Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.

BACKGROUND: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. PATIENTS AND METHODS: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. RESULTS: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. CONCLUSIONS: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.

A new bound on excess frequency noise in second harmonic generation in PPKTP at the 10⁻¹9 level.

We report a bound on the relative frequency fluctuations in nonlinear second harmonic generation. A 1,064 nm Nd:YAG laser is used to read out the phase of a Mach-Zehnder interferometer while PPKTP, a nonlinear crystal, is placed in each arm to generate second harmonic light. By comparing the arm length difference of the Mach Zehnder as read out by the fundamental 1064 nm light, and its second harmonic at 532 nm, we can bound the excess frequency noise introduced in the harmonic generation process. We report an amplitude spectral density of frequency noise with total RMS frequency deviation of 3 mHz and a minimum value of 20 µHz/Hz½ over 250 seconds with a measurement bandwidth of 128 Hz, corresponding to an Allan deviation of 10⁻¹9 at 20 seconds.

The use of mobile technology to support work integrated learning in undergraduate nursing programs: An integrative review.

OBJECTIVES: Investigate the use of mobile technology to support Work Integrated Learning in undergraduate nursing programs. DESIGN: Integrative review with narrative synthesis. DATA SOURCES: Electronic databases searched in February 2021 included CINAHL, ERIC, MEDLINE and APA PsychInfo. REVIEW METHODS: The methodological framework described by Whittemore and Knafl (2005) guided this integrative review. A total of five (5) studies published between 2017 and 2020 were analysed and synthesised. RESULTS: Data was categorised into two themes: 1) Accessibility of Learning Resources, and 2) Effective and Timely Communication. Convenient and easy access to Learning Resources at the point of care improved students' confidence and competence to perform clinical skills, thereby reducing student's anxiety and increasing satisfaction rates. The accessibility to educational and skills-based resources also promoted patient safety at the point of care. Effective and Timely Communication improved engagement and collaboration between students, clinical facilitators and academics, enabling a more supportive environment that improved student autonomy and motivation for self-directed learning. The Effective and Timely Communication of student progression and assessment strategies was found to improve student engagement and motivation to be independent learners. CONCLUSION: This review contributes important knowledge because internationally there is a need to increase knowledge and understanding of how to best support Work Integrated Learning experiences of student nurses. Mobile technology has been recognised as an innovative tool in education, further research investigating its use to support Work Integrated Learning in undergraduate nursing programs is required.

Results from the first English stool bank using faecal microbiota transplant as a medicinal product for the treatment of Clostridioides difficile infection.

BACKGROUND: Faecal Microbiota Transplant (FMT) has improved outcomes for the treatment of Clostridioides difficile infection (CDI) compared to antibiotic therapy. FMT is classified as a medicinal product in the United Kingdom, similar to the USA and Canada, limiting supply via stool banks without appropriate licencing. In the largest UK cohort to date, we describe the clinical outcomes for 124 patients receiving FMT for recurrent or refractory CDI and present a framework to produce FMT as a licenced medicinal product. METHODS: Anonymous unrelated healthy donors, screened via health assessment and microbiological testing donated stool. In aerobic conditions FMT aliquots were prepared for immediate use or frozen storage, following a production framework developed to comply with Good Manufacturing Practice. Outcome measures were clinical response to FMT defined as resolution of diarrhoea within seven days and clinical cure defined as response without diarrhoea recurrence at 90 days. FINDINGS: Clinical response was 83·9% (95% CI 76·0%-90·0%) after one treatment. Clinical cure was 78·2% (95% CI 67·4%-89·0%) across the cohort. Refractory cases appeared to have a lower initial clinical response rate compared to recurrent cases, however at day 90 there were no differences observed between these groups. INTERPRETATION: The methodology developed here enabled successful licencing of FMT by The Medicines and Healthcare products Regulatory Agency as a medicinal product. This has widened the availability of FMT in the National Health Service via a stool bank and can be applied in other centres across the world to improve access to safe and quality assured treatments.

