The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

Inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C (rs11706052) and 12-month evolution of the graft function in renal transplant recipients on mycophenolate-based immunosuppression.

Variant allele at the inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C has been associated with increased enzyme activity and reduced susceptibility to mycophenolic acid (MPA) in vitro. It has been suggested associated with an increased risk of acute rejection in renal transplant recipients on MPA-based immunosuppression, but not unambiguously. We assessed one-year evolution of the estimated glomerular filtration rate (eGFR) in transplanted variant allele carriers and wild-type subjects, while controlling for a number of demographic, pharmacogenetic, (co)morbidity, and treatment baseline and time-varying covariates. The eGFR slopes to day 28 (GMR = 1.01, 95% CI 0.93-1.09), and between days 28 and 365 (GMR = 1.01, 95% CI 0.99-1.02) were practically identical in 52 variant carriers and 202 wild-type controls. The estimates (95%CIs) remained within the limits of ±20% difference even after adjustment for a strong hypothetical effect of unmeasured confounders. Polymorphism IMPDH2 3757T>C does not affect the renal graft function over the 1st year after transplantation.

Combining Complementary and Alternative Medicine (CAM) with Conventional Treatments for Major Depressive Disorder.

For many of the complementary and alternative (CAM) medicine methods, it is biologically plausible to expect that they could provide additional benefits in the treatment of major depressive disorder (e.g., enhanced initial response, augmentation, and tolerability) when combined with conventional treatments. Although most likely not comprehensively, herein we critically review current explicit clinical data pertaining to the most extensively evaluated CAMs in this setting: physical activity/exercise, mind and body methods, acupuncture, light therapy, diet, probiotics, various nutrients, and herbal preparations. While the absolute amount of data is enormous, the number of reliable primary studies (randomized controlled trials) and, particularly, meaningful meta-analyses of such studies are very limited. Consequently, the certainty of evidence about benefit or no benefit is very low for each of the addressed CAMs.

Is there a relationship between attitudes of general practitioners/family doctors and attitudes of their patients regarding industry-sponsored clinical investigations? A cross-sectional survey in a convenience sample of doctors and patients across nine European countries.

AIM: To assess the relationship between the attitudes of general practitioners/family medicine doctors (GP/FD) and of their patients toward industry-sponsored clinical research. METHODS: A cross-sectional survey included volunteer GPs/FDs who then enrolled and interviewed their patients. Data were analyzed in hierarchical models (patients nested in GPs/FDs, nested in countries/regions). RESULTS: A total of 201 GPs/FDs from nine European countries responded to the invitation and enrolled 995 of their patients. We observed mild associations between some of the GPs/FDs' attitudes (general opinion on sponsored clinical studies, appreciation of the general values of such studies, views about the importance of participant protection/privacy) and some of the patients' attitudes (appreciation of the general values and of risks associated with sponsored clinical studies, importance assigned to potential personal benefits from participation). We observed no association between GPs/FDs' attitudes and patients' willingness to participate in such studies. However, willingness to participate increased with higher patients' appreciation of the general values of sponsored studies, decreased with higher patients' appreciation of associated risks, and showed a quadratic trend across the levels of importance assigned by patients to potential personal benefits (willingness was higher when the assigned importance was very low or very high). More importance to GP/FD's advice in this respect was assigned by patients who assigned more importance to potential personal benefits, who were better educated, and who resided in rural/suburban dwellings. CONCLUSIONS: In the present convenience sample, lay-person attitudes about and willingness to participate in industry-sponsored clinical studies were associated with the attitudes of their GPs/FDs.

People exposed to proton-pump inhibitors shortly preceding COVID-19 diagnosis are not at an increased risk of subsequent hospitalizations and mortality: A nationwide matched cohort study.

