Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.

Accuracy of the sonographic determination of estimated fetal weight in anhydramnios.

OBJECTIVE: To determine whether the presence of anhydramnios significantly influences the sonographic estimated fetal weight (EFW) compared to a matched cohort with normal amniotic fluid volume. METHODS: The study sample of this retrospective case-control study consisted of 114 pregnant women who presented to a Tertiary Perinatal Clinic between 2015 and 2020. 57 of them presented with an anhydramnios and a matched cohort of 57 women with normal amniotic fluid volume. At time of admission, gestational age varied between 22 + 4 and 42 + 6 weeks of pregnancy. All women underwent detailed ultrasound assessment for EFW and amniotic fluid index. To determine EFW Hadlock's estimation formula I was used which is based on measurements of biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). The EFW was compared with the weight at delivery. The maximum time interval between measurement and delivery was 5 days. RESULTS: There was neither a significant difference between the case and control group with regard to gestational age at ultrasound in days (median 249 days and 246 days, p = 0.97), nor to gestational age at birth (median 249 days and 247 days, p = 0.98). Concerning the newborns parameters, the body length at birth was not significantly different between the case and control group in centimeters (cm) (median 47 cm and 47 cm, p = 0.79). EFW in gram (g) was lower than birth weight in both groups and did not differ significantly between case and control group (estimated weight median 2247 g and 2421 g, p = 0.46; birth weight median 2440 g and 2475 g, p = 0.47). The difference between EFW and birth weight in percent (%) did not differ between the case and control group (median - 3.9% and - 5.6%, p = 0.70). The maternal parameters showed that the patients in the case group were younger (median 31 years and 38 years p = 0.20) and had a significantly higher body mass index (BMI) (median 27.3 kg/m2 vs 22.0 kg/m2, < 0.001) compared to the control group. CONCLUSION: Our study shows for the first time that EFW in women with anhydramnios can be determined sonographically just as accurately as in a matched cohort with normal amniotic fluid volume. A reliable estimation of fetal weight is crucial for optimal assessment of the newborns prognosis and counseling of the parents especially when advising women in the early weeks of pregnancy at the limit of viability.

TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study.

Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue [p = 0.003] and/or arthritis [p = 0.002] were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex [p = 0.027], more lesions on MRI [p = 0.01] and higher CRP levels [p = 0.03]. Randomized clinical trials are needed to confirm observations and generate evidence.

Data blinding for the nEDM experiment at PSI.

Psychological bias towards, or away from, prior measurements or theory predictions is an intrinsic threat to any data analysis. While various methods can be used to try to avoid such a bias, e.g. actively avoiding looking at the result, only data blinding is a traceable and trustworthy method that can circumvent the bias and convince a public audience that there is not even an accidental psychological bias. Data blinding is nowadays a standard practice in particle physics, but it is particularly difficult for experiments searching for the neutron electric dipole moment (nEDM), as several cross measurements, in particular of the magnetic field, create a self-consistent network into which it is hard to inject a false signal. We present an algorithm that modifies the data without influencing the experiment. Results of an automated analysis of the data are used to change the recorded spin state of a few neutrons within each measurement cycle. The flexible algorithm may be applied twice (or more) to the data, thus providing the option of sequentially applying various blinding offsets for separate analysis steps with independent teams. The subtle manner in which the data are modified allows one subsequently to adjust the algorithm and to produce a re-blinded data set without revealing the initial blinding offset. The method was designed for the 2015/2016 measurement campaign of the nEDM experiment at the Paul Scherrer Institute. However, it can be re-used with minor modification for the follow-up experiment n2EDM, and may be suitable for comparable projects elsewhere.

New Limit on the Permanent Electric Dipole Moment of

We report results of a new technique to measure the electric dipole moment of ^{129}Xe with ^{3}He comagnetometry. Both species are polarized using spin-exchange optical pumping, transferred to a measurement cell, and transported into a magnetically shielded room, where SQUID magnetometers detect free precession in applied electric and magnetic fields. The result from a one week measurement campaign in 2017 and a 2.5 week campaign in 2018, combined with detailed study of systematic effects, is d_{A}(^{129}Xe)=(1.4±6.6_{stat}±2.0_{syst})×10^{-28} e cm. This corresponds to an upper limit of |d_{A}(^{129}Xe)|<1.4×10^{-27} e cm (95% C.L.), a factor of 5 more sensitive than the limit set in 2001.