The social process of international migration.

The social process of network growth helps to explain the rapid increase in the migration of Mexicans to the United States during the 1970s. Migrant networks are webs of social ties that link potential migrants in sending communities to people in receiving societies, and their existence lowers the costs of international movement. With each person that becomes a migrant, the cost of migration is reduced for a set of friends and relatives, inducing them to migrate and further expanding the network. As a result of this dynamic interaction, network connections to the United States have become widespread throughout Mexico, and the probability of international migration from that country is high.

Natural Distribution of the Ixodes dammini spirochete.

Spirochetes believed to be the cause of Lyme disease were isolated from white-footed mice and white-tailed deer, the preferred natural hosts of Ixodes dammini, the tick vector. Evidence suggests that deer act as a reservoir of the disease and provide an overwintering mechanism for both spirochetes and adult ticks. Some tick larvae may acquire the spirochete by transovarial passage and the nymphal stage may transmit the disease to humans.

Use of sirolimus (rapamycin) to treat refractory Crohn's disease.

We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn's disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn's disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn's disease symptoms with the Harvey-Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn's disease.

Emergency nurses' knowledge and understanding of their role in recognising and responding to patients with sepsis: A qualitative study.

AIM: Sepsis is a significant and time-sensitive clinical concern for patients who present to Emergency Departments (EDs). Existing guidelines do not define nurses' roles in managing sepsis. This study explored ED nurses' experiences and perceptions around recognising and responding to patients with sepsis, and their awareness of sepsis screening and prognostic tools. The knowledge and insights gained from this study may be used to inform local and international ED policies, and enrich nursing educational packages that may be used to improve quality of patient care and patient outcomes. METHODS: Qualitative design incorporating semi-structured interviews with 14 ED nurses was undertaken. Thematic and consensus-based content analyses were used to explore transcripts. FINDINGS: Six key themes were identified; (1) contribution of the organisation, (2) appreciation of knowledge, (3) appreciation of clinical urgency, (4) appreciation of importance of staff supervision, (5) awareness of the importance of staff experience, and (6) awareness of the need to seek advice. CONCLUSION: ED nurses' identified deficits in their capacity to recognise and respond to patients with sepsis, despite their vital role within the multidisciplinary team that cares for patients with sepsis. The knowledge and insights gained from this study can be used to inform ED policies, to enrich context-specific educational packages that aim to improve quality of patient care and outcomes and identify areas for further research. Development and implementation of a nurse-inclusive sepsis pathway may address many deficits identified in this study.

Electric discharge machine for preparation of diamond anvil cell sample chambers.

We have designed and constructed a novel electric discharge machine designed primarily for the preparation of sample chambers in rhenium and stainless steel gaskets for diamond anvil cell experiments. Our design combines automatic stage movement with relatively low voltage (100 V) operation and routinely achieves a drilling/erosion speed of approximately 0.4 µm s-1. The machine is used for preparing 100 µm diameter sample chambers for diamond anvil cell experiments with 250 µm culets and has also been used to prepare 50 µm diameter sample chambers for diamond anvil cell experiments with 100 µm culets to access a pressure of 165 GPa.

Real-world use of fidaxomicin in a large UK tertiary hospital: how effective is it for treating recurrent disease?

All courses of fidaxomicin use in the study hospital were reviewed. It was used for first recurrence (six times), second recurrence (eight times) and one case of third recurrence. One patients received fidaxomicin as first-line treatment. Eight patients initially responded to therapy; of these, three patients were asymptomatic at 90 days, three patients remained asymptomatic at 30 days, and two patients had recurrences five and nine days after stopping therapy. Four patients failed to respond; of these, two patients required faecal transplantation and one patient required a colectomy. Two patients deteriorated and two patients died. Fidaxomicin was well tolerated. These findings suggest that the utility of fidaxomicin at this stage of infection is unclear.

Enhancing OSCE preparedness with video exemplars in undergraduate nursing students. A mixed method study.

