The Diagnostic Value of ACSL1, ACSL4, and ACSL5 and the Clinical Potential of an ACSL Inhibitor in Non-Small-Cell Lung Cancer.

Abnormal expression of ACSL members 1, 3, 4, 5, and 6 is frequently seen in human cancer; however, their clinical relevance is unclear. In this study, we analyzed the expression of ACSLs and investigated the effects of the ACSL inhibitor Triacsin C (TC) in lung cancer. We found that, compared to normal human bronchial epithelial (NHBE) cells, ACSL1, ACSL4, and ACSL6 were highly expressed, while ACSL3 and ACSL5 were lost in the majority of lung cancer cell lines. ACSL activity was associated with the expression levels of the ACSLs. In primary lung tumors, a higher expression of ACSL1, ACSL4, and ACSL5 was significantly correlated with adenocarcinoma (ADC). Moreover, ACSL5 was significantly reversely related to the proliferation marker Ki67 in low-grade tumors, while ACSL3 was positively associated with Ki67 in high-grade tumors. Combination therapy with TC and Gemcitabine enhanced the growth-inhibitory effect in EGFR wild-type cells, while TC combined with EGFR-TKIs sensitized the EGFR-mutant cells to EGFR-TKI treatment. Taken together, the data suggest that ACSL1 may be a biomarker for lung ADC, and ACSL1, ACSL4, and ACSL5 may be involved in lung cancer differentiation, and TC, in combination with chemotherapy or EGFR-TKIs, may help patients overcome drug resistance.

Respiratory Infections in the Aging Lung: Implications for Diagnosis, Therapy, and Prevention.

Respiratory infections pose a significant health problem among elderly individuals, particularly during the COVID-19 pandemic. The increased mortality and morbidity rates among individuals over 65 highlight the criticality of these infections. The normal aging process in the lungs increases vulnerability to respiratory infections due to the accumulation of cellular damage and senescence. Consequently, the lung environment undergoes major changes in mechanical function and other systemic factors. This review aims to examine the influence of aging on respiratory infections from a clinical perspective by analyzing clinical studies. Additionally, the review will emphasize potential prevention and diagnostic developments to enhance therapy options available for elderly patients over 65 years of age.

Long-term interplay between COVID-19 and chronic kidney disease.

PURPOSE: The COVID-19 pandemic may have an impact on the long-term kidney function of survivors. The clinical relevance is not clear. METHODS: This review summarises the currently published data. RESULTS: There is a bidirectional relationship between chronic kidney disease and COVID-19 disease. Chronic kidney diseases due to primary kidney disease or chronic conditions affecting kidneys increase the susceptibility to COVID-19 infection, the risks for progression and critical COVID-19 disease (with acute or acute-on-chronic kidney damage), and death. Patients who have survived COVID-19 face an increased risk of worse kidney outcomes in the post-acute phase of the disease. Of clinical significance, COVID-19 may predispose surviving patients to chronic kidney disease, independently of clinically apparent acute kidney injury (AKI). The increased risk of post-acute renal dysfunction of COVID-19 patients can be graded according to the severity of the acute infection (non-hospitalised, hospitalised or ICU patients). The burden of chronic kidney disease developing after COVID-19 is currently unknown. CONCLUSION: Post-acute COVID-19 care should include close attention to kidney function. Future prospective large-scale studies are needed with long and complete follow-up periods, assessing kidney function using novel markers of kidney function/damage, urinalysis and biopsy studies.

Neutrophil-to-lymphocyte ratio-a new diagnostic and prognostic marker of acute kidney injury. Barriers to broad clinical application.

Hospital-acquired acute kidney injury is a heterogeneous clinical syndrome that has multiple aetiologies, widely differing pathogeneses, variable clinical manifestations, and diverse outcomes. There is a persistent unmet need for novel biomarkers that offer timely diagnosis and accurate prediction of the short- and long-term sequelae of acute kidney injury (AKI). AKI is associated with systemic and intrarenal inflammation. The neutrophil-to-lymphocyte ratio (NLR), a readily available marker of inflammation and physiologic stress, has gained increasing attention as universal marker in AKI patients. Numerous retrospective cross-sectional studies assessed the clinical usefulness of this test in high-risk patients with a known time point of the renal injury (surgery, radiological procedures). Strong associations have been demonstrated between high NLR and early onset, progression or recovery of AKI, and the in-hospital and post-discharge mortality of these patients. However, the results were contradictory. The huge heterogeneity of reporting concerning the timing and numbers of blood samples, calculation of the optimal cut-off and the demographic and clinical features of the patient cohorts were confounders. Uncertainty in the optimal cut-off values defining high NLR, the lack of prospective validation of this test and limited understanding of the strengths of associations between NLR and clinical outcomes were further barriers for the clinical adoption of NLR as a valid diagnostic and prognostic test in AKI patients.