CD14+ monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression.

The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1ß release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for "drivers" of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets.

Sensitive and stable vector magnetometer for operation in zero and finite fields.

We report on an optically pumped magnetometer that uses multiple laser beams to pump and probe spin-polarized Cs atoms. The selected sensor geometry allows for operation in finite magnetic fields as well as close to zero field. In finite fields the magnetometer employs free spin precession signals to determine the field modulus and direction as described in a separate publication. This publication focuses on the magnetometer operation close to zero field, which is based on a ground state Hanle resonance. The four laser beams permit the simultaneous measurement of two orthogonal magnetic field components in a differential detection scheme that greatly suppresses technical laser power noise. Sensitivities better than 54 fT/Hz1/2 could be demonstrated simultaneously for both measurement channels in a well shielded environment. A minimum Allan deviation, limited by residual field fluctuations, of better than 40 fT was observed for integration times of 2s. The magnetometer achieves high sensitivity and stability in offset fields as well as close to zero field and is, thus, a universal tool for low frequency magnetic field measurements.

Anxiety, depression and quality of life in family caregivers of palliative cancer patients during home care and after the patient's death.

We examined psychological parameters in family caregivers of palliative cancer patients before and after the death of the patients. Caregivers' data about depression and anxiety (Hospital Anxiety and Depression Scale), quality-of-life (Short Form-8 Health Survey), and social support (Oslo Social Support Scale) were collected at the beginning of home care (t1) and 2 months after the patient had died (t2). Regression models were employed to examine factors related to depression and anxiety in the bereaved caregivers. We interviewed 72 relatives, who were the primary caregiver of a patient. One-third (31.9%) of caregivers had high anxiety levels and 29.2% had high depression levels (t1, cut-off = 10). At t2, anxiety and depression had decreased significantly. There were no changes in quality-of-life over time. At both points of assessments, quality-of-life was lower than in the general population. Relevant factors for higher anxiety and depression in the bereaved caregivers were high levels of distress at t1, insufficient social support and low physical function. Bereaved caregivers were particularly depressed when they had been the spouse of the patient. Healthcare professionals should consider social isolation of caring relatives both during homecare and afterwards. Thus, it seems to be important to routinely offer support to spouses.

Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis.

BACKGROUND: Improvement of postoperative pain and other perioperative outcomes remain a significant challenge and a matter of debate among perioperative clinicians. This systematic review aims to evaluate the effects of perioperative i.v. lidocaine infusion on postoperative pain and recovery in patients undergoing various surgical procedures. METHODS: CENTRAL, MEDLINE, EMBASE, and CINAHL databases and ClinicalTrials.gov, and congress proceedings were searched for randomized controlled trials until May 2014, that compared patients who did or did not receive continuous perioperative i.v. lidocaine infusion. RESULTS: Forty-five trials (2802 participants) were included. Meta-analysis suggested that lidocaine reduced postoperative pain (visual analogue scale, 0 to 10 cm) at 1-4 h (MD -0.84, 95% CI -1.10 to -0.59) and at 24 h (MD -0.34, 95% CI -0.57 to -0.11) after surgery, but not at 48 h (MD -0.22, 95% CI -0.47 to 0.03). Subgroup analysis and trial sequential analysis suggested pain reduction for patients undergoing laparoscopic abdominal surgery or open abdominal surgery, but not for patients undergoing other surgeries. There was limited evidence of positive effects of lidocaine on postoperative gastrointestinal recovery, opioid requirements, postoperative nausea and vomiting, and length of hospital stay. There were limited data available on the effect of systemic lidocaine on adverse effects or surgical complications. Quality of evidence was limited as a result of inconsistency (heterogeneity) and indirectness (small studies). CONCLUSIONS: There is limited evidence suggesting that i.v. lidocaine may be a useful adjuvant during general anaesthesia because of its beneficial impact on several outcomes after surgery.

