Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Subcutaneous emphysema and pneumomediastinum in patients with COVID-19 disease; case series from a tertiary care hospital in Pakistan.

Since December 2019, the clinical symptoms of coronavirus disease 2019 (COVID-19) and its complications are evolving. As the number of COVID patients requiring positive pressure ventilation is increasing, so is the incidence of subcutaneous emphysema (SE). We report 10 patients of COVID-19, with SE and pneumomediastinum. The mean age of the patients was 59 ± 8 years (range, 23-75). Majority of them were men (80%), and common symptoms were dyspnoea (100%), fever (80%) and cough (80%). None of them had any underlying lung disorder. All patients had acute respiratory distress syndrome on admission, with a median PaO2/FiO2 ratio of 122.5. Eight out of ten patients had spontaneous pneumomediastinum on their initial chest x-ray in the emergency department. The median duration of assisted ventilation before the development of SE was 5.5 days (interquartile range, 5-10 days). The highest positive end-expiratory pressure (PEEP) was 10 cmH2O for patients recieving invasive mechanical ventilation, while 8 cmH2O was the average PEEP in patients who had developed subcutaneous emphysema on non-invasive ventilation. All patients received corticosteroids while six also received tocilizumab, and seven received convalescent plasma therapy, respectively. Seven patients died during their hospital stay. All patients either survivor or non-survivor had prolonged hospital stay with an average of 14 days (range 8-25 days). Our findings suggest that it is lung damage secondary to inflammatory response due to COVID-19 triggered by the use of positive pressure ventilation which resulted in this complication. We conclude that the development of spontaneous pneumomediastinum and SE whenever present, is associated with poor outcome in critically ill COVID-19 ARDS patients.

Association of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Ureaplasma species infection and organism load with cervicitis in north Indian population.

Cervicitis is predominantly caused by Neisseria gonorrhoeae and Chlamydia trachomatis, which accounts for almost half of all the cases of cervicitis. The role of newer organisms like Mycoplasma genitalium and Ureaplasma sp. and association of bacterial load with cervicitis are also not well established. So the study aimed to determine the relative frequency of these organisms and their load in association with cervicitis cases from north India. A case-control study involving 300 women was conducted using quantitative real-time PCR from endocervical swabs for identification of organisms and quantification of bacterial load. Among 150 cervicitis cases, C. trachomatis, N. gonorrhoeae, M. genitalium and Ureaplasma parvum were detected in 5 (3·3%), 10 (6·6%), 37(24·6%) and 47 (31·3%) respectively. Old age (<0·001, chi-squared test) and irregular menstrual cycles (<0·001, chi-squared test) were significantly associated with cervicitis. M genitalium was the only organism to be associated significantly with cervicitis with regard to age (<0·031) and symptoms like discharge (P < 0·033, chi-squared test) and dysuria (P < 0·044, chi-squared test) in multivariate analysis. Our finding suggests that the bacterial load of these organisms is not significantly associated with cervicitis. However, we found significant association of M. genitalium infection with clinical characteristics of cervicitis cases.

Diagnostic accuracy of Xpert MTB/RIF ultra for detection of Mycobacterium tuberculosis in children: a prospective cohort study.

The Xpert MTB/RIF Ultra is a recent advancement in molecular diagnostics of tuberculosis (TB) with higher sensitivity compared to its predecessor, the Xpert MTB/RIF assay. Prospective studies evaluating the performance of Xpert MTB/RIF Ultra in children with suspected TB are lacking. In this study, we evaluated the Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis in samples from 156 children, of which one was excluded from the analysis. Of the remaining 155 samples, 6·5% (10/155), 21·3% (33/155), 20% (31/155) and 21·9% (34/155) were positive by smear examination, MGIT culture, Xpert MTB/RIF and Xpert MTB/RIF Ultra, respectively. The Xpert MTB/RIF and Xpert MTB/RIF Ultra had a similar overall sensitivity of 81·8% (95% CI: 64·5-93) and 84·8% (95% CI: 68·1-94·9), respectively. In suspected pediatric TB patients, the Xpert MTB/RIF Ultra had higher sensitivity compared to the Xpert MTB/RIF (72·7 vs 63·6). The AUC (area under the curve) of 0·905 for the Xpert MTB/RIF and 0·893 for the Xpert MTB/RIF Ultra indicate similar and good overall performance. Both Xpert assays were found to be equally efficient, however Xpert MTB/RIF Ultra showed better detection rate in suspected TB cases.