Mediastinal Rhabdomyosarcoma Feeding Off the Left Anterior Descending Artery.

We report the rare case of a 51-year-old patient with a 15 cm mediastinal rhabdomyosarcoma with blood supply from the left anterior descending artery presenting as a large mass including the pericardium with extensive contact to the epicardium compressing heart and left lung. The tumor was successfully removed through median sternotomy, blunt dissection from the heart and the left lung, resection of the infiltrated pericardium, and ligation of the tumor-feeding vessels using off-pump stabilizers. Histopathological examination revealed a spindle cell rhabdomyosarcoma with R0 resection. The postoperative course was uneventful, and patient is feeling well at 3-month follow-up.

Dimorphic Response of Sex and Hospital-acquired Acute Kidney Injury.

The risk of hospital-acquired acute kidney injury (HA-AKI) depends on a person's intrinsic susceptibility, the presence of risk factors, and on the type and extent of exposure to kidney insults. Older cohort studies have focused on male-only or mostly male populations, assuming a lower incidence of HA-AKI in women. Insufficient statistical power suggested that female sex was a shared susceptibility factor for HA-AKI. It was included as a risk factor in risk prediction models of HA-AKI. With the inclusion of women in clinical research studies, this presumption was challenged. Recent meta-analyses of sex-stratified studies showed that the risk for HA-AKI was significantly higher in men. These results suggested a protective role of female sex hormones. However, these studies were complicated by the inclusion of women across an age spectrum that includes the menopausal shift. Preliminary clinical and basic research data suggest that postmenopausal women lose their protection from HA-AKI. The number, size, and quality of reported clinical studies are low. There is an unmet need to characterize the susceptibility factor sex, to assess its clinical relevance and to evaluate renoprotection by sex hormone administration.

Advanced meta-analyses comparing the three surgical techniques total disc replacement, anterior stand-alone fusion and circumferential fusion regarding pain, function and complications up to 3 years to treat lumbar degenerative disc disease.

PURPOSE: The purpose of our meta-analyses is to find the most appropriate surgical technique treating lumbar degenerative disc disease (DDD). Spinal fusion is the conventional treatment for lumbar DDD. Total disc replacement (TDR) has been developed to avoid negative effects of fusions by preserving functionality. To our knowledge, there is no evaluation comparing meta-analytically the clinical results of three different surgical techniques with same inclusion and exclusion criteria for treating DDD. METHODS: The surgical techniques TDR, anterior lumbar interbody fusion (ALIF) and circumferential fusion (CFF) are pairwise meta-analytically compared. Primary outcomes are pain measured by the Visual Analogue Scale (VAS) and function measured by the Oswestry Disability Index (ODI). Secondary outcomes are the mean number of complications per case (MNOC) at surgery and follow-up and the overall MNOC. RESULTS: In our systematic search, we found finally six prospective studies with the minimum follow-up of two years: four randomized controlled trials and two cohort studies. In VAS and ODI, TDR is proved to be superior to ALIF and CCF (p < 0.05), whereat ALIF is more effective than CFF without statistical significance. CFF presents the best result in complications with the lowest overall MNOC (0.1), followed by TDR (1.2) and ALIF (1.5). CONCLUSION: According to our meta-analyses, we regard TDR to be the most appropriate surgical technique treating DDD, followed by ALIF. Further studies with a longer follow-up are needed using the same methodical approach to strengthen the VAS and ODI results and to explain the discrepant result to complications.

Risk of lung cancer and renin-angiotensin blockade: a concise review.

PURPOSE: The blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is one of the most common treatments for hypertension, heart failure and renal diseases. However, concerns have been raised about a possible link between RAAS-blockers and an increased risk of cancer, particularly of lung cancer. This narrative review aims to give a critical appraisal of current evidence and to help physicians understand potential links between RAAS blockade and de novo lung cancer development. METHODS: Numerous pharmaco-epidemiologic studies, mostly retrospective cohort analyses, evaluated the association of RAAS blockade with lung cancer incidence and reported inconsistent findings. Meta-analyses could not further clarify a possible link between RAAS blockade and the risk of lung cancer. RESULTS: International regulatory agencies (FDA, EMA) have concluded that the use of RAAS blockers is not associated with an increased risk of developing lung cancer. Co-administration of RAAS blockers to systemic therapy of advanced non-small cell lung cancer seems to have positive effects on the outcome. CONCLUSION: Until more comprehensive analyses have been completed, there is no need to change clinical practise. Additional prospective randomized trials with long-term follow-up are needed to investigate the effects of these drugs on the development and progression of lung cancer.

