Pharmacokinetic and pharmacodynamic similarity of biosimilar natalizumab (PB006) to its reference medicine: a randomized controlled trial.

BACKGROUND: PB006 (Polpharma Biologics S.A; marketed as Tyruko®, Sandoz) is an approved biosimilar to natalizumab (Tysabri®; Biogen [ref-NTZ]). This multicenter, double-blind, randomized, single-dose study was conducted to demonstrate pharmacokinetic/pharmacodynamic (PK/PD) similarity between PB006 and ref-NTZ. RESEARCH DESIGN AND METHODS: Healthy participants (N = 453) were randomized to receive 3 mg/kg infusion of PB006, US-licensed, or EU-approved ref-NTZ before an 85-day follow-up. Primary PK endpoint was total natalizumab serum concentration over time; secondary PK endpoints explored concentration changes. Primary PD endpoints compared CD19+ cell counts and percentage α4-integrin receptor saturation, per natalizumab's mechanism of action. Secondary PD endpoints explored serum changes in sVCAM-1 and sMAdCAM-1, CD34+, and CD19+ cells. Safety, tolerability, and immunogenicity were assessed. RESULTS: The primary PK endpoint was met, with 90% confidence intervals (CIs) of the geometric mean for serum test/reference ratios contained within a prespecified margin (0.8-1.25). All primary PD endpoints were met, with 90% and 95% CIs within this similarity margin for baseline-adjusted CD19+ cell counts and percentage α4-integrin receptor saturation. All secondary endpoints were similarly contained, except sVCAM. No notable differences in safety, tolerability, or immunogenicity were observed. CONCLUSION: Similarity was confirmed, with PB006 demonstrating PK/PD behavior consistent with that of ref-NTZ. CLINICAL TRIAL REGISTRATION: EudraCT number 2019-003874-15.

PB006 (developed by Polpharma Biologics S.A; and marketed as Tyruko® by Sandoz) is an approved biosimilar to the reference medicine, natalizumab (Tysabri®, Biogen [ref-NTZ]) used to treat relapsing forms of multiple sclerosis. Approved biosimilar medicines have been shown to be as safe and effective as their reference medicines via different types of comparisons to the reference medicine, confirming that physicians and patients can expect the same clinical outcome.This study was conducted to confirm that PB006 acts the same way in the body as ref-NTZ. Healthy participants received one dose of either PB006, ref-NTZ from the US or ref-NTZ from Europe. During the study, blood samples were tested to confirm how much of each medicine was present in participants' blood, as well as to assess changes in immune cells or proteins related to how natalizumab works. The study also measured whether any treatment caused unwanted side effects or caused any changes in the immune system that may stop the medicine working.The results showed that PB006 behaved in the same way as ref-NTZ in the blood. All reported side effects were similar between groups and were as expected for this medicine, and neither PB006 nor ref-NTZ caused any important or unexpected changes to the immune system. This study showed that biosimilar natalizumab, PB006, behaves in the same way as ref-NTZ, and the same treatment outcomes can be expected.

Incorporation of CAD (computer-aided detection) with thin-slice lung CT in routine 18F-FDG PET/CT imaging read-out protocol for detection of lung nodules.