EUGLYCEMIC DIABETIC KETOACIDOSIS (EDKA) IN A PATIENT RECEIVING DAPAGLIFLOZIN.

SGLT-2 inhibitors have gained importance in recent years because of their cardio-protective and reno-protective properties in diabetes. SGLT-2 inhibitors, when introduced in diabetic patients, may cause euglycemic diabetic ketoacidosis. A 55-year-old woman presented with low-grade fever, vomiting, and lethargy. She was started on dapagliflozin two years back. On workup, she was diagnosed with euglycemic diabetic ketoacidosis (EDKA) and was managed accordingly. She improved clinically while her dapagliflozin was stopped. With a literature search, we have identified 15 case reports of EDKA with dapagliflozin since 2015. There are no standard guidelines regarding the monitoring of patients for this rare but potentially morbid complication. Moreover, the exact mechanism for this is unknown. Various precipitating factors are linked with SGLT-2 inhibitors in promoting EDKA. We recommend that customary plans should comprise educating the patient about this rare complication before commencing medication, close follow-up with serial electrolyte monitoring, and discontinuing medications in the state of infection, dehydration and recent surgery and serious illness requiring hospitalization.

Loop mediated isothermal amplification assay for detection of Trichomonas vaginalis in vaginal swabs among symptomatic women from North India.

Trichomonas vaginalis is one of the most common curable sexually transmitted pathogens infecting both men and women worldwide. Unlike traditional methods such as microscopy and culture, nucleic acid amplification tests rapidly detect this agent, assisting in treatment. Conventional polymerase chain reaction (PCR), the loop-mediated isothermal amplification (LAMP), and the Xpert TV assay were evaluated using 28 microscopy positive T. vaginalis samples and 125 microscopy negative samples from symptomatic females of reproductive age. The sensitivity of all tests was 100% and the specificity was 100%, 100%, and 99·2% for PCR, Xpert TV, and LAMP, respectively. The inter-rater reliability was excellent for PCR: Xpert TV (kappa-coefficient = 1) and good for LAMP assay: Xpert TV/PCR (kappa-coefficient = 0·98) and conventional PCR: LAMP (kappa-coefficient = 0·98). The study highlights the importance of PCR for screening T. vaginalis in women, particularly in laboratories where the Xpert-TV assay is not available or not affordable. The LAMP assay showed a lower positive predictive value which merits further evaluation. SIGNIFICANCE AND IMPACT OF THE STUDY: Trichomonas vaginalis is a common sexually transmitted pathogen associated with considerable morbidity and risk of complications. Due to the limitations of traditional diagnostic modalities, three molecular assays were compared: conventional polymerase chain reaction (PCR), Xpert TV assay, and loop mediated isothermal amplification (LAMP) assay for detecting T. vaginalis in symptomatic females. All tests had a sensitivity of 100% and the inter-rater reliability was excellent for PCR: Xpert TV, and good for LAMP assay: Xpert TV/PCR. The translational impact of this study lies in the possible use of conventional PCR and LAMP in laboratories where the Xpert TV assay is not available or not affordable.

A loop-mediated isothermal amplification assay for the diagnosis of pulmonary tuberculosis.

Quantitated Mycobacterium tuberculosis (M.tb) H37Rv DNA was used to analyse the sensitivity and the specificity was assessed using DNA isolated from the reference strain H37Rv, 12 nontuberculous mycobacterium (NTM) species and five nonmycobacterium species. Furthermore, performance of the assay was evaluated on the sputum samples and compared with smear microscopy, culture and PCR. mpt64 (also called mpb64 or Rv1980c) loop-mediated isothermal amplification (LAMP) successfully detected 1 pg DNA within 40 min and successfully rejected NTMs and other bacterial species tested. It specifically detected all the 119 confirmed TB cases and 100 of the 104 control cases. The resulting sensitivity and specificity of LAMP assay was found to be 100% (95% CI: 96·79-100%) and 96·15% (95% CI; 90·44-98·94%) respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: Loop-mediated isothermal amplification (LAMP) is a technique for isothermal DNA amplification suitable for cost-limited settings as it prevents the use of sophisticated instruments. Using mpt64 antigenic protein gene, we developed a LAMP assay especially for organisms of the M. tuberculosis complex. mpt64 LAMP assay showed 100% sensitivity and detected all the bacteriologically and clinically positive TB cases not detected by smear, culture or PCR methods.

Chemical and nutritional evaluation of major genotypes of nectarine (Prunus persica var nectarina) grown in North-Western Himalayas.