Current Approach to Successful Liberation from Renal Replacement Therapy in Critically Ill Patients with Severe Acute Kidney Injury: The Quest for Biomarkers Continues.

Recovery of sufficient kidney function to liberate patients with severe acute kidney injury (AKI-D) from renal replacement therapy (RRT) is recognized as a vital patient-centred outcome. However, no clinical consensus guideline provides specific recommendations on when and how to stop RRT in anticipation of renal recovery from AKI-D. Currently, wide variations in clinical practice regarding liberation from RRT result in early re-start of RRT to treat uraemia after premature liberation or in the unnecessary prolonged exposure of unwell patients after late liberation. Observational studies, predominantly retrospective in nature, have attempted to assess numerous surrogate markers of kidney function or of biomarkers of kidney damage to predict successful liberation from RRT. However, a substantial heterogeneity in the timing of measurement and cut-off values of most biomarkers across studies allows no pooling of data, and impedes the comparison of outcomes from such studies. The accuracy of most traditional and novel biomarkers cannot be assessed reliably. Currently, the decision to discontinue RRT in AKI-D patients relies on daily clinical assessments of the patient's status supplemented by measurement of creatinine clearance (> 15 ml/min) and 24-h urine output (> 2000 ml/min with diuretics). Clinical trials objectively comparing the success of validated biomarkers for guiding optimal timed liberation from RRT in AKI-D will be required to provide high-quality evidence for guidelines.

Meta-analyses comparing spine simulators with cadavers and finite element models by analysing range-of-motion data before and after lumbar total disc replacement.

BACKGROUND: Range-of-motion (ROM) data generated by the in vitro test methods of spine simulators with cadavers (SSCs) and finite element models (FEMs) are used alternatively and complementarily for in vitro evaluations. AIM OF REVIEW: Our purpose is to compare exemplary segmental ROM data from SSCs and FEMs before and after ball-and-socket total disc replacement (bsTDR) to determine whether the two test methods provide the same data for the same evaluation subjects. KEY SCIENTIFIC CONCEPTS OF REVIEW: We performed 70 meta-analyses (MAs) and 20 additional comparative analyses based on data from 21 SSC studies used for 39 MAs and 16 FEM studies used for 31 MAs. Only fifty-nine percent (n = 23/39) of SSC MAs show a restored ROM after bsTDR, whereas in FEM MAs, the ROM is restored in ninety percent (n = 28/31). Among the analyses comparing data from the same spinal segments, motion directions and bsTDR, SSC and FEM data are significantly different in ten percent (n = 2/20). According to our results, data generated by SSCs and FEMs cannot be used as alternative and complementary data without restriction. The quality of the evaluation methods itself as well as potential technical reasons for the discrepant results were not our evaluation target. Further SSC and FEM data should be compared using the same approach.

Detection of community-acquired respiratory viruses in allogeneic stem-cell transplant recipients and controls-A prospective cohort study.

BACKGROUND: Community-acquired respiratory viruses (CARV) cause upper and lower respiratory tract infections (URTI/LRTI) and may be life-threatening for recipients of an allogeneic stem cell transplantation (allo-SCT). METHODS: In a prospective study encompassing 4 winter-seasons, we collected throat gargles (TG) at random time points from allo-SCT recipients (patients) and controls and followed them up for at least 3 weeks including repetitive sampling and documentation of symptoms. A Multiplex-PCR system to identify 20 CARV and Mycoplasma pneumoniae was used to detect CARV. RESULTS: One hundred ninety-four patients with 426 TG and 273 controls with 549 TG were included. There were more patients with a positive test result (25% vs 11% in the controls), and the patients had a higher number of positive TG (70 = 16%) compared to controls (32 = 6%) (P < .001). Altogether, 115 viruses were detected. Multiple viruses in one TG (11/48, 34%) and prolonged shedding were only observed in patients (13/48, 27%). Patients had more RSV (18/83, 26%) and adenovirus (15/83, 21%) than controls (both viruses 2/32, 6%). Independent risk factors for the detection of CARV included age >40 years (OR 3.38, 95% CI 1.8-6.4, P < .001) and presence of URTI-symptoms (OR 3.22, 95% CI 1.9-5.5, P < .001). No controls developed a LRTI or died whereas 4/48 (8%) patients developed a LRTI (coronavirus in 2, RSV in 1 and influenza A H1N1 in 1 patient). One patient died of CARV (influenza A H1N1). CONCLUSION: Allo-SCT-recipients have more CARV-infections, exhibit a different epidemiology, have more cases of co-infection or prolonged shedding and have a higher rate of LRTI and mortality.