BACKGROUND: Objective structured clinical examinations (OSCEs) are designed to assess clinical skill performance and competency of students in preparation for 'real world' clinical responsibilities. OSCEs are commonly used in health professional education and are typically associated with high levels of student anxiety, which may present a significant barrier to performance. Students, including nursing students, have identified that flexible access to exemplar OSCEs might reduce their anxiety and enable them to better prepare for such examinations. AIM: To implement and evaluate an innovative approach to preparing students for OSCEs in an undergraduate (registration) acute care nursing course. METHOD: A set of digitized OSCE exemplars were prepared and embedded in the University-based course website as part of usual course learning activities. Use of the exemplars was monitored, pre and post OSCE surveys were conducted, and qualitative data were collected to evaluate the approach. OSCE grades were also examined. FINDINGS: The online OSCE exemplars increased self-rated student confidence, knowledge, and capacity to prepare and provided clarity around assessment expectations. OSCE exemplars were accessed frequently and positively received; but did not impact on performance. CONCLUSION: Video exemplars aid student preparation for OSCEs, providing a flexible, innovative and clear example of the assessment process. Video exemplars improved self-rated student confidence and understanding of performance expectations, leading to increased engagement and reduced anxiety when preparing for the OSCE, but not overall OSCE performance. Such OSCE exemplars could be used to increase staff capacity and improve the quality of the student learning experience.

Prolonged Delayed Renal Graft Function Secondary to Venous Hypertension.

The case of a 39-year-old highly sensitized woman who underwent second renal transplantation after being on warfarin because of a history of frequent thromboses of her left femoral arteriovenous graft (AVG) is reported here. The patient received a flow cytometric positive crossmatch kidney transplant from a deceased donor. Her posttransplant course was complicated by prolonged delayed graft function (DGF) lasting for 9 months. Antibody-mediated rejection occurred in the immediate postoperative period. This resolved after treatment, and resolution was confirmed by repeat biopsy. Despite this, she had persistent DGF and remained dialysis dependent. A computed tomography scan due to the development of perinephric hematoma after posttransplant biopsy demonstrated venous collateralization around the allograft. At 7 months posttransplant, a venogram during declotting of AVG revealed chronic thrombus in the inferior vena cava (IVC) above the level of native renal veins with a venous gradient of 26 mmHg. After declotting of the graft, iliac venoplasty, and subsequent IVC stent, her renal function continues to improve with a most recent creatinine of 1.4 mg/dL at 36 months posttransplant. Venous hypertension secondary to IVC thrombosis in presence of patent femoral AVG should be considered as a rare cause of prolonged DGF.

Molecular markers in stored kidneys using perfluorocarbon-based preservation solution: preliminary results.

BACKGROUND: Delayed graft function (DGF) is a problem in kidney transplantation and cold ischemia has been identified as a risk factor. Perfluorocarbons (PFC) have an enhanced ability to dissolve and release oxygen. We evaluated histologically and a number of molecular changes induced by ischemia in stored kidneys with University of Wisconsin (UW) and PFC-based preservation solutions (PFC-UW). MATERIALS AND METHODS: ACI rats were used as kidney donors. UW (control group) or PFC-UW (study group) preservation solutions were used for kidney perfusion. All kidneys were stored at 4 degrees C for 12, 24, and 36 hours. After this time, intragraft histologic evaluation as well as mRNA HO-1 and iNOS levels were also analyzed. RESULTS: In the kidneys stored at 24 hours, mRNA HO-1 levels were elevated in the study group when compared with the control and mRNA iNOS was decreased. CONCLUSION: We observed overexpression of HO-1 and underexpression of iNOS in the kidney tissue stored with PFC-UW solution at 24 hours. These preliminary data suggest that increasing oxygen delivery by PFC added to the perfusion solution triggers cytoprotective mechanism in kidney transplantation.

Personal and ambient PM2.5 exposure assessment in the city of Agra.