Nectarine is an important stone fruit after plum and peach. The area under peach cultivation is now getting replaced by nectarine due to its fuzzless nature and high nutritive value. Nectarines are juicy, delicious fruits having low calorific value and have high antioxidant capacity. In India, its cultivation is confined to North-Western and North-Eastern Himalayas. In this study, five major nectarine cultivars growing in India namely, 'Silver Queen', 'Red Gold', 'Spring Bright', 'Independence' and 'Missourie' were harvested at commercial maturity and analyzed for various chemical and nutritional aspects. Our results showed that there were quantitative differences among the genotypes in different parameters analyzed. The predominant sugar in nectarine was fructose which was highest in 'Silver Queen' (14.48 mg 100 g-1 FW) and lowest in 'Independence' (9.04 mg 100 g-1 FW). Major organic acids were malic, succinic, citric and acetic acid. The highest malic acid content was recorded in 'Independence' (1.13 mg 100 g-1 FW) and lowest in 'Red Gold' (0.61 mg 100 g-1 FW). Nectarine genotypes chiefly contained phloridizin dihydrate and chlorogenic acid as the phenolic component. However, chlorogenic acid was highest in 'Spring Bright' (17.63 µg g-1 FW) and lowest in 'Red Gold' (3.67 µg g-1 FW). Similarly, a wider variability was recorded in major and minor mineral concentrations among the genotypes. Based on these observations, it can be concluded that among the major nectarine varieties cultivated in India, 'Silver Queen' have higher mineral nutrients than other varieties, and 'Spring Bright' have higher phenolics and antioxidants.

Hemorrhagic Herpes Simplex Virus Type 1 Nephritis: An Unusual Cause of Acute Allograft Dysfunction.

Interstitial nephritis due to viruses is well-described after solid organ transplantation. Viruses implicated include cytomegalovirus; BK polyomavirus; Epstein-Barr virus; and, less commonly, adenovirus. We describe a rare case of hemorrhagic allograft nephritis due to herpes simplex virus type 1 at 10 days after living donor kidney transplantation. The patient had a favorable outcome with intravenous acyclovir and reduction of immunosuppression.

GenoType MTBDRplus assay for screening and characterization of isoniazid and rifampicin resistance-associated mutations in multidrug-resistant Mycobacterium tuberculosis from India.

Multidrug resistant tuberculosis (MDR-TB) is rising and the World Health Organization has recommended the line probe assay (LPA) for screening. In this study we assess LPA at a tertiary care centre from North India in 1758 samples from suspected MDR-TB cases. All smear-positive and/or Mycobacterium tuberculosis culture confirmed cases (n = 1170) were subjected to the GenoType-MTBDR assay. Amongst these the majority were retreatment cases, smear-positive at diagnosis (n = 637). An MDR prevalence of 7·8% was observed with the highest cases reported amongst MDR contacts (33·3%). The most common rifampicin resistance encoding mutation seen overall and in individual patient groups was H531L (53·3%). A higher prevalence of H526D mutation was observed in retreatment cases, smear-positive at 4 months of anti-tubercular therapy vs other patient groups (P = 0·052). The most common mutation encoding isoniazid resistance was S315T1 in the katG (79·9%) and C-15T in the inhA gene (91·1%). Thirty rifampicin and nine isoniazid resistant isolates had wild type gene deletion but no detectable mutation by LPA. Although LPA is a practical and rapid screening method for most mutations expected to result in MDR-TB, we observed that it only detects the known major mutations in specific genes. Such studies can provide the knowledge required to formulate customized strips based on prevalent mutations in our region and in specific patient groups. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge this is the largest study evaluating the GenoType-MTBDR line probe assay from India. We have studied the prevalence of mutations encoding rifampicin and isoniazid resistance in different patient groups based on criteria for multidrug resistance (MDR) suspicion. The translational impact of this study is in the design of customized country- or region-wise line probe assay strips. The identification of a few mutations in particular patient groups and the detection of wild type deletion mutants with no observable mutations both point toward the need for such customization enabling us to combat the rising trend of MDR tuberculosis.

Temporal IgG Subtype Changes in Recurrent Idiopathic Membranous Nephropathy.

