Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis.

OBJECTIVE: Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. DESIGN: Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. RESULTS: After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. CONCLUSIONS: The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. TRIAL REGISTRATION NUMBER: NCT04777812.

Preoperative Delirium Risk Screening in Patients Undergoing a Cardiac Surgery: Results from the Prospective Observational FINDERI Study.

OBJECTIVE: Postoperative delirium (POD) is a common complication of cardiac surgery that is associated with higher morbidity, longer hospital stay, cognitive decline, and mortality. Preoperative assessments may help to identify patients´ POD risk. However, a standardized screening assessment for POD risk has not been established. DESIGN: Prospective observational FINd DElirium RIsk factors (FINDERI) study. PARTICIPANTS: Patients aged ≥50 years undergoing cardiac surgery. MEASUREMENTS: The primary aim was to analyze the predictive value of the Delirium Risk Screening Questionnaire (DRSQ) prior to cardiac surgery. Secondary aims are to investigate cognitive, frailty, and geriatric assessments, and to use data-driven machine learning (ML) in predicting POD. Predictive properties were assessed using receiver operating characteristics analysis and multivariate approaches (regularized LASSO regression and decision trees). RESULTS: We analyzed a data set of 504 patients (68.3 ± 8.2 years, 21.4% women) who underwent cardiac surgery. The incidence of POD was 21%. The preoperatively administered DRSQ showed an area under the curve (AUC) of 0.68 (95% CI 0.62, 0.73), and the predictive OR was 1.25 (95% CI 1.15, 1.35, p <0.001). Using a ML approach, a three-rule decision tree prediction model including DRSQ (score>7), Trail Making Test B (time>118), and Montreal Cognitive Assessment (score ≤ 22) was identified. The AUC of the three-rule decision tree on the training set was 0.69 (95% CI 0.63, 0.75) and 0.62 (95% CI 0.51, 0.73) on the validation set. CONCLUSION: Both the DRSQ and the three-rule decision tree might be helpful in predicting POD risk before cardiac surgery.

Evaluating palliative care case conferences in primary care for patients with advanced non-malignant chronic conditions: a cluster-randomised controlled trial (KOPAL).

BACKGROUND: Patients with congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and dementia are underrepresented in specialist palliative home care (SPHC). However, the complexity of their conditions requires collaboration between general practitioners (GPs) and SPHC teams and timely integration into SPHC to effectively meet their needs. OBJECTIVE: To facilitate joint palliative care planning and the timely transfer of patients with advanced chronic non-malignant conditions to SPHC. METHODS: A two-arm, unblinded, cluster-randomised controlled trial. 49 GP practices in northern Germany were randomised using web-based block randomisation. We included patients with advanced CHF, COPD and/or dementia. The KOPAL intervention consisted of a SPHC nurse-patient consultation followed by an interprofessional telephone case conference between SPHC team and GP. The primary outcome was the number of hospital admissions 48 weeks after baseline. Secondary analyses examined the effects on health-related quality of life and self-rated health status, as measured by the EuroQol 5D scale. RESULTS: A total of 172 patients were included in the analyses. 80.4% of GP practices had worked with SHPC before, most of them exclusively for cancer patients. At baseline, patients reported a mean EQ-VAS of 48.4, a mean quality of life index (EQ-5D-5L) of 0.63 and an average of 0.80 hospital admissions in the previous year. The intervention did not significantly reduce hospital admissions (incidence rate ratio = 0.79, 95%CI: [0.49, 1.26], P = 0.31) or the number of days spent in hospital (incidence rate ratio = 0.65, 95%CI: [0.28, 1.49], P = 0.29). There was also no significant effect on quality of life (∆ = -0.02, 95%CI: [-0.09, 0.05], P = 0.53) or self-rated health (∆ = -2.48, 95%CI: [-9.95, 4.99], P = 0.51). CONCLUSIONS: The study did not show the hypothesised effect on hospitalisations and health-related quality of life. Future research should focus on refining this approach, with particular emphasis on optimising the timing of case conferences and implementing discussed changes to treatment plans, to improve collaboration between GPs and SPHC teams.