AIMS: To assess whether exposure to proton-pump inhibitors (PPIs) shortly preceding COVID-19 diagnosis affected the risk of subsequent hospitalizations and mortality. METHODS: This population-based study embraced first COVID-19 episodes in adults diagnosed up to 15 August 2021 in Croatia. Patients were classified based on exposure to PPIs and burden of PPI-requiring morbidities as nonusers (no issued prescriptions, no recorded treatment-requiring conditions between 1 January 2019 and COVID-19 diagnosis), possible users (no issued prescriptions, but morbidities present; self-medication possible) and users (≥1 prescription within 3 months prior to the COVID-19 diagnosis; morbidities present). Subsets were mutually exactly matched for pre-COVID-19 characteristics. The contrast between users and possible users informed about the effect of PPIs that is separate of the effect of PPI-requiring conditions. RESULTS: Among 433 609 patients, users and possible users were matched 41 195 (of 55 098) to 17 334 (of 18 170) in the primary and 33 272 to 16 434 in the sensitivity analysis. There was no relevant difference between them regarding mortality (primary: relative risk [RR] = 0.93 [95% confidence interval 0.85-1.02; absolute risk difference [RD] = -0.34% [-0.73, 0.03]; sensitivity: RR = 0.88 [0.78-0.98]; RD = -0.45% [-0.80, -0.11]) or hospitalizations (primary: RR = 1.04 [0.97-1.13]; RD = 0.29% [-0.16, 0.73]; sensitivity: RR = 1.05 [0.97-1.15]; RD = 0.32% [-0.12, 0.75]). The risks of both were slightly higher in possible users or users than in nonusers (absolutely by ~0.4-1.6%) indicating the effect of PPI-requiring morbidities. CONCLUSION: Premorbid exposure to PPIs does not affect the risk of death or hospitalization in adult COVID-19 patients, but PPI-requiring morbidities seemingly slightly increase the risk of both.

Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of subsequent hospitalization and death compared to their non-prescribed peers: population-based matched cohort study.

PURPOSE: To assess the effect of exposure to fluvoxamine around the COVID-19 diagnosis on subsequent hospitalizations and mortality in COVID-19 outpatients in a real-life setting. METHODS: Using nationwide administrative data, we identified adult COVID-19 outpatients diagnosed up to August 15, 2021 and conducted two cohort studies. Study 1 included subjects prescribed fluvoxamine around the index COVID-19 diagnosis (Cohort A), their peers suffering similar psychiatric difficulties but not prescribed fluvoxamine (Cohort B) and those free of psychiatric difficulties/treatments (Cohort C). Study 2 included subjects prescribed fluvoxamine (Cohort Fluvoxamine) and their peers prescribed paroxetine (Cohort Paroxetine). Cohorts were mutually exactly matched and incidence of COVID-19-related hospitalization, 30-day all-cause hospitalization and of COVID-19-related mortality was estimated. RESULTS: Of the 416,030 first-episode outpatients, Study 1 included 1016 Cohort A, 95,984 Cohort B and 275,804 Cohort C patients. Matched Cohort A (n = 749) vs. Cohort B (n = 31,336) relative risks (95%CI/CrI), frequentist and Bayes with skeptical, otpimistic and pesimistic priors, were COVID-related hospitalization 1.37 (0.56-3.33), 1.15 (0.55-2.11), 1.03 (0.56.1.96) and 1.43 (0.63-2.94), respectively; 30-day all-cause hospitalization 1.88 (0.76-4.67), 1.76 (1.39-2.25), 1.76 (1.39-2.24) and 1.86 (1.43-2.38), respectively; COVID-19-related mortality 0.73 (0.35-1.55), 0.93 (0.53-1.76), 0.79 (0.40-1.54) and 0.88 (0.37-2.11), respectively. Matched Cohort A vs. C (866 vs. 222,792) comparison yielded similar estimates, as did the matched Cohort Fluvoxamine vs. Paroxetine comparison in Study 2 (344 of 994 matched to 535 of 1796 patients). CONSLUSION: Outpatients prescribed fluvoxamine around the time of COVID-19 diagnosis were not at a reduced risk of hospitalizations and mortality compared to their non-prescribed peers.

Bearing variant alleles at uridine glucuronosyltransferase polymorphisms UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) has no relevant consequences for lamotrigine troughs in adults with epilepsy.