OBJECTIVE: To evaluate the detection rate and performance of 18F-FDG PET alone (PET), the combination of PET and low-dose thick-slice CT (PET/lCT), PET and diagnostic thin-slice CT (PET/dCT), and additional computer-aided detection (PET/dCT/CAD) for lung nodules (LN)/metastases in tumor patients. Along with this, assessment of inter-reader agreement and time requirement for different techniques were evaluated as well. METHODS: In 100 tumor patients (56 male, 44 female; age range: 22-93 years, mean age: 60 years) 18F-FDG PET images, low-dose CT with shallow breathing (5 mm slice thickness), and diagnostic thin-slice CT (1 mm slice thickness) in full inspiration were retrospectively evaluated by three readers with variable experience (junior, mid-level, and senior) for the presence of lung nodules/metastases and additionally analyzed with CAD. Time taken for each analysis and number of the nodules detected were assessed. Sensitivity, specificity, positive and negative predictive value, accuracy, and Receiver operating characteristic (ROC) analysis of each technique was calculated. Histopathology and/or imaging follow-up served as reference standard for the diagnosis of metastases. RESULTS: Three readers, on an average, detected 40 LN in 17 patients with PET only, 121 LN in 37 patients using ICT, 283 LN in 60 patients with dCT, and 282 LN in 53 patients with CAD. On average, CAD detected 49 extra LN, missed by the three readers without CAD, whereas CAD overall missed 53 LN. There was very good inter-reader agreement regarding the diagnosis of metastases for all four techniques (kappa: 0.84-0.93). The average time required for the evaluation of LN in PET, lCT, dCT, and CAD was 25, 31, 60, and 40 s, respectively; the assistance of CAD lead to average 33% reduction in time requirement for evaluation of lung nodules compared to dCT. The time-saving effect was highest in the less experienced reader. Regarding the diagnosis of metastases, sensitivity and specificity combined of all readers were 47.8%/96.2% for PET, 80.0%/81.9% for PET/lCT, 100%/56.7% for PET/dCT, and 95.6%/64.3% for PET/CAD. No significant difference was observed regarding the ROC AUC (area under the curve) between the imaging methods. CONCLUSION: Implementation of CAD for the detection of lung nodules/metastases in routine 18F-FDG PET/CT read-out is feasible. The combination of diagnostic thin-slice CT and CAD significantly increases the detection rate of lung nodules in tumor patients compared to the standard PET/CT read-out. PET combined with low-dose CT showed the best balance between sensitivity and specificity regarding the diagnosis of metastases per patient. CAD reduces the time required for lung nodule/metastasis detection, especially for less experienced readers.

The value of bone SPECT/CT in evaluation of foot and ankle arthrodesis and adjacent joint secondary osteoarthritis.

OBJECTIVE: To evaluate the value of SPECT/CT (single photon emission computed tomography/computed tomography) in foot and ankle arthrodesis and development of secondary osteoarthritis in the adjacent joints. MATERIALS AND METHODS: SPECT/CT of 140 joints in the foot and ankle (34 upper ankle (UA), 28 lower ankle (LA), 27 talonavicular (TN), 12 calcaneo-cuboidal (CC), and 39 other smaller joints after arthrodesis in 72 patients were evaluated retrospectively regarding fusion grade in CT (0 = no fusion, 1 = < 50% fusion, 2 = > 50% fusion, 3 = complete fusion) and radiotracer uptake (0 = no uptake, 1 = mild uptake, 2 = moderate uptake, 3 = high uptake) on SPECT/CT. Severity of osteoarthritis (1 = mild, 2 = moderate, 3 = severe) and radiotracer uptake grade in adjacent joints was also assessed. In 54 patients, clinical information about interventions in the follow-up was available. RESULTS: According to the SPECT/CT, arthrodesis was successful (grade 2 or 3 CT fusion and grade 0 or 1 uptake) in 73% (25/34) of UA joints, 71% (20/28) of LA joints, 67% (18/27) TN, 100% (12/12) CC joints, and 62% (24/39) of other smaller joints. In 12 joints, there were discrepant findings in SPECT/CT (fusion grade 2 and uptake grade 2 or 3 (n = 9); or, fusion grade 0 or 1 and uptake grade 1 (n = 3)). The fusion rate 6-12 months after arthrodesis was 42% (14/33), 59% (20/34) after 13-24 months, and 89% (65/73) after more than 24 months, respectively. Average radiotracer uptake in arthrodesis decreased with age: 6-12 months: 1.60, 12-24 months: 1.32, > 24 months: 0.38. There was a significant negative correlation between radiotracer uptake grade and CT fusion grade. Osteoarthritis was observed in 131 adjacent joints. During the post scan follow-up, additional arthrodeses were performed in 33 joints, of which 11 joints were re-arthrodesis and 22 were new arthrodeses in osteoarthritic adjacent joints. All these 11 joints with failed arthrodesis had grade 0 of CT fusion and grade 2 or 3 of radiotracer uptake. All 22 adjacent joints with osteoarthritis, which subsequently underwent arthrodesis, had grade 2 or 3 radiotracer uptake, and the primary arthrodesis joints were healed and fused in all these cases. CONCLUSION: Bone SPECT/CT is a valuable hybrid imaging tool in the evaluation of foot and ankle arthrodesis and gives additional useful information about the development of secondary osteoarthritis in the adjacent joints with higher value for the assessment of secondary osteoarthritis. A practical four-type classification ('Lucerne Criteria') combining metabolic and morphologic SPECT/CT information for evaluation of arthrodesis joints has been proposed.

MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value.

Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O6-methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment.

The influence of the menstrual cycle and hormonal contraceptives on cardiorespiratory fitness in physically active women: A systematic review and meta-analysis.

Objective: To systematically review and summarize the existing evidence related to the influence of the menstrual cycle (MC) and hormonal contraceptive (HC) use on V˙O2max in physically active women. Methods: This systematic review and meta-analysis conforms to the PRISMA statement guidelines. Four (sub-)meta-analyses were performed. Two focused on longitudinal studies examining the same women several times to compare the V˙O2max during the different menstrual phases or oral contraceptive (OC) use and withdrawal. Two meta-analyses examined if there is a difference in V˙O2max between OC users and normally menstruating women by analyzing cross-sectional studies assigning physically active women to one of these two groups as well as intervention-based studies (cross-over studies, randomized controlled trials considering only the data of the intervention group) comparing women intra-individually with and without OCs. Results: Nine of the included studies (107 women) evaluated the influence of the MC, five studies (69 women) the impact of OCs on V˙O2max, and six studies investigated both topics (88 women). A mean difference of V˙O2max -0.03 ml/kg/min (95%CI -1.06 to 1.01) between the early follicular and luteal menstrual phase was observed. Between the active and inactive phases of OCs, a mean difference of -0.11 ml/kg/min (95%CI -2.32 to 2.10) was found. The inter-individual comparison of naturally menstruating women and OC users showed a mean difference in V˙O2max of 0.23 ml/kg/min (95% CI -2.33 to 2.79) in favor of OC use. The intra-individual comparison of the same women showed a mean decrease in V˙O2max of -0.84 ml/kg/min (95% CI -2.38 to 0.70) after a new start with OCs. Conclusions: Our meta-analyses showed no effects of the MC or the OCs on V˙O2max. More high-quality studies are needed determining the MC phases more precisely, including OCs with the current standard formulations and comparing the influence of different progestins.

Less is more: Antibiotics at the beginning of life.

Antibiotic exposure at the beginning of life can lead to increased antimicrobial resistance and perturbations of the developing microbiome. Early-life microbiome disruption increases the risks of developing chronic diseases later in life. Fear of missing evolving neonatal sepsis is the key driver for antibiotic overtreatment early in life. Bias (a systemic deviation towards overtreatment) and noise (a random scatter) affect the decision-making process. In this perspective, we advocate for a factual approach quantifying the burden of treatment in relation to the burden of disease balancing antimicrobial stewardship and effective sepsis management.

Reducing morbidity associated with subdural drain placement after burr-hole drainage of unilateral chronic subdural hematomas: a retrospective series comparing conventional and modified Nelaton catheter techniques.