Evaluation of the non-invasive Temple Touch Pro temperature monitoring system compared with oesophageal temperature in paediatric anaesthesia (PETER PAN): A prospective observational study.

BACKGROUND: Monitoring peri-operative body temperature in children is currently mainly achieved through invasive devices. The Temple Touch Pro Temperature Monitoring System estimates core temperature noninvasively based on heat flux thermometry. OBJECTIVE: To investigate the agreement of this noninvasive sensor against standard oesophageal core temperature. DESIGN: A prospective observational study. SETTING: University hospital recruiting between April and July 2021. PATIENTS: One hundred children (32 girls) aged 6 years or younger scheduled for noncardiac surgery, resulting in 6766 data pairs. Exclusion criteria were contraindication for the insertion of an oesophageal temperature probe, and procedures in which one of the measurement methods would interfere with the surgical field. MAIN OUTCOME MEASURES: Primary outcome was the agreement analysis by a Bland-Altman comparison with multiple measurements. Posthoc, we performed another agreement analysis after exclusion of a statistically determined equilibration time. Secondary outcomes were the temperature differences over time and subgroup analysis of hypothermic, normothermic and hyperthermic temperature ranges, age, sex and sensor's side by type III analysis of variance. Further, we correlated the sonographically determined depth of the artery with trueness. RESULTS: The mean difference was -0.07°C (95% CI -0.15 to +0.05) with limits of agreement of -1.00 and +0.85°C. After adjusting for an equilibration time of 13 min, the mean difference improved to -0.04°C (95% CI -0.08 to +0.01) with limits of agreement of -0.68 and +0.60°C. Concordance correlation coefficient was 0.83 (95% CI 0.82 to 0.84). Differences between the skin sensor and oesophageal reference increased over time by -0.05°C per hour. Subgroup analysis showed no clinically relevant differences. Depth of artery negatively correlated with trueness by 0.03°C per millimetre. CONCLUSIONS: Although the Temple Touch Pro sensor showed acceptable accuracy after allowing for an equilibration time, it still needs further investigation for routine use in children. This particularly affects accuracy in hypothermic ranges, imprecise positioning and applicability in children with immature or vulnerable skin. TRIAL REGISTRATION: German Clinical Trials Register, identifier: DRKS00024703.

The impact of orthodontic-surgical treatment on facial expressions-a four-dimensional clinical trial.

OBJECTIVE: The objective of this clinical trial was to compare facial expressions (magnitude, shape change, time, and symmetry) before (T0) and after (T1) orthognathic surgery by implementing a novel method of four-dimensional (4D) motion capture analysis, known as videostereophotogrammetry, in orthodontics. METHODS: This prospective, single-centre, single-arm trial included a total of 26 adult patients (mean age 28.4 years; skeletal class II: n = 13, skeletal class III: n = 13) with indication for orthodontic-surgical treatment. Two reproducible facial expressions (maximum smile, lip purse) were captured at T0 and T1 by videostereophotogrammetry as 4D face scan. The magnitude, shape change, symmetry, and time of the facial movements were analysed. The motion changes were analysed in dependence of skeletal class and surgical movements. RESULTS: 4D motion capture analysis was feasible in all cases. The magnitude of the expression maximum smile increased from 15.24 to 17.27 mm (p = 0.002), while that of the expression lip purse decreased from 9.34 to 8.31 mm (p = 0.01). Shape change, symmetry, and time of the facial movements did not differ significantly pre- and postsurgical. The changes in facial movements following orthodontic-surgical treatment were observed independently of skeletal class and surgical movements. CONCLUSIONS: Orthodontic-surgical treatment not only affects static soft tissue but also soft tissue dynamics while smiling or lip pursing. CLINICAL RELEVANCE: To achieve comprehensive orthodontic treatment plans, the integration of facial dynamics via videostereophotogrammetry provides a promising approach in diagnostics. TRIAL REGISTRATION NUMBER: DRKS00017206.

[Clinical trials as a central part of patient-centered clinical research]. / Klinische Studien als zentraler Bestandteil patientenorientierter Forschung.

