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Introduction: We map the patient journey from symptom onset to intervention and describe primary treatment in a retrospective population-based cohort study of patients in a large healthcare-provider., Methods: Newly diagnosed adult patients diagnosed with stages I-III non-small cell lung cancer (NSCLC) between 2016 and 2019 were identified from the Israel National Cancer Registry and chart review was performed to extract de-identified data. The following timelines were constructed: from symptom onset to imaging, imaging to biopsy, and biopsy to primary treatment initiation. Cutoff: 31st December 2021. The initial symptom was captured up to one year prior to biopsy., Results: Among 302 patients (41 % female, 70 % >=65 years, 79 % former or current smoking, 62 % adenocarcinoma), 34.1 % stage I, 10.3 % stage II, 42.1 % stage III and 13.6 % unknown (AJCC ver. 8). In the baseline year, 80.5 % of patients reported at least one symptom to their physician, and 12.3 % reported four or more symptoms. The most common symptoms reported were cough (29.8 %), pneumonia (24.2 %), chest pain (18.5 %), bronchitis (17.5 %) and wheezing (17.2 %). For patients with an initial symptom (n=243) median time from symptom onset to imaging was 5.5 months (95% CI:4.8-6.3), and time from imaging to primary treatment initiation was 2.6 (2.3-2.9) months in all patients. Total duration from symptom to intervention was 8.5 months (7.6-9.3). Over 93 % of stage I patients underwent surgery and 4.9 % received definitive radiation. Over 83 % of stage II patients underwent surgery; of these, 54.8 % received adjuvant/neoadjuvant chemotherapy. Of stage III patients, 68.5 % received definitive chemoradiation (half received durvalumab), and the remaining underwent surgery with adjuvant/neoadjuvant treatment., Conclusion: A total of 80.5 % of patients were symptomatic and the median duration from symptom onset to treatment initiation was 8.5 month long. Improving patient and physician awareness to lung cancer symptoms, and the introduction of screening programs are essential for reducing those delays., Competing Interests: Declaration of Competing Interest This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Maccabi and MSD wrote the protocol. Maccabi submitted IRB approval, developed the analytic data set, wrote the statistical analysis plan, performed all analyses and wrote the final report. MSD and Maccabi reviewed the preliminary and final results, and are co-authors of this manuscript. SSM, LA, GC, SG, NSD have no conflict of interest. SY is an employee of MSD Ltd., Hod Hasharon, Israel and own stocks in Merck & Co., Inc., Rahway, NJ, USA. BP and MvR are employees of MSD, AA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and all own stocks in Merck & Co., Inc., Rahway, NJ, USA., (Copyright © 2024 Moser. Published by Elsevier Ltd.. All rights reserved.)

Background: Health-care providers in the US revealed that a substantial proportion of mNSCLC patients do not receive any first-line therapy and the biggest gaps in care are time inefficiencies in the diagnostic process. The goal of this study was to determine whether such gaps are found in Israel where healthcare is universal and participation in a medical insurance plan is free and compulsory., Methods: We conducted a retrospective, observational cohort study using the computerized data of Maccabi Healthcare Services, a 2.5 million-member state-mandated health-service. Patients with mNSCLC diagnosed between 2017 and 2018 were followed until December 2019., Results: Among 434 patients (62% male, mean age 68 y, 74% adenocarcinoma), 345 (79%) initiated first-line treatment. Compared to treated, untreated patients (n = 89) were more likely to be older (mean [SD]=71 years [10] vs. 67 [10], p < 0.001), have a higher co-morbidity index (5.6 ([4.4] vs. 4.0 [3.4], p < 0.001), smokers (84% vs. 66%, p = 0.001), and require hospitalization in the year prior to diagnosis (80% vs 61%, p = 0.002). There was no difference in socioeconomic status. Time from first symptom to imaging was longer for untreated than treated patients (6.51 months [4.24, 7.33] vs 3.48 months [2.76, 4.34] respectively, p = 0.22). Predictors of treatment initiation included age< 70 years, non-smokers, EGFR testing performed, ECOG performance status 0-1 and shorter wait from first symptom to imaging. Median time from first symptom to initiation of 1 L, was 7.76 months (6.51-8.75)., Conclusion: The proportion of untreated mNSCLC patients are comparable to those reported in the US; we did not find health disparities between socioeconomic levels. Our