Determination of the IgG subtypes within the immune deposits in membranous nephropathy (MN) may be helpful in the differential diagnosis. IgG4 is the predominant subtype in idiopathic MN and recurrent MN, while IgG1, IgG2, and IgG3 subtypes are more common in secondary MN and de novo disease in the allograft. The temporal change of IgG subclasses in individual patients and its correlation with clinical variables have not been studied. We reviewed all posttransplantation protocol and indication biopsies (49) in 18 patients with recurrent MN who underwent transplantation at our center between 1998 and 2013 and performed IgG subtyping (IgG1-4). We tested serum for M-type phospholipase A2 receptor (PLA2 R) autoantibodies or performed PLA2 R antigen staining on the kidney biopsy. IgG4 was the (co)dominant IgG subtype in 10 of 14 biopsies at the diagnosis of recurrence regardless of PLA2 R association. In 8 of 12 transplantations with serial biopsies, the (co)dominant subtype did not change over time. There was a trend toward IgG1 and IgG3 (co)dominance in biopsies >1 year from recurrence and more IgG1 (co)dominant subtyping in the setting of more-advanced EM deposits. Treatment with rituximab did not affect the IgG subtype. In conclusion, the dominant IgG subtype did not change over time in recurrent MN.

Determinants of bacteriological outcomes in exacerbations of chronic obstructive pulmonary disease.

PURPOSE: Changes in sputum microbiology following antibiotic treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), including patterns of bacteriological relapse and superinfection are not well understood. Sputum microbiology at exacerbation is not routinely performed, but pathogen presence and species are determinants of outcomes. Therefore, we determined whether baseline clinical factors could predict the presence of bacterial pathogens at exacerbation. Bacterial eradication at end of treatment (EOT) is associated with clinical resolution of exacerbation. We determined the clinical, microbiological and therapeutic factors that were associated with bacteriological eradication in AECOPD at EOT and in the following 8 weeks. METHODS: Sputum bacteriological outcomes (i.e., eradication, persistence, superinfection, reinfection) from AECOPD patients (N = 1352) who were randomized to receive moxifloxacin or amoxicillin/clavulanate in the MAESTRAL study were compared. Independent predictors of bacterial presence in sputum at exacerbation and determinants for bacteriological eradication were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: Significantly greater bacteriological eradication with moxifloxacin was mainly driven by superior Haemophilus influenzae eradication (P = 0.002, EOT). Baseline clinical factors were a weak predictor of the presence of pathogens in sputum (AUCROC = 0.593). On multivariate analysis, poorer bacterial eradication was associated with antibiotic resistance (P = 0.0001), systemic steroid use (P = 0.0024) and presence of P. aeruginosa (P = 0.0282). CONCLUSIONS: Since clinical prediction of bacterial presence in sputum at AECOPD is poor, sputum microbiological analysis should be considered for guiding antibiotic therapy in moderate-to-severe AECOPD, particularly in those who received concomitant systemic corticosteroids or are at risk for infection with antibiotic-resistant bacteria.

Anti-phospholipase A2 receptor antibodies in recurrent membranous nephropathy.

About 70% of patients with primary membranous nephropathy (MN) have circulating anti-phospholipase A2 receptor (PLA2R) antibodies that correlate with disease activity, but their predictive value in post-transplant (Tx) recurrent MN is uncertain. We evaluated 26 patients, 18 with recurrent MN and 8 without recurrence, with serial post-Tx serum samples and renal biopsies to determine if patients with pre-Tx anti-PLA2R are at increased risk of recurrence as compared to seronegative patients and to determine if post-Tx changes in anti-PLA2R correspond to the clinical course. In the recurrent group, 10/17 patients had anti-PLA2R at the time of Tx versus 2/7 patients in the nonrecurrent group. The positive predictive value of pre-Tx anti-PLA2R for recurrence was 83%, while the negative predictive value was 42%. Persistence or reappearance of post-Tx anti-PLA2R was associated with increasing proteinuria and resistant disease in 6/18 cases; little or no proteinuria occurred in cases with pre-Tx anti-PLA2R and biopsy evidence of recurrence in which the antibodies resolved with standard immunosuppression. Some cases with positive pre-Tx anti-PLA2R were seronegative at the time of recurrence. In conclusion, patients with positive pre-Tx anti-PLA2R should be monitored closely for recurrent MN. Persistence or reappearance of antibody post-Tx may indicate a more resistant disease.

Direct costs of first-generation protease inhibitors for the treatment of genotype 1 chronic hepatitis C viral infection.