Human exposure to fine particles can have significant harmful effects on the respiratory and cardiovascular system. To investigate daily exposure characteristics to PM2.5 with ambient concentrations in an urban environment, a personal exposure measurements were conducted for school children, office workers and at their residents, in the city of Taj 'Agra', India. In order to account for all the sources of particulate matter exposure, measurements on several different days during December 2013 to February 2014 were carried out. Personal environment monitors (PEM) and APM 550 were used to measure PM2.5 concentration. The research findings provide insight into possible sources and their interaction with human activities in modifying the human exposure levels.

Cytomegalovirus Infection and Rates of Antiviral Resistance Following Intestinal and Multivisceral Transplantation.

BACKGROUND: Cytomegalovirus (CMV) disease is a common and clinically significant complication following intestinal or multivisceral transplantation. CMV disease is more common in cases of serologic mismatch between donor and recipient. Though in some cases it may be asymptomatic, in the immunosuppressed population it often manifests with evidence of systemic infection or end-organ disease. METHODS: We conducted a retrospective review of all patients undergoing intestinal or multivisceral transplantation over 8 years at our institution. RESULTS: Forty-eight transplantations were performed, with 40% of the patients (19/48) having ≥1 episode of CMV viremia, which rose to 90% in the "donor-positive, recipient-negative" (DPRN) serologic mismatch group. The median time to 1st episode following transplantation was 22.3 weeks (range, 1-78) and median duration of each episode was 4.9 weeks (range, 1.6-37.4). Six of the 19 viremic patients (31.6%) developed virologic resistance with 4 of these occurring in the DPRN group. Four of the 6 patients with drug-resistant CMV died with CMV viremia. All patients with drug resistance acquired ganciclovir resistance; these patients were more challenging to manage with second-line toxicity-limited treatments, including foscarnet, cidofovir, and leflunomide. CMV immunoglobulin has been used and we briefly discuss the use of CMV-specific adoptive T-lymphocyte transfer in the management of 1 case. CONCLUSIONS: Post-transplantation CMV disease continues to be challenging to manage, and there is little consensus on optimal management strategies in this patient group, with a significant requirement for novel therapies; these may be pharmacologic or cell based. Extensive multidisciplinary discussion is important for most cases, but particularly for those patients who acquire virologic resistance.

The carbohydrate moiety of aminopeptidase N of rabbit intestinal brush-border membrane.

Endoglycosidase F was used to eliminate the N-linked complex glycans from intestinal aminopeptidase N. The glycans which were probably O-linked remaining after the endoglycosidase F treatment exhibited the human blood group A and H determinants expressed in enzymes from A+ or A- rabbits, respectively. The molecular mass estimation of the two types of glycans by SDS-polyacrylamide gel electrophoresis and the sugar composition of aminopeptidase from A+ and A- rabbits strongly suggested the presence of eight N-linked complex glycans and two O-linked oligosaccharides bearing the human group antigenicity.

Febrile reaction to inhaled acetylcysteine.

This report describes a hitherto unreported severe reaction to aerosolized acetylcysteine (Mucomyst). It was documented by bronchial provocation.

Recovery units: the future of postoperative cardiac care.

In the current climate of scarce financial resources health care managers have had to question the financial viability of a 36-hour stay in an ICU for patients undergoing cardiac surgery. The management of this group of patients has had to be reexamined. The solution to this problem appears to lie in the utilisation of a designated recovery area for the management of this group of patients. This paper is an audit of the first 100 cardiac patients who recovered in such a designated recovery unit. The audit examines types of operations performed, average length of time patients required artificial ventilation, blood loss in the first 4h, average length of stay in hospital, and postoperative complications. Possible methods of improving the utilisation of a recovery area in the management of postoperative cardiac patients are discussed. The conclusion is that utilisation of a designated recovery area for the immediate postoperative management of cardiac surgical patients is a financially viable alternative to an intensive care environment. More importantly, high quality service and care is maintained without increasing the utilisation of resources.