data suggest that the main barrier to effective diagnostic process is the wait between symptom complaint and imaging., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The many respiratory viruses that cause influenza-like illness (ILI) are reported and tracked as one entity, defined by the CDC as a group of symptoms that include a fever of 100 degrees Fahrenheit, a cough, and/or a sore throat. In the United States alone, ILI impacts 9-49 million people every year. While tracking ILI as a single clinical syndrome is informative in many respects, the underlying viruses differ in parameters and outbreak properties. Most existing models treat either a single respiratory virus or ILI as a whole. However, there is a need for models capable of comparing several individual viruses that cause respiratory illness, including ILI. To address this need, here we present a flexible model and simulations of epidemics for influenza, RSV, rhinovirus, seasonal coronavirus, adenovirus, and SARS/MERS, parameterized by a systematic literature review and accompanied by a global sensitivity analysis. We find that for these biological causes of ILI, their parameter values, timing, prevalence, and proportional contributions differ substantially. These results demonstrate that distinguishing the viruses that cause ILI will be an important aspect of future work on diagnostics, mitigation, modeling, and preparation for future pandemics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Recent international guidelines recommend thromboprophylaxis in patients with cancer at intermediate-high venous thromboembolism (VTE) risk., Objectives: We aimed to assess the current incidence, risk factors and management of cancer-associated VTE and associated health care resource utilization in a 2.5-million-member state-mandated health service in Israel., Methods: Patients aged ≥18 years with newly diagnosed cancer, initiating systemic anticancer treatment from 2010 through 2018 were identified from the Israel National Cancer Registry. The index date was fixed as the first day of systemic anticancer treatment. The cumulative VTE incidence from the first day of systemic anticancer treatment and the respective hazard ratios for VTE risk factors were calculated at 12 months of follow-up. Health care resource utilization (primary care physician, emergency room, and hospital visits) during the study period was compared between patients with and without VTE., Results: A total of 15 388 patients were included, and 338 had VTE with a 12-month cumulative incidence of 2.2% (95% confidence interval, 1.96%-2.43%). In a multivariable model, older age, higher comorbidity index, intermediate-high-risk Khorana score, certain malignancy types, and chemotherapy were significantly associated with an increased VTE risk in the year after initiating anticancer treatment. Compared with matched controls, the VTE subcohort were more likely to be hospitalized (81.4% vs 35.2%), have longer hospital stays (20.1 days vs 13.1 days), have an emergency room visit (41.5% vs 19.3%), and have a larger number of primary care physician visits (17.6 vs 12.5)., Conclusion: Several risk factors, including the Khorana score, were associated with VTE incidence. VTE was associated with long-term use of anticoagulation. Health care utilization was higher in patients with VTE., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Adverse effects of calcineurin inhibitors (CNI), such as hypertension, hyperkalemia, acidosis, hypomagnesemia and hypercalciuria, have been linked to dysfunction of the distal convoluted tubule (DCT). To test this, we generated a mouse model with an inducible DCT-specific deletion of the calcineurin regulatory subunit B alpha (CnB1-KO). Three weeks after CnB1 deletion, these mice exhibited hypomagnesemia and acidosis, but no hypertension, hyperkalemia or hypercalciuria. Consistent with the hypomagnesemia, CnB1-KO mice showed a downregulation of proteins implicated in DCT magnesium transport, including TRPM6, CNNM2, SLC41A3 and parvalbumin but expression of calcium channel TRPV5 in the kidney was unchanged. The abundance of the chloride/bicarbonate exchanger pendrin was increased, likely explaining the acidosis. Plasma aldosterone levels, kidney renin expression, abundance of phosphorylated sodium chloride-cotransporter and abundance of the epithelial sodium channel were similar in control and CnB1-KO mice, consistent with a normal sodium balance. Long-term potassium homeostasis was maintained in CnB1-KO mice, but in-vivo and ex-vivo experiments indicated that CnB1 contributes to acute regulation of potassium balance and sodium