PURPOSE: To estimate whether epilepsy patients with variant UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) alleles differ from their wild-type (wt) peers in exposure to lamotrigine. METHODS: Consecutive adults on lamotrigine monotherapy or lamotrigine + valproate co-treatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for UGT2B7 -161C > T and UGT1A4*3 c.142 T > G. Heterozygous, variant homozygous, or combined heterozygous/variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, rs7668258/rs2011425, polymorphisms of efflux transporter proteins ABCG2 c.421C > A (rs2231142) and ABCB1 1236C > T (rs1128503), and level of exposure to valproate using covariate entropy balancing. RESULTS: Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were co-treated with valproate. Dose-adjusted lamotrigine troughs in UGT2B7 -161C > T heterozygous (CT, n = 237) or variant homozygous (TT, n = 115) subjects were closely similar to those in their wt controls (CC, n = 119): geometric means ratios (GMRs) (frequentist and Bayes) 1.00 (95%CI 0.86-1.16) and 1.00 (95%CrI 0.83-1.22) for CT vs. CC; and 0.97 (0.81-1.17) and 0.97 (0.80-1.20) for TT vs. CC subjects. Lamotrigine troughs were also closely similar in UGT1A4*3 c.142 T > G variant carriers (n = 106: 102 TG + 4 GG subjects) and wt controls (TT, n = 365): GMR = 0.95 (0.81-1.12) frequentist, 0.96 (0.80-1.16) Bayes. GMRs for variant carriers vs. wt controls were around unity also at different levels of exposure to valproate. CONCLUSION: Dose-adjusted lamotrigine troughs in epilepsy patients with variant UGT2B7 -161C > T or UGT1A4*3 c.142 T > G alleles are equivalent to those in their respective wt peers.

Association between serological indicators of past contacts with Herpesviridae and a slower resolution of chronic spontaneous urticaria in children.

AIM: To evaluate the relationship between serological indicators of Herpesviridae infection and evolution of symptoms in children with chronic spontaneous urticaria (CSU). METHODS: In this observational study, consecutive children with CSU underwent, at presentation, clinical and laboratory work-up, autologous serum skin test (ASST) to identify autoimmune urticaria (CAU), disease severity assessment (urticaria activity score 7, UAS7), serological diagnostics for Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus-6 (HHV-6), and parvovirus B19, as well as for Mycoplasma pneumoniae and Chlamydia pneumoniae. Children were re-assessed at 1, 6, and 12 months after the commencement of antihistamine/antileukotriene treatment. RESULTS: None of the 56 included children had an acute CMV/EBV or HHV-6 infection, but 17 (30.3%) had IgG antibodies against CMV, EBV, or HHV-6 (five were also seropositive for parvovirus B19); 24 (42.8%) suffered from CAU; and 9 (16.1%) were seropositive for Mycoplasma/Chlamydia pneumoniae. The initial symptom severity was moderate-to-severe (UAS7 quartiles 18-32) and comparable between Herpesviridae-seropositive and Herpesviridae-seronegative patients. At 1, 6, and 12 months, UAS7 was consistently higher in seropositive children. In a multivariable analysis (adjusted for age, baseline UAS7, ASST, mean platelet volume, and other serology), Herpesviridae seropositivity was associated with higher UAS scores: mean difference 4.2 score points (95% confidence interval 0.5-7.9; Bayes estimate 4.2, 95% credible interval 1.2-7.3) in a mixed model for repeated measures. This estimate was comparable between children with positive (CAU) and negative (CSU) ASST. CONCLUSION: A history of CMV/EBV/HHV-6 infection might contribute to a slower-resolving CSU in children.

Increased carotid intima-media thickness is associated with higher odds of unfavorable outcomes in adults without advanced vascular diseases presenting with non-severe COVID-19 pneumonia: a nested case-control study.