PURPOSE: Placement of a subdural drain after burr-hole drainage of chronic subdural hematoma (cSDH) significantly reduces risk of its recurrence and lowers mortality at 6 months. Nonetheless, measures to reduce morbidity related to drain placement are rarely addressed in the literature. Toward reducing drain-related morbidity, we compare outcomes achieved by conventional insertion and our proposed modification. METHODS: In this retrospective series from two institutions, 362 patients underwent burr-hole drainage of unilateral cSDH with subsequent subdural drain insertion by conventional technique or modified Nelaton catheter (NC) technique. Primary endpoints were iatrogenic brain contusion or new neurological deficit. Secondary endpoints were drain misplacement, indication for computed tomography (CT) scan, re-operation for hematoma recurrence, and favorable Glasgow Outcome Scale (GOS) score (≥ 4) at final follow-up. RESULTS: The 362 patients (63.8% male) in our final analysis included drains inserted in 56 patients by NC and 306 patients by conventional technique. Brain contusions or new neurological deficits occurred significantly less often in the NC (1.8%) than conventional group (10.5%) (P = .041). Compared with the conventional group, the NC group had no drain misplacement (3.6% versus 0%; P = .23) and significantly fewer non-routine CT imaging related to symptoms (36.5% versus 5.4%; P < .001). Re-operation rates and favorable GOS scores were comparable between groups. CONCLUSION: We propose the NC technique as an easy-to-use measure for accurate drain positioning within the subdural space that may yield meaningful benefits for patients undergoing treatment for cSDH and vulnerable to complication risks.

Supplementary dydrogesterone is beneficial as luteal phase support in artificial frozen-thawed embryo transfer cycles compared to micronized progesterone alone.

Introduction: The number of frozen embryo transfers increased substantially in recent years. To increase the chances of implantation, endometrial receptivity and embryo competency must be synchronized. Maturation of the endometrium is facilitated by sequential administration of estrogens, followed by administration of progesterone prior to embryo transfer. The use of progesterone is crucial for pregnancy outcomes. This study compares the reproductive outcomes and tolerability of five different regimens of hormonal luteal phase support in artificial frozen embryo transfer cycles, with the objective of determining the best progesterone luteal phase support in this context. Design: This is a single-center retrospective cohort study of all women undergoing frozen embryo transfers between 2013 and 2019. After sufficient endometrial thickness was achieved by estradiol, luteal phase support was initiated. The following five different progesterone applications were compared: 1) oral dydrogesterone (30 mg/day), 2) vaginal micronized progesterone gel (90 mg/day), 3) dydrogesterone (20 mg/day) plus micronized progesterone gel (90 mg/day) (dydrogesterone + micronized progesterone gel), 4) micronized progesterone capsules (600 mg/day), and (5) subcutaneous injection of progesterone 25 mg/day (subcutan-P4). The vaginal micronized progesterone gel application served as the reference group. Ultrasound was performed after 12-15 days of oral estrogen (≥4 mg/day) administration. If the endometrial thickness was ≥7 mm, luteal phase support was started, up to six days before frozen embryo transfer, depending on the development of the frozen embryo. The primary outcome was the clinical pregnancy rate. Secondary outcomes included live birth rate, ongoing pregnancy, and miscarriage and biochemical pregnancy rate. Results: In total, 391 cycles were included in the study (median age of study participants 35 years; IQR 32-38 years, range 26-46 years). The proportions of blastocysts and single transferred embryos were lower in the micronized progesterone gel group. Differences among the five groups in other baseline characteristics were not significant. Multiple logistic regression analysis, adjusting for pre-defined covariates, showed that the clinical pregnancy rates were higher in the oral dydrogesterone only group (OR = 2.87, 95% CI 1.38-6.00, p=0.005) and in the dydrogesterone + micronized progesterone gel group (OR = 5.19, 95% CI 1.76-15.36, p = 0.003) compared to micronized progesterone gel alone. The live birth rate was higher in the oral dydrogesterone-only group (OR = 2.58; 95% CI 1.11-6.00; p=0.028) and showed no difference in the smaller dydrogesterone + micronized progesterone gel group (OR = 2.49; 95% CI 0.74-8.38; p=0.14) compared with the reference group. Conclusion: The application of dydrogesterone in addition to micronized progesterone gel was associated with higher clinical pregnancy rate and live birth rate and then the use of micronized progesterone gel alone. DYD should be evaluated as a promising LPS option in FET Cycles.

Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy: an observational study from central Switzerland.

BACKGROUND: In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. MATERIALS AND METHODS: The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology [IO] group, n = 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n = 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. RESULTS: Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval [CI] 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. CONCLUSION: These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype.

Prevalence of an insufficient vitamin D status at the onset of a spinal cord injury - a cross-sectional study.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: This study aimed to investigate the vitamin D status after acute spinal cord injury (SCI) onset. SETTING: Specialized SCI rehabilitation center in Switzerland. METHODS: Patients admitted to the center after an acute SCI onset were included. The prevalence of a deficient (25(OH)D ≤ 50 nmol/l), insufficient (50 < 25(OH)D ≤ 75 nmol/l) and sufficient (25(OH)D > 75 nmol/l) vitamin D status were determined after admission. Vitamin D status was compared between different patient groups based on demographic and SCI characteristics. The occurrence of bed rest, falls and pressure injuries were also assessed. RESULTS: In total, 87 patients (median (interquartile range); 53 (39-67) years, 25 females, 66 traumatic SCI, 54 paraplegia) were included. Assessed a median of 15 (9-22) days after SCI onset, median vitamin D status was 41 (26-57) (range 8-155) nmol/l. The majority of patients had a deficient (67%, 95% confidence interval (95% CI) 0.56-0.76) or insufficient (25%, 95% CI 0.17-0.36) vitamin D status. A moderate negative correlation was found between vitamin D status and body mass index (p = 0.003). A moderate positive correlation was found between vitamin D and calcium status (p = 0.01). CONCLUSION: A deficient or insufficient vitamin D status directly after SCI onset is highly prevalent. Vitamin D status should be carefully observed during acute SCI rehabilitation. We recommend that all patients with recent SCI onset should receive vitamin D supplementation with a dosage depending on their actual vitamin D status.

[Role of computed tomography in the preoperative diagnosis of otosclerosis]. / Stellenwert der Computertomographie in der präoperativen Diagnostik der Otosklerose.

BACKGROUND: Otosclerosis is an osteodystrophy of the otic capsule and presents with progressive conductive hearing loss. Imaging studies, especially computed tomography (CT) and cone-beam CT, have gained increased relevance in the diagnosis of otosclerosis. OBJECTIVE: This study investigated whether there is a correlation between the extent of otosclerosis in high-resolution or cone-beam CT and hearing loss in pure-tone audiometry. MATERIALS AND METHODS: Based on an existing classification of otosclerotic foci, a classification was established. Preoperative CT scans of patients undergoing stapedotomy between 2015 and 2019 were evaluated and classified by two independent otorhinolaryngologists. The preoperative pure-tone audiograms were analysed and compared to the results of CT. RESULTS: A total of 168 CT studies (i.e., 168 ears) in 156 patients with intraoperatively confirmed otosclerosis were included in our study. A correlation between the extent of the otosclerotic focus or the calculated scores and hearing loss in pure-tone audiometry (air conduction, bone conduction and air-bone-gap) could not be proven. CONCLUSION: Preoperative CT is not obligatory. However, preoperative imaging using CT or cone-beam CT can be helpful to confirm the diagnosis and exclude other middle or inner ear pathologies as well as in planning of the surgical procedure in the overall context of otoscopy and audiometry. A correlation with the degree of hearing impairment could not be demonstrated and remains unclear.

Mean kurtosis-Curve (MK-Curve) correction improves the test-retest reproducibility of diffusion kurtosis imaging at 3 T.