Proton-pump inhibitors and chronic kidney disease: Hidden consequences of an inappropriate drug use?

Proton-pump inhibitors (PPIs) are the most effective therapy for gastric acid- related diseases. They are generally well tolerated with rare, often self-limiting adverse reactions. On the other hand, there is growing concern regarding the increased public access and inappropriate PPI use. This review aims to give a critical appraisal of current literature and to analyze a possible relationship between renal disorders and PPI use. A plethora of observational pharmacoepidemiological studies link PPI therapy to the development of acute interstitial nephritis (AIN). Most of these studies show a higher risk for acute kidney injury, de novo chronic kidney disease, and end-stage renal disease. However, current evidence is inadequate to establish a causal relationship between PPI use and many of the proposed renal syndromes. Residual confounding and bias related to study design and the over extrapolation of quantitatively small treatment effects contributed to the unnecessary controversy about PPI safety. Undoubtedly, PPI use may rarely induce AIN. Given the worldwide use of PPIs, the number of patients with biopsy- proven AIN is extremely small. However, more research is required to explore the underlying pathophysiological mechanisms and possible differences between commercially available PPIs regarding adverse renal effects. Till then, the PPIs should be used in the lowest effective dose, and inappropriate use should be avoided.

Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: A prospective pilot study.

BACKGROUND: Tuberculosis (TB) remains a global health problem. The application of rifampicin-based regimens for antimycobacterial therapy is hampered by its marked hepatotoxicity which results in poor adherence and may contribute to prolonged therapy or treatment failure. The purpose of this prospective investigation was to evaluate the hepatoprotective effectiveness of oral ursodeoxycholic acid (UDCA) (250-500 mg TID) administered to TB- or non-TB mycobacterial (NTM)-infected patients with drug-induced hepatotoxicity and ongoing therapy. METHODS: Study population: During 2009-2017, 27 patients (11 women, 16 men, aged 19-90 years; median age 44 years, 16 Caucasians, 10 Africans, 1 Asian) out of 285 patients with active TB (24/261) or NTM infections (3/24) treated at our TB Center developed clinically relevant hepatotoxicity. Oral UDCA was administered to treat hepatotoxicity. RESULTS: Twenty-one out of 27 patients (77.8%) showed normalization of elevated enzymes (alanine transferase and aspartate aminotransferase), alkaline phosphatase, and bilirubin while continuing TB treatment and 5 patients demonstrated a significant reduction of liver enzymes (18.5%). No change was observed in 1 patient (3.7%). Drug dose was not reduced in all patients; they all showed radiological and clinical improvement. There were no significant side effects. CONCLUSION: Oral administration of UDCA to TB patients developing anti-TB drug-induced liver injury may reverse hepatotoxicity in adults.

[A complicated clinical course of tick-borne rickettsiosis after safari in South Africa]. / Komplizierte Zeckenstich-Rickettsiose nach Safari-Tour in Südafrika.

HISTORY: A healthy 41 year old man was bitten by a tick while on safari in the Kruger National Park in South Africa. He developed severe fever and malaise 5 days later. A characteristic red skin sore with a dark centre and surrounding erythema (eschar, tache noir) developed at the site of the tick bite. The travel history and clinical picture were strongly suggestive of a tick borne fever. DIAGNOSTIC PROCEDURES: The diagnosis of tick bite fever caused by rickettsia (spotted fever group) was proven serologically. The clinical course of the disease was complicated by myocarditis, indicated by an elevated troponin I and later confirmed by cardio-MRI. The complicated clinical course and the singular eschar suggested Rickettsia conorii as the etiological agent. CLINICAL COURSE: The rickettsial infection was treated with doxycycline, which led to a rapid improvement of the patient's clinical status. However, recovery from this imported infection was delayed due to myocarditis. CONCLUSION: Rickettsioses should be included in the differential diagnosis in travellers returning from Africa. The clinical course is usually mild but can be complicated by involvement of major organs even in formerly healthy young people.

[Obesity and kidney disease - renal consequences of an "epidemic"]. / Übergewicht und Nierenerkrankungen ­ renale Risiken einer "Epidemie".