As the continuation and implementation of findings from basic (pre­)clinical research, clinical trials make a significant contribution to medical research. They form the central building block of translational medicine and thus make a decisive contribution to bringing medical knowledge into general care. This helps to make possible a healthcare system that is aligned to the needs of patients and functions efficiently in the long term. Based on the specific objective, clinical trials must comply with national, but increasingly also with European and international regulatory requirements. In academia in particular, expertise in a variety of fields is required in order to make investigator-driven clinical trials a success. This expertise can be provided by a clinical trial center based within the institution conducting the trial.

[Clinical trials as a central part of patient-centered clinical research]. / Klinische Studien als zentraler Bestandteil patientenorientierter Forschung.

As the continuation and implementation of findings from basic (pre-)clinical research, clinical trials make a significant contribution to medical research. They form the central building block of translational medicine and thus make a decisive contribution to bringing medical knowledge into general care. This helps to make possible a healthcare system that is aligned to the needs of patients and functions efficiently in the long term. Based on the specific objective, clinical trials must comply with national, but increasingly also with European and international regulatory requirements. In academia in particular, expertise in a variety of fields is required in order to make investigator-driven clinical trials a success. This expertise can be provided by a clinical trial center based within the institution conducting the trial.

Whole-body cryotherapy for the treatment of rheumatoid arthritis: a monocentric, single-blinded, randomised controlled trial.

OBJECTIVES: To evaluate effects of whole-body cryotherapy (WBC) in rheumatoid arthritis (RA). METHODS: Patients with active RA undergoing a 16-day multimodal rheumatologic complex treatment were randomly assigned to either WBC (6 applications in 14 days at -130°C for 3 min) or no treatment. The primary outcome was the difference between groups in pain on a numerical rating scale after intervention. Secondary outcomes assessed effects on i) disease activity, ii) functional capacity, iii) cytokine levels, and iv) use of analgesics. RESULTS: A total of 56 RA patients completed the trial (intervention group [IG]: 31 patients, control group [CG]: 25 patients). The mean change (± standard error) in pain after intervention was -2 in the IG (95% confidence interval [CI] -2.75 to -1.31, p<0.001) and -0.88 (95% CI -1.43 to -0.33, p=0.003) in the CG, with a baseline-adjusted between-group difference of -1.31 ± 0.4 (95% CI -2.1 to -0.53; p=0.002). Pain at the 12-week follow-up visit remained significantly below baseline values in the IG. Disease activity and functional capacity showed statistically and clinically meaningful improvement after intervention but were not significant at the 12-week follow up. TNF and IL-6 levels changed significantly in the IG. Eighteen of 31 (58%) patients of the IG reduced or discontinued analgesics at the 12-week follow-up. No WBC-related side effects were reported. CONCLUSIONS: WBC in RA reduces pain and disease activity significantly and in a clinically meaningful manner, resulting in a reduction of analgesics. These effects are potentially based on a change in cytokine levels.

Effects of multimodal rheumatologic complex treatment in patients with rheumatoid arthritis: a monocentric prospective study.

OBJECTIVES: To prospectively evaluate the effects of multimodal rheumatologic complex treatment (MRCT), a special concept of in-patient physical treatment (PT), in patients with rheumatoid arthritis (RA). METHODS: RA patients receiving a 16-day MRCT were eligible. MRCT was delivered to participants in 64 PT sessions of various modalities with a minimum of 1.400 Minutes of treatment. The primary outcome was the change in pain levels measured on a numeric rating scale (0-10) between baseline and discharge. Secondary outcomes were assessments of i) disease activity, ii) functional disabilities, iii) serum cytokine levels, iv) analgesic usage, v) patient global health and vi) patient's satisfaction with their therapeutic response to MRCT from baseline to discharge and over a 12-week follow-up. RESULTS: 53 RA patients completed the study and were analysed. Pain levels were reduced significantly and clinically meaningfully (mean ± standard error: -2.1 ± 0.3, p<0.001). Effects of MRCT lasted up to 12 weeks after discharge. After MRCT and during the 12-week follow-up use of analgesics was reduced compared to baseline. Regression analyses revealed no influencing factors on change in pain levels. Patient global health assessment remained improved throughout the entire follow-up period. No MRCT-related side effects were recorded. CONCLUSIONS: MRCT as a multimodal treatment concept with a strong emphasis on PT reduces pain significantly and in a clinically meaningful manner allowing for reduced analgesic usage.