Diffusion kurtosis imaging (DKI) is applied to gain insights into the microstructural organization of brain tissues. However, the reproducibility of DKI outside brain white matter, particularly in combination with advanced estimation to remedy its noise sensitivity, remains poorly characterized. Therefore, in this study, we investigated the variability and reliability of DKI metrics while correcting implausible values with a fit method called mean kurtosis (MK)-Curve. A total of 10 volunteers (four women; age: 41.4 ± 9.6 years) were included and underwent two MRI examinations of the brain. The images were acquired on a clinical 3-T scanner and included a T1-weighted image and a diffusion sequence with multiple diffusion weightings suitable for DKI. Region of interest analysis of common kurtosis and tensor metrics derived with the MK-Curve DKI fit was performed, including intraclass correlation (ICC) and Bland-Altman (BA) plot statistics. A p value of less than 0.05 was considered statistically significant. The analyses showed good to excellent agreement of both kurtosis tensor- and diffusion tensor-derived MK-Curve-corrected metrics (ICC values: 0.77-0.98 and 0.87-0.98, respectively), with the exception of two DKI-derived metrics (axial kurtosis in the cortex: ICC = 0.68, and radial kurtosis in deep gray matter: ICC = 0.544). Non-MK-Curve-corrected kurtosis tensor-derived metrics ranged from 0.01 to 0.52 and diffusion tensor-derived metrics from 0.06 to 0.66, indicating poor to moderate reliability. No structural bias was observed in the BA plots for any of the diffusion metrics. In conclusion, MK-Curve-corrected DKI metrics of the human brain can be reliably acquired in white and gray matter at 3 T and DKI metrics have good to excellent agreement in a test-retest setting.

Analysis of Antibiotic Exposure and Early-Onset Neonatal Sepsis in Europe, North America, and Australia.

Importance: Appropriate use of antibiotics is life-saving in neonatal early-onset sepsis (EOS), but overuse of antibiotics is associated with antimicrobial resistance and long-term adverse outcomes. Large international studies quantifying early-life antibiotic exposure along with EOS incidence are needed to provide a basis for future interventions aimed at safely reducing neonatal antibiotic exposure. Objective: To compare early postnatal exposure to antibiotics, incidence of EOS, and mortality among different networks in high-income countries. Design, Setting, and Participants: This is a retrospective, cross-sectional study of late-preterm and full-term neonates born between January 1, 2014, and December 31, 2018, in 13 hospital-based or population-based networks from 11 countries in Europe and North America and Australia. The study included all infants born alive at a gestational age greater than or equal to 34 weeks in the participating networks. Data were analyzed from October 2021 to March 2022. Exposures: Exposure to antibiotics started in the first postnatal week. Main Outcomes and Measures: The main outcomes were the proportion of late-preterm and full-term neonates receiving intravenous antibiotics, the duration of antibiotic treatment, the incidence of culture-proven EOS, and all-cause and EOS-associated mortality. Results: A total of 757 979 late-preterm and full-term neonates were born in the participating networks during the study period; 21 703 neonates (2.86%; 95% CI, 2.83%-2.90%), including 12 886 boys (59.4%) with a median (IQR) gestational age of 39 (36-40) weeks and median (IQR) birth weight of 3250 (2750-3750) g, received intravenous antibiotics during the first postnatal week. The proportion of neonates started on antibiotics ranged from 1.18% to 12.45% among networks. The median (IQR) duration of treatment was 9 (7-14) days for neonates with EOS and 4 (3-6) days for those without EOS. This led to an antibiotic exposure of 135 days per 1000 live births (range across networks, 54-491 days per 1000 live births). The incidence of EOS was 0.49 cases per 1000 live births (range, 0.18-1.45 cases per 1000 live births). EOS-associated mortality was 3.20% (12 of 375 neonates; range, 0.00%-12.00%). For each case of EOS, 58 neonates were started on antibiotics and 273 antibiotic days were administered. Conclusions and Relevance: The findings of this study suggest that antibiotic exposure during the first postnatal week is disproportionate compared with the burden of EOS and that there are wide (up to 9-fold) variations internationally. This study defined a set of indicators reporting on both dimensions to facilitate benchmarking and future interventions aimed at safely reducing antibiotic exposure in early life.