Unexpectedly high incidences of chronic non-bacterial as compared to bacterial osteomyelitis in children.

Historically, osteomyelitis was considered an infectious disorder. More recently, inflammatory mechanisms were recognized causing a significant proportion of pediatric osteomyelitis. This study was to compare characteristics of children with chronic non-bacterial (CNO) and bacterial osteomyelitis (BOM). A chart review of osteomyelitis patients from the departments of pediatrics, pediatric surgery, orthopedic surgery, and oral and maxillofacial surgery was conducted in a tertiary referral center, covering the years 2004-2014. Institutional incidences of CNO (n = 49) and BOM (n = 56) were comparable. Differentiation between CNO and BOM based on clinical or laboratory findings was mostly impossible. However, children with BOM more frequently presented with local inflammatory signs (47 vs. 68 %, p = 0.040), fever (12 vs. 38 %, p = 0.003), and abscesses (0 vs. 39 %, p < 0.001). Peripheral arthritis (14 vs. 0 %, p < 0.001), inflammatory bowel disease (10 vs. 2 %, p = ns), and hyperostosis (29 vs. 4 %, p = 0.001) were more common in CNO. Whole-body MRI was performed in 76 % of CNO patients, unveiling multifocal lesions in 80 % (CRMO). Though considered a rare disorder, institutional incidences of CNO were comparable to BOM, and the discrimination between CNO and BOM solely based on clinical aspects was mostly impossible. This is of special interest, since a correct and timely diagnosis is of utmost importance for long-term outcomes in both disorders. Whole-body MRIs should be considered in chronic osteomyelitis to (1) detect clinically inapparent lesions in CNO and (2) indirectly exclude (usually unifocal) chronic bacterial infections. Prospective studies are warranted to establish evidence-based diagnostic and therapeutic approaches to CNO.

New limit on Lorentz-invariance- and CPT-violating neutron spin interactions using a free-spin-precession He3-Xe129 comagnetometer.

We report on the search for a CPT- and Lorentz-invariance-violating coupling of the He3 and Xe129 nuclear spins (each largely determined by a valence neutron) to posited background tensor fields that permeate the Universe. Our experimental approach is to measure the free precession of nuclear spin polarized He3 and Xe129 atoms in a homogeneous magnetic guiding field of about 400 nT using LTC SQUIDs as low-noise magnetic flux detectors. As the laboratory reference frame rotates with respect to distant stars, we look for a sidereal modulation of the Larmor frequencies of the colocated spin samples. As a result we obtain an upper limit on the equatorial component of the background field interacting with the spin of the bound neutron b(⊥)(n)<8.4 × 10(-34) GeV (68% C.L.). Our result improves our previous limit (data measured in 2009) by a factor of 30 and the world's best limit by a factor of 4.

[Differences of analgesic efficacy and complication rates between ultrasound and nervestimulator guided peripheral nerve catheters : Database analysis on patient-relevant target parameters]. / Vergleich der Analgesiequalität und Komplikationen von ultraschall- und nervenstimulatorgesteuerten peripheren Nervenkathetern : Datenbankanalyse zu patientenrelevanten Zielparametern.

BACKGROUND: Peripheral nerve catheters (PNC) play an important role in postoperative pain treatment following major extremity surgery. There are several trials reported in the literature which investigated the efficacy and safety of ultrasound (US) and nerve stimulator (NS) guided PNC placement; however, most of these trials were only small and focused mainly on anesthesiologist-related indicators of block success (e.g. block onset time and procedure time) but not primarily on patient-related outcome data including postoperative pain during movement. AIM: This retrospective analysis compared the analgesic efficacy and safety of US versus NS guided peripheral nerve catheters (PNC) for postoperative pain therapy in a large cohort of patients. MATERIAL AND METHODS: Data of patients (June 2006-December 2010) treated with US (nus = 368 June 2008-December 2010) and NS (nns = 574, June 2006-May 2008) guided PNC were systematically analyzed. Apart from demographic data, postoperative pain scores [numeric rating scale (NRS): 0-10] on each treatment day, the number of patients with need for additional opioids, cumulative local anesthetic consumption and catheter-related complications were compared. RESULTS: On the day of surgery patients treated with US-guided PNC reported lower NRS at rest (p = 0.034) and during movement (p < 0.001). Additionally, the number of patients requiring additional opioids on the day of surgery was lower in the US group (absolute difference 12.4 %, p = 0.001). Furthermore, the number of multiple puncture attempts (absolute difference 5.6 %, p < 0.001) and failed catheter placements (absolute difference 3.4 %, p = 0.06) were lower in the US group. There were no patients in both groups with long-lasting neurological impairment. CONCLUSION: This database analysis demonstrated that patients treated with US-guided PNC reported significantly lower postoperative pain scores and the number of patients requiring additional opioids was significantly lower on the day of surgery. The numbers of multiple punctures and failed catheter placements were reduced in the US group, which might be seen as an advantage of US-guided regional anaesthesia.