AIM: To evaluate the association between carotid intima-media thickness (CIMT) at hospital admission and unfavorable outcomes in adults without advanced vascular diseases presenting with non-severe COVID-19 pneumonia to assess the feasibility of evaluating CIMT as a risk stratification aid in this setting. METHODS: This proof-of-concept nested case-control study enrolled consecutive non-vaccinated adults free of advanced vascular diseases presenting with verified non-severe COVID-19 pneumonia between December 2020 and June 2021. CIMT was measured at admission, and patients were managed in line with the national Ministry of Health guidelines. Those who died or required mechanical ventilation (MV) during the index hospital stay were considered cases and were matched (entropy balancing, exact matching) on a set of covariates to survivors not requiring MV (controls). Frequentist and Bayesian logistic models were fitted to the case status. RESULTS: The study enrolled 207 patients: 27 (13%) cases and 180 controls. All were retained in the analysis after entropy balancing, while 27 cases were exactly matched to 99 controls. Higher CIMT at the proximal internal carotid artery (both left and right) was consistently associated with higher odds of being a case: all odds ratio point-estimates were ≥1.50 with lower limits of the 99% confidence intervals/credibility intervals ≥1.00 with two-sided probabilities of OR>1.00 greater than 99.5%. The susceptibility of the estimates to unmeasured confounding was low. CONCLUSION: This study supports the feasibility of CIMT as a risk stratification aid in adults free of advanced vascular disease presenting with non-severe COVID-19 pneumonia.

ASSOCIATION BETWEEN SYMPTOM SEVERITY AND INTENSITY OF ACUTE PSYCHOLOGICAL DISTRESS IN NEWLY DIAGNOSED PATIENTS WITH CHRONIC RHINITIS AND CHRONIC RHINOSINUSITIS.

Chronic rhinitis and rhinosinusitis (CR and CRS) can lead to impairment of the health-related quality of life (HRQL) with higher psychological perceived distress, resulting in disease worsening and poor treatment outcomes. W aimed to evaluate the potential association between disease severity and HRQL impairment with the perceived acute psychological distress in newly diagnosed CR/CRS patients. This single-center cross-sectional study included otherwise healthy consecutive adults with newly diagnosed CR/CRS (European position paper on rhinosinusitis and nasal polyp criteria and International Consensus Statement on Allergy and Rhinology - Allergic Rhinitis criteria or non-allergic rhinitis), who were evaluated for CR/CRS symptom severity and HRQL (Sino Nasal Outcome Test 22 [SNOT-22], visual analog scale [VAS]) and acute perceived distress (Perceived Stress Scale [PSS]). Principal component analysis (SNOT-22 items, VAS) identified 6 components as CR/CRS severity indicators, i.e,, poor sleep, wakes-up tired, nasopharynx, obstruction, torment and rhinorrhea, which were evaluated for association with PSS score. Of the 63 included patients (20 men, age median 38, range 19-75 years), 27 suffered from CR and 36 from CRS. Upon adjustment for age and sex, higher total SNOT-22 (geometric means ratio [GMR]=1.04, 95% CI 1.01-1.06), higher "torment" (GMR=1.13, 1.04-1.24), higher "poor sleep" (GMR=1.11, 1.02-1.21) and higher "wakes-up tired" (GMR=1.11, 1.01-1.21) scores were each associated with a higher PSS score, overall and consistently in CR and CRS patients. In conclusion, more severe CR/CRS is associated with greater perceived psychological distress already at earlier stages of the disease. Paying attention to patient level of distress and anxiety over time may enable better understanding of the connection between exacerbations, symptom severity and psychological burden of the disease.

Assessment of clinically significant portal hypertension by two-dimensional shear wave elastography.