Tablet app-based dexterity training in multiple sclerosis (TAD-MS): a randomized controlled trial.

PURPOSE: Mobile health applications (mHealth apps) may lead to health benefits. In recent years, the use of apps in multiple sclerosis (MS) has increased. Apps to train and improve dexterity in MS are scarce. This study investigated the effectiveness of a tablet app-based home-based training to improve dexterity in individuals with MS. MATERIALS AND METHODS: In a randomized controlled trial, two standardized 4-week home-based interventions focussing on different aspects of dexterity and upper limb function were compared. Assessments were done at baseline, post-intervention and 12-week follow-up. The primary endpoint was the Arm Function in Multiple Sclerosis Questionnaire, a dexterity-related measure of patient-reported activities of daily living. Secondary endpoints were dexterous function, grip strength and health-related quality of life. RESULTS: Forty-eight individuals were randomly assigned to a tablet app-based program (n = 26) or a control strengthening exercise program (n = 22). No significant differences were found for the primary endpoint (p = 0.35). Some significant differences in favour of the app-group were found in fine coordinated finger movements and strength. No significant differences were found at the 12-week follow-up for all endpoints. Adherence in both groups was above 90%. CONCLUSIONS: App-based training was not superior compared to a control strengthening exercise program concerning the arm- and hand function from the participant's perspective. However, app-based training was found to be effective in improving specific dimensions (finger movements and strength), and can easily be applied at home. Therefore, individuals living with MS with impaired dexterity should consider app-based training. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT03369470.

This study provides initial evidence for the effectiveness of a home-based app-based program for improving dexterous function in individuals living with multiple sclerosis through the implementation of a tablet app-based dexterity training.App-based training was not superior compared to a control strengthening exercise program concerning the arm- and hand function from the participant's perspective.Patients attending the app-based dexterity program showed some statistically significant improvements in fine coordinated finger movements and strength.

A Novel Tool to Predict Postoperative Opioid Need after Laparoscopic Appendectomy in Children: A Step toward Evidence-Based Pain Management.

BACKGROUND: Optimizing postoperative pain treatment is essential to minimize morbidity, lower costs, and ensure patient and parent satisfaction. This study aims at identifying pre- and intraoperative parameters predicting opioid needs after laparoscopic appendectomy to enable timely and adequate postoperative pain control. MATERIALS AND METHODS: A retrospective analysis of patients treated with laparoscopic appendectomy for appendicitis between January 2018 and March 2019 was performed. Multiple logistic regression was applied to identify predictors of opioid demand. RESULTS: Based on our analysis, we developed a prediction tool for opioid requirements after laparoscopic appendectomies in children. The integrated parameters are: presence of turbid fluid, age, white-blood-cell count, symptom duration, and body temperature. CONCLUSION: We developed an algorithm-based predictor tool that has the potential to better anticipate postoperative pain and, thereby, optimize pain management following laparoscopic appendectomies in children. The proposed predictor tool will need validation through further prospective studies.

Improved gesturing in left-hemispheric stroke by right inferior parietal theta burst stimulation.