chloride-cotransporter. Tacrolimus treatment of control and CnB1-KO mice demonstrated that CNI-related hypomagnesemia is linked to impaired calcineurin-signaling in DCT, while hypocalciuria and hyponatremia occur independently of CnB1 in DCT. Transcriptome and proteome analyses of isolated DCTs demonstrated that CnB1 deletion impacts the expression of several DCT-specific proteins and signaling pathways. Thus, our data support a critical role of calcineurin for DCT function and provide novel insights into the pathophysiology of CNI side effects and involved molecular players in the DCT., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: About every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis., Methods: This study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n = 110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n = 1058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n = 1143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples., Results: Network analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria. Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods., Conclusions: Genetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the efficacy profile and safety of recombinant human C1 esterase inhibitor (rhC1INH) in the prevention of contrast-associated acute kidney injury after elective coronary angiography., Background: Contrast-associated acute kidney injury is caused by tubular cytotoxicity and ischemia/reperfusion injury. rhC1INH is effective in reducing renal ischemia/reperfusion injury in experimental models., Methods: In this placebo-controlled, double-blind, single-center trial 77 patients with chronic kidney disease were randomized to receive 50 IU/kg rhC1INH before and 4 h after elective coronary angiography or placebo. The primary outcome was the peak change of urinary neutrophil gelatinase-associated lipocalin within 48 h, a surrogate marker of kidney injury., Results: Median peak change of urinary neutrophil gelatinase-associated lipocalin was lower in the rhC1INH group (4.7 ng/ml vs. 22.5 ng/ml; p = 0.038) in the per-protocol population but not in the modified intention-to-treat analysis, and in patients with percutaneous coronary interventions (median, 1.8 ng/ml vs. 26.2 ng/ml; p = 0.039 corresponding to a median proportion peak change of 11% vs. 205%; p = 0.002). The incidence of a cystatin C increase ≥10% within 24 h was lower in the rhC1INH group (16% vs. 33%; p = 0.045), whereas the frequency of contrast-associated acute kidney injury was comparable. Adverse events during a 3-month follow-up were similarly distributed., Conclusions: Administration of rhC1INH before coronary angiography may attenuate renal injury as reflected by urinary neutrophil gelatinase-associated lipocalin and cystatin C. The safety profile of rhC1INH was favorable in a patient population with multiple comorbidities. (Recombinant Human C1 Esterase Inhibitor in the Prevention of Contrast-induced Nephropathy in High-risk Subjects [PROTECT]; NCT02869347)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ultrasound guidance allows for the use of much lower volumes of local anaesthetics for nerve blocks, which may be associated with less aberrant spread and fewer complications. This randomized, controlled study used contrast magnetic resonance imaging to view the differential-volume local anaesthetic distribution, and compared analgesic efficacy and respiratory impairment., Methods: Thirty patients undergoing shoulder surgery were randomized to receive ultrasound-guided interscalene block by a single, blinded operator with injection of ropivacaine 0.75% (either 20 or 5 ml) plus the contrast dye gadopentetate dimeglumine, followed by magnetic resonance imaging. The primary outcome was epidural spread. Secondary outcomes were central non-epidural spread, contralateral epidural spread, spread to the phrenic nerve, spirometry, ultrasound investigation of the diaphragm, block duration, pain scores during the first 24 h, time to first analgesic consumption, and total analgesic consumption., Results: All blocks provided fast onset and adequate intra- and postoperative analgesia, with no significant differences in pain scores at any time point. Epidural spread occurred in two subjects of each group (13.3%); however, spread to the intervertebral foramen and phrenic nerve and extensive i.m. local anaesthetic deposition were significantly more frequent in the 20 ml group. Diaphragmatic paralysis occurred twice as frequently (n=8 vs 4), and changes from baseline peak respiratory flow rate were larger [Δ=-2.66 (1.99 sd) vs -1.69 (2.0 sd) l min(-1)] in the 20 