BACKGROUND AND AIMS: To evaluate two-dimensional shear wave elastography (2DSWE) in parallel with transient elastography (TE) for diagnosing clinically significant portal hypertension (CSPH) and high-risk varices (HRV) in patients with chronic liver disease. PATIENTS AND METHODS: Consecutive patients with suspicion of compensated advanced chronic liver disease (cACLD) [liver stiffness measurement (LSM) ≥ 10 kPa by TE, or morphological signs suggestive of cACLD on imaging], with no history of liver decompensation, underwent hepatic venous pressure gradient (HVPG) measurement, transjugular liver biopsy and esophagogastroduodenoscopy, which served as the reference methods for diagnosing CSPH, cACLD and HRV. All patients underwent LSM and spleen stiffness measurements (SSM) by 2DSWE and TE. RESULTS: Seventy-six (76) patients were included (78% men, mean age 62 years, body mass index 28.3 kg/m2 , 36.8% alcoholic, 30.3% non-alcoholic fatty liver disease, 14.5% viral hepatitis). Of them, 80.3%, 69.7%, 52.6% and 22.4% had cACLD, cirrhosis, CSPH and HRV respectively. LSM performed better than SSM in diagnosing CSPH and HRV. For CSPH, AUROCs (0.926 vs. 0.866), optimal cut-offs (20.1 vs. 20.2 kPa) and sensitivity/specificity (80.5%/94.3% vs. 77.5% /86.1%) were comparable for 2DSWE and TE. Ruling-out of CSPH by 2DSWE (LSM at cut-off with ≥90% sensitivity (13.5 kPa) and platelets ≥ 150 x 109 /L) performed comparably to TE, with 1/24 cases falsely classified as negative. For HRV, AUROCs were similar (0.875 2DSWE, 0.851 TE) with similar optimal LSM cut-offs enabling 100% sensitivity and ruling-out HRV. CONCLUSION: Liver stiffness measurement by 2DSWE appears to perform equally well as TE for diagnosing CSPH and ruling-out HRV in compensated chronic liver disease.

DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine-based protocols.

AIMS: Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798 and rs56038477). We evaluated the relationship between three further DPYD polymorphisms: c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265) and the risk of severe AEs. METHODS: Consecutive FP-treated adult patients were genotyped for "standard" and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms). RESULTS: Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhoea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n = 127) than in controls (n = 376) [OR = 5.20 (95% CI 1.88-14.3), Bayesian OR = 5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in c.2194G>A variant carriers (n = 58) than in controls (n = 432) [OR = 1.88 (0.95-3.73), Bayesian OR = 1.90 (1.03-3.56)]. c.85T>C did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). CONCLUSION: DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.

Postoperative acute kidney injury and renal replacement therapy after DCD lung transplantation.

Acute kidney injury (AKI) after lung transplantation (LTx) is a common complication. We aimed to assess whether donation after circulatory death (DCD) is associated with an increased risk of AKI and renal replacement therapy (RRT) in the early postoperative period compared to the donation after brain death (DBD). Retrospective data on a cohort (N = 95) of LTx patients (DCD n = 17, DBD n = 78) characterized by no use of ex-vivo lung perfusion were analyzed for the incidence of AKI within 30 postoperative days and incidence of RRT within 7 and 30 days. After optimal full matching, an imbalance remained between the DCD and DBD patients in respect to intraoperative use of cardiopulmonary bypass (CPB). Therefore, a further subset (n = 77) was defined that excluded CPB patients, and matching was repeated (DCD n = 13 vs. DBD n = 63) resulting in a fair balance on a range of preoperative characteristics and intraoperative use of ECMO. In both matched subsets, DCD was associated with around twice higher risk of AKI and RRT within 7 and 30 postoperative days. In conclusion, data suggest that DCD could be associated with worse early renal outcomes in a subset of LTx patients and justify further studies on the topic in order to refine further renal care pathways perioperatively.

Loss of function polymorphisms in SLCO1B1 (c.521T>C, rs4149056) and ABCG2 (c.421C>A, rs2231142) genes are associated with adverse events of rosuvastatin: a case-control study.