Objectives: Apraxia is a common syndrome of left hemispheric stroke. A parieto-premotor-prefrontal network has been associated with apraxia, in which the left inferior parietal lobe (IPL-L) plays a major role. We hypothesized that transcranial continuous theta burst stimulation (cTBS) over the right inferior parietal lobe (IPL-R) improves gesturing by reducing its inhibition on the contralateral IPL in left hemispheric stroke patients. It was assumed that this effect is independent of lesion volume and that transcallosal connectivity is predictive for gestural effect after stimulation. Materials and methods: Nineteen stroke patients were recruited. Lesion volume and fractional anisotropy of the corpus callosum were acquired with structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Each patient had pseudorandomised sessions with sham or with stimulation over the IPL-R or over the right inferior frontal gyrus IFG-R. Gesturing was assessed in a double-blinded manner before and after each session. We tested the effects of stimulation on gesture performance using a linear mixed-effects model. Results: Pairwise treatment contrasts showed, that, compared to sham, the behavioral effect was higher after stimulation over IPL-R (12.08, 95% CI 6.04 - 18.13, p < 0.001). This treatment effect was approximately twice as high as the contrasts for IFG-R vs. sham (6.25, 95% CI -0.20 - 12.70, p = 0.058) and IPL-R vs. IFG-R vs. sham (5.83, 95% CI -0.49 - 12.15, p = 0.071). Furthermore, higher fractional anisotropy in the splenium (connecting the left and right IPL) were associated with higher behavioral effect. Relative lesion volume did not affect the changes after sham or stimulation over IPL-R or IFG-R. Conclusion: One single session of cTBS over the IPL-R improved gesturing after left hemispheric stroke. Denser microstructure in the corpus callosum correlated with favorable gestural response. We therefore propose the indirect transcallosal modulation of the IPL-L as a promising model of restoring interhemispheric balance, which may be useful in rehabilitation of apraxia.

Machine Learning Used to Compare the Diagnostic Accuracy of Risk Factors, Clinical Signs and Biomarkers and to Develop a New Prediction Model for Neonatal Early-onset Sepsis.

BACKGROUND: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. STUDY DESIGN: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. RESULTS: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. CONCLUSIONS: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

Newborns with Bloody Stools-At the Crossroad between Efficient Management of Necrotizing Enterocolitis and Antibiotic Stewardship.

The onset of bloody stools in neonates often results in antibiotic treatment for suspected necrotizing enterocolitis (NEC). Food protein-induced allergic proctocolitis (FPIAP) is an often-neglected differential diagnosis. We performed a retrospective analysis of antibiotic exposure at our tertiary center from 2011 to 2020 that included three time periods of differing antimicrobial stewardship goals. We compared these data with the conventional treatment guidelines (modified Bell's criteria). In our cohort of 102 neonates with bloody stools, the length of antibiotic exposure was significantly reduced from a median of 4 to 2 days. The proportion of treated neonates decreased from 100% to 55% without an increase in negative outcomes. There were 434 antibiotic days. Following a management strategy according to modified Bell's criteria would have led to at least 780 antibiotic days. The delayed initiation of antibiotic treatment was observed in 7 of 102 cases (6.9%). No proven NEC case was missed. Mortality was 3.9%. In conclusion, with FPIAP as a differential diagnosis of NEC, an observational management strategy in neonates with bloody stools that present in a good clinical condition seems to be justified. This may lead to a significant reduction of antibiotic exposure. Further prospective, randomized trials are needed to prove the safety of this observational approach.

Implementation of a Bundle of Care in Colorectal Surgery to Reduce Surgical Site Infections Successfully at Cantonal Hospital Lucerne: Study Protocol for a Prospective Observational Study.

BACKGROUND: Surgical site infections (SSIs) remain a relevant problem in colorectal surgery. The aim of this study is to implement a bundle of care in order to reduce SSIs in colorectal surgery. METHODS: All patients undergoing colorectal surgery between October 2018 and December 2021 will be included in a prospective observational study. Since our colorectal bundle has been established gradually, patients will be grouped in a pre-implementation (2018-2019), implementation (2019-2020) and post implementation phase (2021), in order to assess the effectiveness of the actions undertaken. Primary endpoint of this study will be surgical site infection (SSI) rate, while secondary endpoints encompass potential risk factors for SSIs. We assume that obesity, age, diabetes, alcoholism and smoking may lead to a higher risk for SSIs. DISCUSSION: This study aims to determine whether the colorectal bundle designed and implemented at Cantonal Hospital Lucerne, will lead to a significant reduction of SSIs. The impact of potential risk factors for SSIs will additionally be evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04677686. Registered retrospectively 18 December 2020. HIGHLIGHTS: A bundle of care might reduce the occurence of surgical site infections after colorectal surgery.Analysis of risk factors may detect patient's with high probability of developing surgical site infections.