ml group., Conclusions: This study demonstrates that interscalene block is associated with epidural spread irrespective of injection volume; however, less central (foraminal) and aberrant spread after low-volume injection may be associated with a more favourable risk profile., Clinical Trial Registration: This study was registered with the European Medicines Agency (Eudra-CT number 2013-004219-36) and with the US National Institutes' of Health registry and results base, clinicaltrials.gov (identifier NCT02175069)., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Metastatic basal cell carcinoma (MBCC) is defined as primary cutaneous basal cell carcinoma (BCC) that spreads to distant sites as histologically similar metastatic deposits of BCC. BCCs are semimalignant, destructive, and invasive. Metastases are very rare, with an incidence of 0.0028%-0.5%., Case Report: A female patient with Gorlin-Goltz syndrome and a rare case of a basal cell carcinoma with an additional regional lymph node metastasis is presented., Conclusions: This case highlights the importance of a multidisciplinary approach to and frequent monitoring of patients with Gorlin-Goltz syndrome. Early diagnosis and surgical treatment are still the treatment of first choice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In this study, we analyze the outcomes of transplant renal artery stenosis (TRAS), determine the different anatomical positions of TRAS, and establish cardiovascular and immunological risk factors associated with its development. One hundred thirty-seven of 999 (13.7%) patients had TRAS diagnosed by angiography; 119/137 (86.9%) were treated with angioplasty, of which 113/137 (82.5%) were stented. Allograft survival in the TRAS+ intervention, TRAS+ nonintervention and TRAS- groups was 80.4%, 71.3% and 83.1%, respectively. There was no difference in allograft survival between the TRAS+ intervention and TRAS- groups, p = 0.12; there was a difference in allograft survival between the TRAS- and TRAS+ nonintervention groups, p < 0.001, and between the TRAS+ intervention and TRAS+ nonintervention groups, p = 0.037. TRAS developed at the anastomosis, within a bend/kink or distally. Anastomotic TRAS developed in living donor recipients; postanastomotic TRAS (TRAS-P) developed in diabetic and older patients who received grafts from deceased, older donors. Compared with the TRAS- group, patients with TRAS-P were more likely to have had rejection with arteritis, odds ratio (OR): 4.83 (1.47-15.87), p = 0.0095, and capillaritis, OR: 3.03 (1.10-8.36), p = 0.033. Patients with TRAS-P were more likely to have developed de novo class II DSA compared with TRAS- patients hazard ratio: 4.41 (2.0-9.73), p < 0.001. TRAS is a heterogeneous condition with TRAS-P having both alloimmune and traditional cardiovascular risk factors., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor and uncoupler of nitric oxide synthase. By promoting the formation of peroxynitrite, ADMA is believed to contribute to several aspects of asthma pathogenesis (ie, airway inflammation, oxidative stress, bronchial hyperresponsiveness, and collagen deposition). The aim of the present study was to compare this mediator in healthy children and children with asthma using the completely noninvasive exhaled breath condensate (EBC) technique., Methods: We recruited 77 children with asthma (5-16 years of age) and 65 healthy children (5-15 years of age) who underwent EBC collection and spirometry. Serum ADMA levels and fractional exhaled nitric oxide levels were measured on the same day in a subgroup of children with asthma. EBC was collected using the Turbo-Deccs (Medivac). ADMA levels were measured using the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique., Results: ADMA could be detected in the EBC of 71 subjects with asthma and 64 healthy subjects. ADMA levels in the EBC of children with asthma were significantly higher than in the healthy control subjects (median, 0.12 [interquartile range, 0.05-0.3] vs 0.07 [0.05-0.12]; P = .017), whereas no difference emerged between the children with asthma who were or were not receiving inhaled steroid treatment. No correlation was found between serum and EBC ADMA levels (P &gt; .5)., Conclusions: We measured ADMA in EBC by UPLC-MS/MS, a reference analytical technique. Higher ADMA levels were found in children with asthma, supporting a role for this mediator in asthma pathogenesis. This oxidative stress-related mediator also seems to be scarcely affected by steroid therapy. We speculate that ADMA might be a target for new therapeutic strategies designed to control oxidative stress in asthma.