PURPOSE: The study aims to evaluate relationship between polymorphisms associated with a reduced function of two transporter proteins resulting in increased exposure to rosuvastatin - organic anion transporter 1B1 (OATP1B1) (SLCO1B1 c.521T>C) and ATP binding cassette subfamily G member 2 (ABCG2) (ABCG2 c.421C>A) and occurrence of rosuvastatin related myotoxicity/hepatotoxicity. METHODS: In a case-control study, cases (rosuvastatin treated patients developing myotoxicity or hepatotoxicity) and controls (concurrent rosuvastatin treated patients free of adverse events) were prospectively recruited over a 2 year period in a single tertiary center specialized in treatment of metabolic disorders. Subjects were evaluated for clinical, comorbidity, and comedication characteristics and for genotype predicted metabolizing phenotypes regarding cytochrome P450 enzymes CYP2C9 and CYP2C19. Standard regression analysis and analysis in matched sets of cases and controls (optimal full matching) were undertaken by fitting frequentist and Bayesian models (covariates/matching variables: age, sex, diabetes, liver/renal disease, hypertension, CYP2C9 and C19 phenotype, use of CYP or transporter inhibitors, non evaluated transporter genotype). RESULTS: A total of 88 cases (81 with myotoxicity, 6 with hepatotoxicity, 1 with both) and 129 controls were recruited. Odds of variant SLCO1B1 c.521T>C allele were 2.2-2.5 times higher in cases than in controls (OR = 2.45, 95% CI 1.34-4.48; Bayesian OR = 2.59, 95% CrI 1.42-4.90 in regression analysis; OR = 2.20, 1.10-4.42; Bayesian OR = 2.26, 1.28-4.41 in matched analysis). Odds of variant ABCG2 c.421C>A allele were 2.1-2.3 times higher in cases than in controls (OR = 2.24, 1.04-4.83; Bayesian OR = 2.35, 1.09-4.31 in regression analysis; OR = 2.10, 0.83-5.31; Bayesian OR = 2.17, 1.07-4.35 in matched analysis). CONCLUSION: Loss of function polymorphisms in SLCO1B1 c.521T>C and ABCG2 c.421C>A genes are associated with the presence of rosuvastatin related myotoxicity and/or hepatotoxicity.

Validation of the New Diagnostic Criteria for Clinically Significant Portal Hypertension by Platelets and Elastography.

BACKGROUND AND AIMS: We aimed to validate newly proposed noninvasive criteria for diagnosing clinically significant portal hypertension (CSPH) using liver stiffness measurements (LSM) by transient elastography (TE) and platelet count. METHODS: Diagnostic performance of these new criteria for CSPH (LSM ≥ 25 kPa to rule in and Plt ≥ 150 × 109/L + LSM ≤ 15 kPa to rule out CSPH) were retrospectively tested in an independent cohort of consecutive patients who underwent hepatic venous pressure gradient (HVPG) measurements and liver biopsy due to suspicion of compensated advanced chronic liver disease. Suspicion of cACLD was based on LSM ≥ 10 kPa by TE or results of liver imaging, without overt signs of CSPH. Patients with conditions known to affect results of LSM (ALT > 5 × ULN, liver congestion, extrahepatic biliary obstruction, infiltrative liver neoplasms) were excluded. RESULTS: Seventy six (76) patients were included: 78.9% males, mean age 62 years, 36.8% suffered from alcoholic, 30.3% nonalcoholic fatty liver disease, 14.5% chronic viral hepatitis, 30.3% were obese, 52.6% had HVPG ≥ 10 mmHg, 56.6% had platelet count ≥ 150 × 109/L. LSM ≥ 25 kPa had 88.9% specificity (95% CI 73.9-96.9) to rule in, whereas Plt ≥ 150 + LSM ≤ 15 kPa had 100% sensitivity (95% CI 91.1-100) to rule out CSPH. CONCLUSION: By using these simple noninvasive criteria 49/76 (64.5%) patients could be classified correctly for the presence/absence of CSPH, thus obviating the need for HVPG measurements.

Comparing mid-term outcomes of Cox-Maze procedure and pulmonary vein isolation for atrial fibrillation after concomitant mitral valve surgery: A systematic review.

