Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study.

BACKGROUND: Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week. METHODS: We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases. RESULTS: Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths. CONCLUSIONS: CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases. IMPACT: In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs.

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.

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.

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.

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.

[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.

C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study.

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours.

Small fiber neuropathy: Swiss cohort characterization.

INTRODUCTION/AIM: There is currently insufficient clinical and epidemiological data concerning small fiber neuropathy (SFN). This research analyzes data from medical records to determine epidemiology, demographics, clinical characteristics and etiology of SFN. METHODS: This is a retrospective, observational study of sequential patients diagnosed with definite SFN (typical clinical features, normal nerve conduction studies, abnormal epidermal nerve fiber density) from the end of November 2016 to the middle of July 2019 at the Cantonal Hospital Lucerne, central Switzerland. RESULTS: A total of 84 patients (64.3% female) with a mean age of 54.7 y were analyzed. Symptoms had been present in patients for an average of 4.8 y when entering the study. A length dependent clinical pattern was seen in 79.8%. All patients had sensory discomfort. Etiology could not be determined in 35.7% of patients, who were diagnosed with idiopathic SFN; 34.5% of patients had an apparently autoimmune SFN, followed by14.3% of patients with metabolic causes. The estimated incidence was at least 4.4 cases/100.000 inhabitants/y. The minimum prevalence was 131.5 cases/100.000 inhabitants. DISCUSSION: This study indicates significant incidence and prevalence rates of SFN in Switzerland. SFN can vary greatly in its symptoms and severity. Extensive work-up resulted in two thirds of the patients being assigned an etiological association. The largest group of patients could not be etiologically defined, underlining the importance of further research on etiologic identification. We expect increased awareness of the developing field of SFN.

Rating the aesthetic results after auricular reconstructive surgery for congenital aural atresia with microtia.

OBJECTIVE: This retrospective study aimed to establish a robust rating system for assessing post-operative outcomes in congenital aural atresia patients undergoing auricular reconstruction. The newly introduced EAR scale, a weighted grading system, not only considers anatomical landmarks but also factors such as ear alignment. In addition, the outer-ear cartilage scale and the visual analogue scale (VAS) were introduced. These scales were compared among themselves and against two established scales. METHODS: Nine raters assessed 17 eligible patients who underwent auricular reconstruction between 2001 and 2020. RESULTS: The study compared inter-rater agreement among scales, with the EAR scale proving the most reliable (Krippendorff's alpha coefficient, α = 0.45), outperforming existing measures. The outer-ear cartilage scale and the VAS exhibited lower inter-rater agreement, indicating inferiority in assessing aesthetic outcomes. CONCLUSION: The EAR scale emerged as an effective tool for evaluating post-operative outcomes in congenital aural atresia auricular reconstruction.

Quantitative bone single photon emission computed tomography/computed tomography in symptomatic and asymptomatic foot and ankle osteoarthritis.

PURPOSE: The purpose of this study was to evaluate and quantify the prevalence of increased uptake in SPECT/CT in symptomatic and asymptomatic foot and ankle joints in patients with osteoarthritis. METHODS: In 63 patients with osteoarthritis (OA), the painful symptomatic foot (SF) and asymptomatic contralateral foot (AF) were imaged with bone SPECT/CT. Presence, localization, and maximum standardized uptake value (SUVmax) of the active joints were assessed for SF and AF. CT OA grade (grade 1: mild, grade 2: moderate, grade 3: severe) and presence of five morphological features of OA (joint space narrowing, subchondral sclerosis, subchondral cysts, irregular joint margins, and osteophytes) were evaluated. RESULTS: In total 32 (51%) patients showed additional uptake in the AF, whereas 31 (49%) patients showed it only in the SF. SF showed more active joints than AF (106 vs. 43). CT OA grades positively correlated with SUVmax (Kendall's tau b = 0.62, P < 0.001). SUVmax values (per foot) in SF were higher in patients with uptake in bilateral feet (SF+, AF+) [median (IQR): 17.9 (10.7-23.3)] as compared with patients with active sites only in the SF (SF+, AF-) [10.4 (6.4-19.1); P < 0.001]. Number of active OA joints in SF was higher in patients with bilateral uptake (P = 0.017). CONCLUSION: In conclusion, half of the patients exhibited increased uptake in the contralateral asymptomatic foot. SUVmax showed a significant correlation to CT osteoarthritis grade, in the symptomatic and asymptomatic foot. Future follow-up studies will provide further insights into the prognostic and therapeutic value of these findings.

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.

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.

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.

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.

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.

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.