Identification of risk factors for delirium, cognitive decline, and dementia after cardiac surgery (FINDERI-find delirium risk factors): a study protocol of a prospective observational study.

BACKGROUND: Postoperative delirium is a common complication of cardiac surgery associated with higher morbidity, longer hospital stay, risk of cognitive decline, dementia, and mortality. Geriatric patients, patients undergoing cardiac surgery, and intensive care patients are at a high risk of developing postoperative delirium. Gold standard assessments or biomarkers to predict risk factors for delirium, cognitive decline, and dementia in patients undergoing cardiac surgery are not yet available. METHODS: The FINDERI trial (FINd DElirium RIsk factors) is a prospective, single-center, observational study. In total, 500 patients aged ≥ 50 years undergoing cardiac surgery at the Department of Cardiovascular and Thoracic Surgery of the University of Göttingen Medical Center will be recruited. Our primary aim is to validate a delirium risk assessment in context of cardiac surgery. Our secondary aims are to identify specific preoperative and perioperative factors associated with delirium, cognitive decline, and accelerated dementia after cardiac surgery, and to identify blood-based biomarkers that predict the incidence of postoperative delirium, cognitive decline, or dementia in patients undergoing cardiac surgery. DISCUSSION: This prospective, observational study might help to identify patients at high risk for delirium prior to cardiac surgery, and to identify important biological mechanisms by which cardiac surgery is associated with delirium. The predictive value of a delirium screening questionnaire in cardiac surgery might be revealed. Finally, the identification of specific blood biomarkers might help to predict delirium, cognitive decline, and dementia in patients undergoing cardiac surgery. TRIAL REGISTRATION: Ethics approval for this study was obtained from the IRB of the University of Göttingen Medical Center. The investigators registered this study in the German Clinical Trials Register (DRKS; https://www.drks.de ) (DRKS00025095) on April 19th, 2021.

Target insertion depth of nasopharyngeal temperature probes in children: A prospective observational study analyzing magnetic resonance images.

BACKGROUND: Core temperature monitoring is indispensable to prevent children from perioperative thermal perturbations. Although nasopharyngeal measurements are commonly used in anesthesia and considered to reflect core temperature accurately, standardized target depths for probe insertion are unknown in children. AIMS: Our primary goal was to determine a target depth of nasopharyngeal temperature probe insertion in children by measuring distances on magnetic resonance imaging (MRI). Secondary aims were to correlate these measurements with biometric variables and facial landmark-distances to derive formulas estimating target depth. METHODS: We conducted a prospective observational study in children ≤12 years undergoing cranial MRI with anesthesia. We documented patient characteristics and measured the landmark-distances nostril-mandible, nostril-tragus, and philtrum-tragus on patient's faces. On MRI, the target point for the probe tip was considered to be the site of the nasopharyngeal mucosa with the closest proximity to the internal carotid artery. After its determination in the transverse axis and triangulation to the sagittal axis, we measured the distance to the nostril. This distance, defined as target insertion depth, was correlated with the patient characteristics and used for univariate and multiple linear regression analysis. RESULTS: One hundred twenty children with a mean age of 4.5 years were included. The target insertion depth ranged from 61.8 mm in infants to 89.8 mm in 12-year-old children. Height correlated best (ρ = 0.685, 95%-CI: [0.57-0.77]). The best-fit estimation in millimeters, "40.8 + height [cm] × 0.32,″ would lead to a placement in the target position in 67% of cases. A simplified approach by categories of 50-80, 80-110, 110-130, and >130 cm height with target insertion depths of 60, 70, 80, and 85 mm, respectively, achieved similar probabilities. CONCLUSIONS: Height-based formulas could be a valuable proxy for the insertion depth of nasopharyngeal temperature probes. Further clinical trials are necessary to investigate their measurement accuracy.

"SpezPat"- common advance directives versus disease-centred advance directives: a randomised controlled pilot study on the impact on physicians' understanding of non-small cell lung cancer patients' end-of-life decisions.