BACKGROUND: Although concomitant pulmonary vein isolation (PVI) is used more frequently than the Cox-Maze procedure, which is currently the gold standard treatment for atrial fibrillation (AF), data on the comparative effectiveness of the two procedures after concomitant mitral valve (MV) surgery are still limited. OBJECTIVE: We conducted a systematic review to identify randomized controlled trials (RCTs) and observational studies comparing the mid-term mortality and recurrence of AF after concomitant Cox-Maze and PVI in patients with AF undergoing MV surgery based on 12-month follow-up. METHODS: Medline, EMBASE databases, and the Cochrane Library were searched from 1987 up to March 2022 for studies comparing concomitant Cox-Maze and PVI. Additionally, a meta-analysis of RCTs was performed to compare the mid-term clinical outcomes between these two surgical ablation techniques. RESULTS: Three RCTs and three observational studies meeting the inclusion criteria were included in this systematic review with 790 patients in total (532 concomitant Cox-Maze and 258 PVI during MV surgery). Most studies reported that the concomitant Cox-Maze procedure was associated with higher freedom from AF at 12-month follow-up than PVI. Regarding AF recurrence, estimates pooled across the three RCTs indicated large heterogeneity and high uncertainty. In the largest and highest quality RCT, 12-month AF recurrence was higher in the PVI arm (risk ratio = 1.58, 95% CI: 0.91-2.73). In two out of three higher-quality observational studies, 12-month AF recurrence was higher in PVI than in the Cox-Maze arm (estimated adjusted probabilities 11% vs. 8% and 35% vs. 17%, respectively). RCTs demonstrated comparable 12-month mortality between concomitant Cox-Maze and PVI, while observational studies demonstrated the survival benefit of Cox-Maze. CONCLUSIONS: Concomitant Cox-Maze in AF patients undergoing MV surgery is associated with better mid-term freedom from AF when compared to PVI with comparable mid-term survival. Large observational studies suggest that there might be a mid-term survival benefit among patients after concomitant Cox-Maze. Further large RCTs with longer standardized follow-up are required to clarify the benefits of concomitant Cox-Maze in AF patients during MV surgery.

Midterm outcomes of venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation: Comparison with nonbridged recipients.

OBJECTIVES: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is increasingly being used in acutely deteriorating patients with end-stage lung disease as a bridge to transplantation (BTT). It can allow critically ill recipients to remain eligible for lung transplants (LTx) while reducing pretransplant deconditioning. We analyzed early- and midterm postoperative outcomes of patients on VV-ECMO as a BTT and the impact of preoperative VV-ECMO on posttransplant survival outcomes. METHODS: All consecutive LTx performed at our institution between January 2012 and December 2018 were analyzed. After matching, BTT patients were compared with nonbridged LTx recipients. RESULTS: Out of 297 transplanted patients, 21 (7.1%) were placed on VV-ECMO as a BTT. After matching, we observed similar 30-day mortality between BTT and non-BTT patients (4.6% vs. 6.6%, p = .083) despite a higher incidence of early postoperative complications (need for ECMO, delayed chest closure, and acute kidney injury). Furthermore, preoperative VV-ECMO did not appear associated with 30-day or 1-year mortality in both frequentist and Bayesian analysis (odds ratio [OR]: 0.35, 95% confidence interval: 0.03-3.49, p = .369; OR: 0.27, 95% credible interval: 0.01-3.82, p = 84.7%, respectively). In sensitivity analysis, both subgroups were similar in respect to 30-day (7.8% vs. 6.5%, p = .048) and 1-year mortality (12.5% vs. 18%, p = .154). CONCLUSIONS: Patients with acute refractory respiratory failure while waiting for LTx represent a high-risk cohort of patients. VV-ECMO as a BTT is a reasonable strategy in adult patients with acceptable operative mortality and 1-year survival comparable to non-BTT patients.

Mortality and morbidity in surgically treated patients with petroclival meningiomas: a systematic review and meta-analysis of case series.