Achieving ultra-low and -uniform residual magnetic fields in a very large magnetically shielded room for fundamental physics experiments.

High-precision searches for an electric dipole moment of the neutron (nEDM) require stable and uniform magnetic field environments. We present the recent achievements of degaussing and equilibrating the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute. We present the final degaussing configuration that will be used for n2EDM after numerous studies. The optimized procedure results in a residual magnetic field that has been reduced by a factor of two. The ultra-low field is achieved with the full magnetic-field-coil system, and a large vacuum vessel installed, both in the MSR. In the inner volume of ∼1.4m3, the field is now more uniform and below 300 pT. In addition, the procedure is faster and dissipates less heat into the magnetic environment, which in turn, reduces its thermal relaxation time from 12h down to 1.5h.

Constraints on spin-dependent short-range interaction between nucleons.

We search for a spin-dependent P- and T-violating nucleon-nucleon interaction mediated by light pseudoscalar bosons such as axions or axionlike particles. We employ an ultrasensitive low-field magnetometer based on the detection of free precession of colocated 3He and 129Xe nuclear spins using SQUIDs as low-noise magnetic flux detectors. The precession frequency shift in the presence of an unpolarized mass was measured to determine the coupling of pseudoscalar particles to the spin of the bound neutron. For boson masses between 2 and 500 µeV (force ranges between 3×1(-4) m and 10(-1) m) we improved the laboratory upper bounds by up to 4 orders of magnitude.

Ultrasound compared with nerve stimulation guidance for peripheral nerve catheter placement: a meta-analysis of randomized controlled trials.

BACKGROUND: The aim of this meta-analysis was to compare the efficacy and safety of ultrasound (US) vs nerve stimulation (NS) guidance for peripheral nerve catheter placement. METHODS: This meta-analysis was performed according to the PRISMA statement and the recommendations of the Cochrane Collaboration. For dichotomous outcomes relative risks [RRs; 95% confidence intervals (CIs)] were calculated, while for continuous outcomes, mean differences (MDs; 95% CI) were calculated. All statistical analyses were performed using the Revman® statistical software (Version 5.1). RESULTS: Fifteen randomized controlled trials including 977 patients satisfied the inclusion criteria. Peripheral nerve catheters placed under US guidance showed a higher RR of 1.14 (95% CI: 1.02-1.27; P=0.02) for an overall successful block in comparison with NS. However, postoperative pain scales at movement (numeric rating scale: 0-10) were comparable between US- vs NS-guided peripheral nerve catheters 24 (MD: 0.08; 95% CI: -0.77 to 0.94; P=0.85) and 48 (MD: 1.0; 95% CI: -0.3 to 2.3; P=0.13) h after surgery. Patients receiving a US-guided peripheral nerve catheter had a lower RR of 0.13 (95% CI: 0.04-0.38; P=0.0002) for an accidental vascular puncture. CONCLUSIONS: There is evidence that US-guided peripheral nerve catheters show a higher success rate and a lower risk for an accidental vascular puncture compared with NS guidance. However, this difference resulted only in marginally lower postoperative pain scores at rest. Nevertheless, these results were influenced by heterogeneity and should be interpreted with caution.

[Interstitial lung disease in polymyositis/dermatomyositis]. / Interstitielle Lungenkrankheit bei Polymyositis/Dermatomyositis.