CD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell-depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders.

A new high-performance liquid chromatography method using a coulometric array detector to simultaneously analyse 4-ethylphenol, 4-ethylguaiacol, 4-vinylphenol, and 4-vinylguaiacol in wine was established. This procedure offers important advantages as it does not require sample preparation, with the exception of filtration, and performs chromatographic separation in short time, making control of wine production processes easier. The method is linear up to concentrations of 2000 microg L(-1) and precise (R.S.D.<3%). Limits of detection are low (1-3 microg L(-1)) and suitable for analytical requirements in the oenological field. When compared to gas-chromatography-flame ionisation detection, the proposed method gives similar results with a shorter execution time.

An unusual case of a mitral annular abscess caused by Streptococcus pneumoniae was diagnosed by transesophageal echocardiography. The patient underwent surgical resection of the abscess and developed outflow tract obstruction. This is an unusual complication of the surgical procedure. The outflow tract obstruction may have been due to anterior displacement of the mitral valve by the abscess.

The diploid yeast strain BR1669 was used to study induction of mitotic and meiotic chromosome gain by selected chemical agents. The test relies on a gene dosage selection system in which hyperploidy is detected by the simultaneous increase in copy number of two alleles residing on the right arm of chromosome VIII: arg4-8 and cup1S (Rockmill and Fogel. 1988; Whittaker et al., 1988). Methyl methanesulfonate (MMS) induced mitotic, but not meiotic, chromosome gain. Methyl benzimidazol-2-yl carbamate (MBC) and ethyl methanesulfonate (EMS) induced both mitotic and meiotic chromosome gain. Propionitrile, a polar aprotic solvent, induced only mitotic chromosome gain; a reliable response was only achieved by overnight incubation of treated cultures at 0 degrees C. MBC is postulated to act by binding directly to tubulin. The requirement for low-temperature incubation suggests that propionitrile also induces aneuploidy by perturbation of microtubular dynamics. The alkylating agents MMS and EMS probably induce recombination which might in turn perturb chromosome segregation. Cyclophosphamide monohydrate and dimethyl sulfoxide (DMSO) failed to induce mitotic or meiotic chromosome gain.

The present investigation was carried out to examine the effect of thiazides on the hypercalciuria of phosphate depletion. Studies were done on 160 to 190 gm male rats, utilizing metabolic balance techniques. Animals were assigned to a phosphate-deficient diet and divided into a vehicle and thiazide-treated group. Both groups raised on a phosphate-deficient diet developed hypophosphatemia, hypercalciuria, and hypercalcemia; the latter was significantly greater in the thiazide-treated group. The magnitude of the hypercalciuria was significantly smaller in the thiazide-treated group. This occurred despite a significantly greater elevation in the concentration of serum calcium and its filtered load in the rats treated with the diuretic. Thiazides failed to produce natriuresis in the phosphate-deficient rats, suggesting a possible tubular resistance to the natriuretic action of the drug in phosphate depletion. Our data demonstrate that thiazide administration blunts the hypercalciuria of phosphate depletion. The results are consistent with the postulates that (1) phosphate depletion suppresses tubular calcium reabsorption at a site proximal to the segment where thiazides enhance calcium transport or (2) thiazide enhances calcium reabsorption at a terminal site in the nephron where a decrease in calcium transport may occur during phosphate depletion.