BACKGROUND: The advance directive represents patients' health care choices and fosters patients' autonomy. Nevertheless, understanding patients' wishes based on the information provided in advance directives remains a challenge for health care providers. Based on the ethical premises of positive obligation to autonomy, an advanced directive that is disease-centred and details potential problems and complications of the disease should help health care providers correctly understand patients' wishes. To test this hypothesis, a pilot-study was conducted to investigate whether physicians could make the correct end-of-life decision for their patients when patients used a disease-centred advance directive compared to a common advance directive.  MATERIAL AND METHODS: A randomised, controlled, prospective pilot study was designed that included patients with non-small cell lung cancer (NSCLC) stage VI from the Department of Haematology and Medical Oncology, University Medical Centre, Goettingen. Patients were randomised into intervention and control groups. The control group received a common advance directive, and the intervention group received a disease-centred advance directive. Both groups filled out their advance directives and returned them. Subsequently, patients were asked to complete nine medical scenarios with different treatment decisions. For each scenario the patients had to decide whether they wanted to receive treatment on a 5-point Likert scale. Four physicians were given the same scenarios and asked to decide on the treatment according to the patients' wishes as stated in their advance directives. The answers by patients and physicians were then compared to establish whether physicians had made the correct assumptions. RESULTS: Recruitment was stopped prior to reaching anticipated sample target. 15 patients with stage IV NSCLC completed the study, 9 patients were randomised into the control group and 6 patients in the intervention group. A total of 135 decisions were evaluated. The concordance between physicians' and patients' answers, was 0.83 (95%-CI 0.71-0.91) in the intervention group, compared to 0.60 (95%-CI 0.48-0.70) in the control group, and the difference between the two groups was statistically significant (p = 0.005). CONCLUSION: This pilot study shows that disease-centred advance directives help physicians understand their NSCLC patients' wishes more precisely and make treatment choices according to these wishes. TRIAL REGISTRATION: The study is registered at the German Clinical Trial Register (no. DRKS00017580, registration date 27/08/2019).

Intraoperative zero-heat-flux thermometry overestimates esophageal temperature by 0.26 °C: an observational study in 100 infants and young children.

In pediatric anesthesia, deviations from normothermia can lead to many complications, with infants and young children at the highest risk. A measurement method for core temperature must be clinically accurate, precise and should be minimally invasive. Zero-heat-flux (ZHF) temperature measurements have been evaluated in several studies in adults. We assessed the agreement between the 3M Bair Hugger™ temperature measurement sensor (TZHF) and esophageal temperature (TEso) in children up to and including 6 years undergoing surgery with general anesthesia. Data were recorded in 5 min-intervals. We investigated the accuracy of the ZHF sensor overall and in subgroups of different age, ASA classification, and temperature ranges by Bland-Altman comparisons of differences with multiple measurements. Change over time was assessed by a linear mixed model regression. Data were collected in 100 children with a median (1st-3rd quartile) age of 1.7 (1-3.9) years resulting in 1254 data pairs. Compared to TEso (range from 35.3 to 39.3 °C; median 37.2 °C), TZHF resulted in a mean bias of +0.26 °C (95% confidence interval +0.22 to +0.29 °C; 95% limits of agreement -0.11 to +0.62 °C). Lin's concordance correlation coefficient was 0.89. There was no significant or relevant change of temperature over time (0.006 °C per hour measurement interval, p = 0.199) and no relevant differences in the subgroups. Due to the mean bias of +0.26 °C in TZHF, the risk of hypothermia may be underestimated, while the risk of hyperthermia may be overestimated. Nevertheless, because of its high precision, we consider ZHF valuable for intraoperative temperature monitoring in children and infants.

Interexaminer reliability of the German version of the DC/TMD.

