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The capability of optical surface topography measurement methods for measurement of steep and tilted surfaces is investigated through modelling of a coherence scanning interferometer. Of particular interest is the effect on the interference signal and measured topography when tilting the object at angles larger than the numerical aperture slope limit (i.e. the specular reflection limit) of the instrument. Here we use theoretical modelling to predict the results across a range of tilt angles for a blazed diffraction grating. The theoretically predicted interference patterns and surface height measurements are then verified directly with experimental measurements. Results illustrate the capabilities, limitations and modelling methods for interferometers to measure beyond the specular reflection limit.

Human coronavirus OC43 is a globally circulating common cold virus sustained by recurrent reinfections. How it persists in the population and defies existing herd immunity is unknown. Here we focus on viral glycoprotein S, the target for neutralizing antibodies, and provide an in-depth analysis of its antigenic structure. Neutralizing antibodies are directed to the sialoglycan-receptor binding site in S1

Candida glabrata is among the most prevalent causes of candidiasis. Unlike Candida albicans, it is not capable of changing morphology between yeast and hyphal forms but instead has developed other virulence factors. An important feature is its unprecedented large repertoire of predicted cell wall adhesins, which are thought to enable adherence to a variety of surfaces under different conditions. Here, we analyzed the wall proteome of PEU1221, a high biofilm-forming clinical strain isolated from an infected central venous catheter, under biofilm-forming conditions. This isolate shows increased incorporation of putative adhesins, including eight proteins that were not detected in walls of reference strain ATCC 2001, and of which Epa22, Awp14, and Awp2e were identified for the first time. The proteomics data suggest that cluster III adhesin Awp14 is relatively abundant in PEU1221. Phenotypic studies with awp14Δ deletion mutants showed that Awp14 is not responsible for the high biofilm formation of PEU1221 onto polystyrene. However, awp14Δ mutant cells in PEU1221 background showed a slightly diminished binding to chitin and seemed to sediment slightly slower than the parental strain suggesting implication in fungal cell-cell interactions. By structural modeling, we further demonstrate similarity between the ligand-binding domains of cluster III adhesin Awp14 and those of cluster V and VI adhesins. In conclusion, our work confirms the increased incorporation of putative adhesins, such as Awp14, in high biofilm-forming isolates, and contributes to decipher the precise role of these proteins in the establishment of C. glabrata infections.

Background Shoulder injections for conditions such as adhesive capsulitis are commonly performed and can be administered through image-based or landmark-based injection approaches. Ultrasound-guided injections are widely used and accurate because ultrasound allows real-time visualization of the needle and injected contrast. Landmark-based injections would be advantageous, if they were accurate, because they would save the time and expense associated with ultrasound. However, few prospective studies have compared well-described landmark-based shoulder injection techniques without ultrasound. Question/purpose Using anatomic landmarks, and without using ultrasound, is the accuracy of glenohumeral injection for adhesive capsulitis greater via the posterior approach or via a new anterior approach? Methods Between 2018 and 2020, we treated 108 patients potentially eligible for adhesive capsulitis treatment. These patients had clinical symptoms of aggravating shoulder pain with a duration of less than 4 months and passively impaired, painful glenohumeral ROM. Due to the exclusion of patients with other shoulder conditions (full-thickness rotator cuff ruptures and posttraumatic stiffness), 95 patients received an injection in this sequential, prospective, comparative study. Between 2018 and 2019, 41 patients (17 males and 24 females; mean age 52 ± 5 years; mean BMI 24 ± 3 kg/m2) were injected through the posterior approach, with the acromion as the anatomical landmark, during the first part of the study period. After that, between 2019 and 2020, 54 patients (20 males and 34 females; mean age 54 ± 4 years; mean BMI 23 ± 3 kg/m2) received an injection through a new anterior approach, with the acromioclavicular joint as the anatomic landmark, during the second part of the study period. Injections via both approaches were administered by two experienced shoulder specialists (both with more than 10 years of experience). Both specialists had experience with the posterior approach before this study, and neither had previous training with the new anterior approach. Injections contained a corticosteroid, local anaesthetic, and contrast medium. Radiographs were taken within 20 minutes after the injection, and a radiologist blinded to the technique determined accuracy. Accurate injections were defined as having contrast fluid limited to the glenohumeral joint, while inaccurate injections displayed leakage of contrast fluid into the soft tissue or subacromial space. All of the enrolled patients were analyzed. Results In the group with the posterior approach, the accuracy was 78% (32 of 41) in contrast to 94% (51 of 54, odds ratio 0.21 [95% CI 0.05 to 0.83]; p = 0.03) in patients with the new anterior approach. Conclusion The new anterior approach without the use of ultrasound was more accurate than the posterior approach. In fact, it was nearly as accurate as previously published ultrasound-guided approaches. We recommend using the new anterior approach for intraarticular glenohumeral injections instead of ultrasound-guided injections because it will save time and costs associated with ultrasound. Still, the clinical effects (anxiety, pain, functional outcome, and adverse events) of the new anterior approach should be compared with ultrasound-guided injections in a randomized study. Level of evidence Level II, therapeutic study.