To evaluate the cost-effectiveness of Hepatitis C therapy, robust real-world data are needed to understand the costs and benefits of treatment alternatives. The objective of this study was to evaluate the true direct cost of treatment in an unselected sequential population of patients treated at a tertiary care centre for hepatitis C virus genotype 1. A total of 200 consecutive patients were treated with interferon, ribavirin and a first-generation direct-acting antiviral agent (DAA) between 2011 and 2013. A total of 41% had cirrhosis, 31% were prior relapsers, and 41% were prior partial or null responders. Costs used were wholesale acquisition cost prices for medications, average hospital costs per day for each diagnosis code based on US inpatient hospital charges. All costs were adjusted to 2013 dollars. Sustained virologic response (SVR) was achieved in 97 patients (48.5%). A total of 14% experienced relapse, 19% breakthrough or nonresponse, and 18.5% discontinued secondary to side effects. Twenty per cent of patients had at least one hospitalization attributable to a complication of therapy. Thirty-seven per cent of patients required erythropoietin-stimulating agents, 16% received filgastrim, and 15% needed a red blood cell transfusion. The mean overall cost of treatment was $83,851 per patient. The cost per SVR was $172,889; $266,670 for patients with cirrhosis. The costs per SVR after treatment with first-generation DAAs are dependent on the stage of disease and therapy side effects. These real-world costs significantly exceed those described in prior cost-effectiveness assessments and should be used instead for future studies.

Effect of fly ash application on soil microbial response and heavy metal accumulation in soil and rice plant.

Fly ash (FA), a byproduct of coal combustion in thermal power plants, has been considered as a problematic solid waste and its safe disposal is a cause of concern. Several studies proposed that FA can be used as a soil additive; however its effect on microbial response, soil enzymatic activities and heavy metal accumulation in soil and grain of rice (cv. Naveen) to fly ash (FA) application was studied in a pot experiment during dry season 2011 in an Inceptisol. Fly ash was applied at a rate of zero per cent (FS), five per cent (FA5), ten per cent (FA10), twenty per cent (FA20), 40 per cent (FA40) and 100 per cent (FA100) on soil volume basis with nitrogen (N), phosphorus (P) and potassium (K) (40:20:20mg N:P:Kkg(-1) soil) with six replications. Heavy metals contents in soil and plant parts were analysed after harvest of crop. On the other hand, microbial population and soil enzymatic activities were analysed at panicle initiation stage (PI, 65 days after transplanting) of rice. There was no significant change in the concentration of zinc (Zn), iron (Fe), copper (Cu), manganese (Mn), cadmium (Cd) and chromium (Cr) with application of fly ash up to FA10. However, at FA100 there was significant increase of all metals concentration in soil than other treatments. Microorganisms differed in their response to the rate of FA application. Population of both fungi and actinomycetes decreased with the application of fly ash, while aerobic heterotrophic bacterial population did not change significantly up to FA40. On the other hand, total microbial activity measured in terms of Fluorescein diacetate (FDA) assay, and denitrifiers showed an increased trend up to FA40. However, activities of both alkaline and acid phosphatase were decreased with the application of FA. Application of FA at lower levels (ten to twenty per cent on soil volume basis) in soil enhanced micronutrients content, microbial activities and crop yield.

Measuring respiratory symptoms in clinical trials of COPD: reliability and validity of a daily diary.

BACKGROUND: Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease. OBJECTIVE: To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT). METHODS: Qualitative: patient focus group and interviews to address content validity. Quantitative: secondary data analyses to test reliability and validity. RESULTS: Qualitative: n=84; mean (SD) age 65 (10) years, FEV1 1.2(0.4) L; 44% male. Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure. Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male. Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough & Sputum, and RS-Chest Symptoms; second-order FA supported a general factor and total score. Reliability (total and subscales): 0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively. VALIDITY: Total scores correlated significantly (p < 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p < 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p < 0.0001 (RS-Cough & Sputum with Symptoms). RS-Breathlessness correlated with rescue medication use (r=0.32, p < 0.0001), clinician-reported mMRC (r=0.33, p < 0.0001), and FEV1% predicted (r=-0.17, p < 0.05). E-RS scores differentiated groups based on chronic bronchitis diagnosis (p < 0.01-0.001), smoking status (p < 0.05-0.001), and rescue medication use (p < 0.05-0.0001). CONCLUSIONS: Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD. Further study of sensitivity to change is warranted.

MicroRNAs in personalized cancer therapy.