Overweight and obesity are widespread in the German population, affecting not only adults but also a significant number of children and adolescents. The risk to develop chronic kidney disease is markedly increased in overweight or adipose children, adolescents and adults.Overweight and obesity induced risk factors have a direct impact on the development of chronic renal disease (obesity-associated focal segmental glomerulosclerosis). They accelerate the progression of coexistent nephropathies (diabetic or hypertensive nephropathy, primary glomerulonephritides) and are independent risk factors for the development of acute kidney injury in critically ill patients.Obesity induced nephropathies are basically preventible. Marked weight reduction, normoglycemia and control of hypertension may contribute to an improved glomerular filtration rate and/or reduced proteinuria in early stages of renal damage.The prevalence of kidney diseases in Germany is 13 % and estimated 80 000 patients need renal replacement therapy. In order to avoid a further rapid increase in numbers, preventive measures should be enforced more rigorously.It is necessary to raise the awareness of the negative consequences of obesity in the general public, to motivate the public to adopt a healthier lifestyle and to install nephrological surveillance to contain the obesity "epidemic".

Obesity, acute kidney injury and outcome of critical illness.

Acute kidney injury is a heterogeneous clinical syndrome encompassing a spectrum of risk factors and acute insults, occurring in multiple settings and affecting both short-term and long-term outcomes. Obesity has become an epidemic. The available literature suggests that AKI is common in critically ill surgical or medical obese patients and that obesity is a novel risk factor for this acute renal syndrome. The pathophysiology of obesity-associated AKI is not completely understood. Obesity-related factors combined with the burden of other comorbidities in elderly obese patients may interact with known precipitating factors such as hypotension, nephrotoxins or sepsis and increase the susceptibility of this population to AKI. Whether or not obesity may counterintuitively be protective and associated with better survival of critically ill patients with AKI ("reverse epidemiology") is a subject for debate. Further investigations exploring the role of novel biomarkers and optimal management are needed urgently.

In vivo screen of genetically conserved Streptococcus pneumoniae proteins for protective immunogenicity.

We evaluated 52 different E. coli expressed pneumococcal proteins as immunogens in a BALB/c mouse model of S. pneumoniae lung infection. Proteins were selected based on genetic conservation across disease-causing serotypes and bioinformatic prediction of antibody binding to the target antigen. Seven proteins induced protective responses, in terms of reduced lung burdens of the serotype 3 pneumococci. Three of the protective proteins were histidine triad protein family members (PhtB, PhtD and PhtE). Four other proteins, all bearing LPXTG linkage domains, also had activity in this model (PrtA, NanA, PavB and Eng). PrtA, NanA and Eng were also protective in a CBA/N mouse model of lethal pneumococcal infection. Despite data inferring widespread genomic conservation, flow-cytometer based antisera binding studies confirmed variable levels of antigen expression across a panel of pneumococcal serotypes. Finally, BALB/c mice were immunized and intranasally challenged with a viulent serotype 8 strain, to help understand the breadth of protection. Those mouse studies reaffirmed the effectiveness of the histidine triad protein grouping and a single LPXTG protein, PrtA.

Assessment of dialysis dose in critically ill maintenance dialysis patients.

Maintenance dialysis patients are admitted more frequently to the intensive care unit (ICU) and have higher ICU mortality than the general population. It is unclear if such dialysis patients receive adequate dialysis in the ICU setting. Using the Daugirdas formula for calculation of spKt/Vurea, single treatment delivered dialysis dose was assessed in 85 critically ill maintenance hemodialysis patients during their first ICU dialysis session. Weekly delivered spKt/Vurea was determined in the surviving 64 patients and compared with their corresponding delivered outpatient dialysis dosages. Outcome measures were ICU and in-hospital mortality and mortality at 6 and 12 months after discharge. Prescribed dose of the first ICU dialysis was a spKt/Vurea of 1.43 ± 0.11, the single treatment delivered dose was 1.02 ± 0.14. The weekly prescribed ICU Kt/Vurea was 4.25 ± 0.12 and delivered ICU Kt/Vurea was 3.48 ± 0.19. Patients with sepsis had the lowest mean spKt/Vurea values (0.87 ± 0.12). Serial measurements of delivered dialysis dose suggest that this gap is explained by variability of volume of urea distribution. ICU mortality was 25% and was related to APACHE II score, but not to delivered intermittent hemodialysis dose. Critically ill maintenance dialysis patients receive suboptimal dialysis doses. The impact of short-term underdialysis on survival of hospitalized maintenance dialysis patients remains unknown. Assessment of dialysis adequacy should be routinely performed in these patients and delivered dialysis should be tracked through the initial clinical course.