AIM: Verification of the interrater reliability of axis I diagnoses of the German version of the DC/TMD. The hypothesis was that the DC/TMD protocol yields comparable results, if examiner instructions are closely followed. MATERIAL AND METHODS: A culturally equivalent German translation of the DC/TMD was developed. During a 1-day calibration workshop at the University of Heidelberg, three examiners were trained by the DC/TMD Training and Calibration Center. According to the calibration guidelines, 16 models (11 cases, five non-cases) were examined by four experienced TMD specialists. Reliability was calculated with reference to the reference standard examiner as percentage agreement and kappa coefficients for DC/TMD diagnoses and intraclass correlation coefficients (ICCs) for findings. RESULTS: Excellent reliability was achieved for the diagnoses myalgia, myofascial pain with referral, arthralgia, headache attributed to TMD, disc displacement (DD) with reduction, DD without reduction without limited opening (κ = 0.85…1.00). Degenerative joint disease was diagnosed with substantial agreement (κ = 0.64), DD with reduction with intermittent locking and DD without reduction with limited opening were not present in our sample. Overall percentage agreement was 94%-100% for all diagnoses. CONCLUSION: The German version of the DC/TMD shows very good reliability and can be recommended for the use in clinical and research settings.

Time-Dependent Apparent Increase in dd-cfDNA Percentage in Clinically Stable Patients Between One and Five Years Following Kidney Transplantation.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is reportedly a valuable tool for graft surveillance following kidney transplantation (KTx). Possible changes in dd-cfDNA(%) reference values over time have not been evaluated. For long-term monitoring after KTx, changes in host cfDNA might represent a biasing factor in dd-cfDNA(%) determinations. METHODS: Plasma samples were obtained (n = 929) 12-60 months after engraftment in a cross-sectional cohort of 303 clinically stable KTx recipients. Total cfDNA(copies/mL), dd-cfDNA(%), and dd-cfDNA(copies/mL) were determined using droplet-digital PCR. Stability of threshold values in these stable KTx recipients over time was assessed by 80th, 85th, and 90th quantile regression. RESULTS: Upper percentiles of total cfDNA showed a significant decline of -1902, -3589, and -4753 cp/mL/log(month) (P = 0.014, <0.001, and 0.017, respectively), resulting in increasing dd-cfDNA(%) percentiles by 0.25, 0.46, and 0.72%/log(month) (P = 0.04, 0.001, and 0.002, respectively), with doubling of the 85th percentile value by 5 years. In contrast, dd-cfDNA(cp/mL) was stable during the observation period (P = 0.52, 0.29, and 0.39). In parallel increasing white blood cell counts and decreasing tacrolimus concentrations over time were observed. After 5 years, the median total cfDNA was still 1.6-fold (P < 0.001) higher in KTx recipients than in healthy controls (n = 135) and 1.4-fold (P < 0.001) higher than patients with other medical conditions (n = 364). CONCLUSIONS: The time-dependent decrease of host cfDNA resulted in an apparent increase of dd-cfDNA fraction in stable KTx patients. For long-term surveillance, measurement of absolute dd-cfDNA concentrations appears to be superior to percentages to minimize false positive results.

Blinded sample size reestimation for negative binomial regression with baseline adjustment.

In randomized clinical trials, it is standard to include baseline variables in the primary analysis as covariates, as it is recommended by international guidelines. For the study design to be consistent with the analysis, these variables should also be taken into account when calculating the sample size to appropriately power the trial. Because assumptions made in the sample size calculation are always subject to some degree of uncertainty, a blinded sample size reestimation (BSSR) is recommended to adjust the sample size when necessary. In this article, we introduce a BSSR approach for count data outcomes with baseline covariates. Count outcomes are common in clinical trials and examples include the number of exacerbations in asthma and chronic obstructive pulmonary disease, relapses, and scan lesions in multiple sclerosis and seizures in epilepsy. The introduced methods are based on Wald and likelihood ratio test statistics. The approaches are illustrated by a clinical trial in epilepsy. The BSSR procedures proposed are compared in a Monte Carlo simulation study and shown to yield power values close to the target while not inflating the type I error rate.

Absolute quantification of donor-derived cell-free DNA as a marker of rejection and graft injury in kidney transplantation: Results from a prospective observational study.

Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma (dd-cfDNA[cp/mL]) was compared to dd-cfDNA fraction (dd-cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy-proven rejection (BPR). dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd-cfDNA(cp/mL) (AUC = 0.83) compared to dd-cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd-cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8 µg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies.

Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends.

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.