the association between ERR for MI with in-hospital process of care measures and 1-year clinical outcomes. Design, Setting, and Participants: Observational analysis of hospitalized patients with MI from National Cardiovascular Data Registry/Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines centers subject to the first cycle of the Hospital Readmissions Reduction Program between July 1, 2008, and June 30, 2011. Exposures: The ERR for MI (MI-ERR) in 2011. Main Outcomes and Measures: Adherence to process of care measures during index hospitalization in the overall study population and risk of the composite outcome of mortality or all-cause readmission within 1 year of discharge and its individual components among participants with available Centers for Medicare and Medicaid Services-linked data. Results: The median ages of patients in the MI-ERR greater than 1 and tertiles 1, 2, and 3 of the MI-ERR greater than 1 groups were 64, 63, 64, and 63 years, respectively. Among 380 hospitals that treated a total of 176 644 patients with MI during the study period, 43% had MI-ERR greater than 1. The proportions of patients of black race, those with heart failure signs at admission, and bleeding complications increased with higher MI-ERR. There was no significant association between adherence to MI performance measures and MI-ERR (adjusted odds ratio, 0.94; 95% CI, 0.81-1.08, per 0.1-unit increase in MI-ERR for overall defect-free care). Among the 51 453 patients with 1-year outcomes data available, higher MI-ERR was associated with higher adjusted risk of the composite outcome and all-cause readmission within 1 year of discharge. This association was largely driven by readmissions early after discharge and was not significant in landmark analyses beginning 30 days after discharge. The MI-ERR was not associated with risk for mortality within 1 year of discharge in the overall and 30-day landmark analyses. Conclusions and Relevance: During the first cycle of the Hospital Readmissions Reduction Program, participating hospitals' risk-adjusted 30-day readmission rates following MI were not associated with in-hospital quality of MI care or clinical outcomes occurring after the first 30 days after discharge.

Short-term symptom change in outpatient psychiatric disorders.

Changes in symptomatology (Hopkins Symptom Checklist scales) during a three- to four-week period were observed in a group of subjects (symptomatic volunteers) who had specific psychiatric disorders (Research Diagnostic Criteria [RDC]) and who were not currently receiving or awaiting treatment. Four of the depressive disorder categories and two of the anxiety disorder categories showed a significant drop in the primary symptomatology. There was a differential effect of diagnosis on the amount of this "spontaneous" symptom reduction; for the HSCL scales depression and panic-phobic anxiety, the RDC disorders with the highest initial levels of those symptoms (major depressive disorder; panic anxiety disorder, combined panic-phobic anxiety disorder) showed the least reduction in that symptomatology.

Life changes. Do people really remember?

The question, "How well do people remember life changes?" was approached in a longitudinal study of nearly 400 healthy men in a responsible profession. Three scales for assessing life changes were administered by questionnaire at two examinations nine months apart. The subjects were asked to report life change events occurring during a specific six-month period--that which immediately preceded the first examination. For all three life change scales there was substantial forgetting over the interval between reports, with a second report yielding total scores 34% to 46% less than those from the first report for the same period. The amount of change over time varied greatly across persons. These findings raise serious questions about the validity of retrospective studies of life change and illness when the period being reported is greater than six months in the past. They do not, however, jeopardize the potential of the method for prospective studies.

Prevalence of depression over a 12-month period in a nonpatient population.

A nonpatient population of air traffic controllers, all of whom remained employed during the observation period, was examined monthly for one year for level of depression using the Zung Self-Rating Depression Scale. The average monthly prevalence of depression was 9.1%, with 7.0% at the symptom level, 1.9% at a level comparable to outpatients, and 0.2% with moderately severe levels. These figures were generally similar to those for other reported population groups, although exact comparisons were difficult because of the preselection for health in this population. Two patterns of depression were observed. One was characterized by an acute, episodic symptomatology returning to nonsymptomatic levels for most of the year, similar to Research Diagnostic Criteria (RDC) category "episodic minor depressive disorder." The other showed a chronic, fluctuating course with significant depressive symptomatology over half the year, similar to RDC category "chronic and intermittent minor depressive disorder."

The working mother in contemporary perspective: a review of the literature.

The purpose of this article is to provide a perspective on the dilemmas working mothers face due to the contradictory messages that emanate from both popular child-rearing books and clinical studies. A review of the working mothers' sections of popular child-rearing books, and an interdisciplinary review of research in the area of maternal employment over the last decade was conducted in order to assess current knowledge in the field. Both popular child-rearing books and books for the working mother tend to reflect the cultural norms of appropriate maternal behavior, but rarely include evidence from empirical research. Findings from a review of literature in medicine, psychology, sociology, and education are discussed in relation to effects of maternal employment on children and families. An understanding of recent research regarding maternal employment will enable the pediatrician to better respond to the needs of the working mothers and their families.

Displacement threshold hyperacuity as a predictor of postsurgical visual performance in patients with cataract.

PURPOSE: To evaluate the ability of Displacement Threshold Hyperacuity (DTH) in predicting the postoperative visual outcome in patients awaiting cataract surgery and discriminating between the relative performance of the neural and optical components of the visual system. To establish eventually the cut-off DTH values to be used clinically in the preoperative evaluation of patients with cataract. METHODS: Forty-five subjects admitted for extracapsular cataract extraction with implant were examined preoperatively and postoperatively. In addition to DTH, logMAR visual acuity (VA), contrast sensitivity, and a cataract classification system were used to obtain a more comprehensive assessment of the patient's visual performance. RESULTS: DTH was found to be sensitive to decreased macular function but relatively unaffected by the severity of the cataract; higher thresholds were associated with denser opacities. A preoperative threshold of 50 seconds of arc was found to be the upper limit under which normal macular function is likely. DTH sensitivity and specificity for decreased macular function was 1.00 and 0.8, respectively. CONCLUSIONS: If preoperative DTH is 50 seconds of arc or lower, the subject will achieve a postoperative logMAR VA better than 0.3 (Snellen equivalent 20/40). On the contrary, higher DTH seems to give no reliable information about the patient's visual function.

Lopinavir.

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.