BACKGROUND: Reports on petroclival meningioma (PCM) surgical mortality and morbidity often deviate from established standards; as such, a comprehensive summary is lacking. METHODS: Eligibility/sources. Peer-reviewed case series of at least 10 PCM patients identified from PubMed, Web of Science, Ovid, or Google Scholar. Outcomes. Primary: mortality, tumor recurrence, any cranial nerve deficit (CND); other: individual CNDs, other complications. Data synthesis. Random-effects meta-analysis/meta-regression [effects: surgical approach (supratentorial, S; infratentorial, I; combined, (C), average age and follow-up, sample size, and percent of patients with gross-total resection (GTR)] of logit-transformed proportions. RESULTS: Data. 73 case-series/3553 patients. Mortality. Adjusted predicted mortalities of 2.4%, 2.5%, and 1.2% (50-month follow-up) for the S, I, and C approaches, respectively, with the upper limits of the 95% credibility intervals at 3.3%, 3.7%, and 3.6%, respectively. Recurrence. Adjusted predicted recurrences of 5.5%, 11.1%, and 12.0% (50-month follow-up and 57% GTR) for the S, I, and C approaches, respectively; recurrence was positively associated with follow-up period and negatively associated with having received GTR. At all covariates at median values but at GTR 90% predictions: 3.1% (95%CI 3.1-9.8), 6.3% (3.8-10.4), and 6.9% (3.4-13.2) with the S, I, and C; prediction credibility intervals 1-4% and 22.4%. Any CND. Adjusted predicted probabilities of 37.2%, 23.4%, and 29.5% (at median covariate values) for the S, I, and C approaches, respectively; prediction credibility intervals ranged from <10% to 78%. Other outcomes. The most common individual CNDs were nVII (14.4%), nV (11.5%), and nIII (10.2%); other common complications included motor deficit (10.8%), infection (9.8%), and CSF leak (7.5%). CONCLUSION: This is the first systematic review on PCM surgical mortality, recurrence, and morbidity. Outcomes differ between surgical approaches and reporting quality varies greatly.

Red Cell Distribution Width in Acute Pulmonary Embolism Patients Improves 30-Day Mortality Risk Stratification Based on the Pulmonary Embolism Severity Index.

PURPOSE: To validate red cell distribution width (RDW) as an improvement in 30-day mortality risk stratification based on the Pulmonary Embolism Severity Index (PESI) in acute pulmonary embolism (PE). PATIENTS AND METHODS: Prospective observational analysis of consecutive adult acute PE patients. RESULTS: Among 731 patients, 30-day mortality was 11.9%. With adjustment for the PESI score and number of covariates, higher RDW was associated with higher mortality (RDW continuous: OR 1.21, 95% CI 1.06-1.38; Bayesian OR 1.22, 1.07-1.40; RDW 'high' [>14.5% in men >16.1% in women] vs normal: OR 3.83, 1.98-7.46; Bayesian OR 3.98, 2.04-7.68]. Crude mortality was 3.6% if PESI 86-105 (intermediate risk), but 1.2% if RDW normal and 7.1% if RDW high; 11.8% if PESI 106-125 (high risk), but 3.6% if RDW normal and 18.8% if RDW high. Adjusted probabilities showed higher mortality (ORs between 3.5-5.8) if RDW was high in any PESI risk subgroup. Crude mortality rates in two random-split subsets (n=365 and n=366) again showed the same patterns. CONCLUSIONS: On-admission RDW above the normal range improves 30-day mortality risk stratification based on PESI score in acute PE. Particularly, it corrects PESI-based intermediate-risk or high-risk allocation by reclassification into very low-risk (<3.5%) or very high-risk (>11.0%).

Current Research on Complementary and Alternative Medicine (CAM) in the Treatment of Major Depressive Disorder: An Evidence-Based Review.

Complementary and alternative medicine (CAM) encompasses a wide range of different non-mainstream therapies that have been increasingly used for treatment or adjunctive treatment of various ailments with mood disorders and "depressive difficulties" being two of the commonly CAM (self-)medicated conditions. We focus specifically on clinically diagnosed (in line with the standard criteria) depressive disorders, primarily major depressive disorder (MDD), and overview evidence of efficacy/safety of a range of CAM modalities addressing exclusively randomized controlled trials (RCTs) and systematic reviews/meta-analyses of RCTs. The list of addressed CAM interventions is not exhaustive: due to space limitation, addressed are interventions with at least a few conducted RCTs in the specific clinical conditions. We try to provide numerical and meaningful data as much as it is possible and to (a) indicate situations in which the reported data/estimates might have been "too enthusiastic" and (b) warn about heterogeneity of results that, together with other possible limitations (various biases and imprecision), results in uncertainty about the effects.