MicroRNAs (miRNAs) are small endogenous noncoding single-stranded RNAs. They critically regulate the post-transcriptional activity of several key physiological and pathological cell processes including cancer. Through their transcriptional regulatory functions, miRNAs control tumor proliferation, invasion and metastasis. The expression of miRNAs is altered in malignancies. It could be either upregulated or downregulated depending upon the role of a particular miRNA in the pathogenetic development of the tumor. The upregulated miRNAs exert an 'oncogenic' effect leading to tumor proliferation and metastasis. The downregulated miRNAs have 'tumor suppressor' effects. Recent studies have demonstrated that miRNAs have a role in the early diagnosis, prognosis and treatment outcome assessment of cancers. Every tumor has specific miRNA alterations, i.e. some are overexpressed and others are downregulated. These altered miRNAs can be used as a tumor-specific 'signature' for potential clinical use in improving the accuracy of diagnosis, determining prognosis and as therapeutic targets for therapy. Specific miRNAs can be targeted using oligonucleotide sequences corresponding to the altered miRNAs. These are referred to as 'antagomirs'. Depending upon the miRNA alterations in the tumor of an individual patient, one could design targeted therapies for personalized medicine in patients. Hence, miRNAs have an immense role in personalized cancer therapy.

Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival.

Staphylococcus aureus is the most clinically relevant pathogen regarding implant-associated bone infection and its capability to invade osteoblasts is well known. The aim of this study was to investigate firstly whether S. aureus is not only able to invade but also to proliferate within osteoblasts, secondly to delineate the mechanism of invasion and thirdly to clarify whether rifampicin or gentamicin can inhibit intracellular proliferation and survival of S. aureus. The SAOS-2 osteoblast-like cell line and human primary osteoblasts were infected with S. aureus EDCC5055 and S. aureus Rosenbach 1884. Both S. aureus strains were able to invade efficiently and to proliferate within human osteoblasts. Immunofluorescence microscopy showed intracellular invasion of S. aureus and transmission electron microscopy images could demonstrate bacterial division as a sign of intracellular proliferation as well as cytosolic bacterial persistence. Cytochalasin D, the major actin depolymerisation agent, was able to significantly reduce S. aureus invasion, suggesting that invasion was enabled by promoting actin rearrangement at the cell surface. 7.5 µg/mL of rifampicin was able to inhibit bacterial survival in SAOS-2 cells with almost complete elimination of bacteria after 4 h. Gentamicin could also kill intracellular S. aureus in a dose-dependent manner, an effect that was significantly lower than that observed using rifampicin. In conclusion, S. aureus is not only able to invade but also to proliferate in osteoblasts. Invasion seems to be associated with actin rearrangement at the cell surface. Rifampicin is effective in intracellular eradication of S. aureus whereas gentamicin only poorly eliminates intracellularly replicating bacteria.

Lip, oral and oropharyngeal cancer incidence among Aboriginal and Torres Strait Islander Peoples: First report from Australian population-based cancer registry, 1999-2018.

BACKGROUND: The Australian Burden of Disease Study has shown that cancer is the single most important entity responsible for the greatest cause of health burden in Australia. Unfortunately, Aboriginal and Torres Strait Islander peoples experience a greater burden of this disease, with cancer of the lung, breast, bowel and prostrate being the most common. Lip, oral cavity and pharyngeal cancer incidence is rapidly rising globally and is now the sixth most common cancer in Australia. This paper aims to summarize, for the first time, the incidence and prevalence trends of lip, oral cavity and pharyngeal cancers in Aboriginal and Torres Strait Islander Australians. METHODS: Data were obtained from the Australian Cancer Database (ACD), which is compiled at the Australian Institute of Health and Welfare (AIHW) from 1999 to 2018 to estimate the incidence and prevalence of certain head and neck cancers (ICD-10 codes C00-C10, C14). The other variables requested were age groups and sex. RESULTS: Results were stratified by ICD-10 code, sex and age group at diagnosis and time period (i.e. grouped years of diagnosis). The total incidence of lip, oral cavity and pharyngeal cancers increased by 1.3 times from 1999 to 2008 (107/100 000) to 2009-2018 (135/100 000). The overall 5-year prevalence of lip, oral cavity and pharyngeal cancers was 0.17% (0.24% for men and 0.09% for women). CONCLUSIONS: The significantly increased incidence of lip, oral cavity and pharyngeal cancers in Aboriginal and Torres Strait Islander peoples in Australia is concerning and should be explored. A targeted, comprehensive and culturally safe model of care for Aboriginal and Torres Strait Islander peoples with lip, oral cavity and pharyngeal cancers is imperative.