Comprehensive screening can disclose evidence of interstitial lung disease (ILD) in about 40 % of patients with polymyositis/dermatomyositis (PM/DM). In most cases this is a non-specific interstitial pneumonia, a histopathological type characterized by a substantial initial inflammatory component. Autoantibody testing, spirometry, including the measurement of the the CO diffusion capacity and high-resolution computed tomography (HRCT) are central to making the diagnosis during the early inflammatory stages of ILD. This article outlines the use of clinical, HRCT and bronchoalveolar lavage (BAL) findings for prognostication and gives an overview of current treatment options.

A large 'Active Magnetic Shield' for a high-precision experiment: nEDM collaboration.

We present a novel Active Magnetic Shield (AMS), designed and implemented for the n2EDM experiment at the Paul Scherrer Institute. The experiment will perform a high-sensitivity search for the electric dipole moment of the neutron. Magnetic-field stability and control is of key importance for n2EDM. A large, cubic, 5 m side length, magnetically shielded room (MSR) provides a passive, quasi-static shielding-factor of about 105 for its inner sensitive volume. The AMS consists of a system of eight complex, feedback-controlled compensation coils constructed on an irregular grid spanned on a volume of less than 1000 m3 around the MSR. The AMS is designed to provide a stable and uniform magnetic-field environment around the MSR, while being reasonably compact. The system can compensate static and variable magnetic fields up to ±50µT (homogeneous components) and ±5µT/m (first-order gradients), suppressing them to a few µT in the sub-Hertz frequency range. The presented design concept and implementation of the AMS fulfills the requirements of the n2EDM experiment and can be useful for other applications, where magnetically silent environments are important and spatial constraints inhibit simpler geometrical solutions.

Ultrasound guidance for neuraxial analgesia and anesthesia in obstetrics: a quantitative systematic review.

PURPOSE: The aim of this quantitative systematic review was to assess the efficacy and safety of ultrasound-guided neuraxial blocks in obstetric analgesia and anesthesia. MATERIALS AND METHODS: A systematic search for clinical trials investigating the efficacy and safety of ultrasound-assisted neuraxial blocks in comparison to any other technique was performed in MEDLINE, EMBASE, CINAHL and CENTRAL. Relative risks (RR) were calculated for dichotomous data (e. g. number of patients with vascular punctures), and mean differences (MD) were calculated for continuous outcomes (e. g. number puncture attempts), along with the respective 95 % confidence intervals (95 % CI). RESULTS: Six clinical trials (published between 2001 and 2009) including the data of 659 patients satisfied the inclusion criteria. Ultrasound-facilitated neuraxial blocks required a lower number of puncture attempts (MD: -0.92; 95 % CI: -1.11 to -0.74; p < 0.00001) and fewer puncture levels (MD: -0.2; 95 % CI: -0.31 to -0.1; p = 0.0002) in comparison with the more conventional loss of resistance. The success rate with the first attempt under ultrasound guidance in supposedly difficult patients was 71 % in comparison to 20 % using a conventional technique. Patients receiving ultrasound-assisted neuraxial blocks had a lower rate of procedure-related complications (post-dural puncture headache, spinal or vascular puncture). CONCLUSION: There is some evidence that ultrasound guidance may improve the efficacy and safety of neuraxial blocks in obstetrics. If technical difficulties are anticipated, ultrasound may lower the rate of procedure-related adverse events.

The very large n2EDM magnetically shielded room with an exceptional performance for fundamental physics measurements.

We present the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute, which features an interior cubic volume with each side of length 2.92 m, thus providing an accessible space of 25 m3. The MSR has 87 openings of diameter up to 220 mm for operating the experimental apparatus inside and an intermediate space between the layers for housing sensitive signal processing electronics. The characterization measurements show a remanent magnetic field in the central 1 m3 below 100 pT and a field below 600 pT in the entire inner volume, up to 4 cm to the walls. The quasi-static shielding factor at 0.01 Hz measured with a sinusoidal 2 µT peak-to-peak signal is about 100 000 in all three spatial directions and increases rapidly with frequency to reach 108 above 1 Hz.

Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression.

Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced (p<0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.