Worldwide, an increasing number of people are diagnosed with atypical Parkinsonism or idiopathic Parkinson's disease (PD). Periods of acute functional decline, triggered by acute disease, are common. Rehabilitation is often necessary to restore functioning. Skilled nursing facilities (SNFs) in the Netherlands have developed evidence-based geriatric rehabilitation for Parkinson (GR-P) programs. However, data on the experiences and needs of patients and their caregivers are lacking. This study aims to address these, in order to propose recommendations for improvement.We performed a qualitative study, using semi-structured interviews in two Dutch SNFs offering GR-P. Nine patients with PD and six informal caregivers were included. We subjected verbatim transcripts of 15 interviews to qualitative analysis.Data saturation was reached after 15 interviews. Three overarching themes emerged: (1) autonomy, (2) sharing information and (3) contact with others. Loss of autonomy was linked to the underlying disease and the rehabilitation environment itself. Patients and caregivers felt overwhelmed by events before and during rehabilitation, expressing a need to receive information and discuss prior experiences. They considered communication between hospitals and SNFs to be poor. Patients did not always appreciate contact with peers. Both patients and caregivers appreciated empathic healthcare personnel with a firm knowledge on PD.Autonomy, sharing information and contact with others are central themes for patients and caregivers during GR-P in SNFs. We recommend actively exploring these three central themes with every patient and caregiver entering a GR-P program and offering staff continuing education on PD, in order to improve care.

We propose a model for coherence scanning interferometry using familiar Fourier optics methods and the spectrum of plane waves for the case where light source spectral bandwidth limits the fringe contrast as a function of optical path length. The model is straightforward to implement, is computationally efficient, and reveals many of the common error sources related to the optical filtering properties of the imaging system. We quantify the limits of applicability of the model related to the geometrical approximations for Fourier optics, particularly for high numerical apertures, and when using the fringe contrast for determining surface heights. These limitations can be overcome using a three-dimensional imaging model.

Background Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. Material and Methods The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium ( Results Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented. Conclusion These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.

Background GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. It is a collaboration between academic investigators, patient organizations and industry, under the sponsorship of the non-profit organization, Global Coalition for Adaptive Research, to support new drug applications for newly diagnosed and recurrent GBM. Material and Methods The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with newly diagnosed or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a master protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common control arm. Based on performance, a drug may graduate and move to a Stage 2 (Phase 3) within the trial, and the totality of the data can be used for a new drug application and registration process. New experimental therapies are added as information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic.GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received initial approval from the United States FDA in April 2019, and in Europe through the Voluntary Harmonization Procedure (VHP) in April, 2021. As of 2022, AGILE has screened over 1000 patients studying multiple investigational treatments. Enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. Currently, there are 41 sites activated in the US, 4 in Canada and 2 in Switzerland and an estimated 24 sites yet to open in Germany, France, Switzerland, Italy and Austria. In addition to the continued expansion in Europe, effort is undergoing to extend the trial to China and Australia as well. Clinical trial information: NCT03970447

The cytochrome P450s (CYPs) comprise a superfamily of haem-containing proteins that are predominantly expressed in the liver and catalyse the metabolism of a broad range of exogenous and endogenous molecules. The inhibition of P450-mediated drug metabolism may result in undesirable elevations in plasma drug concentrations; therefore, an understanding of the potential for CYP inhibition is important from a therapeutic efficacy and safety stand-point. This chapter will highlight and exemplify medicinal chemistry strategies to reduce CYP inhibitory activity and hence the potential for drug–drug interactions.

A powerful technique for interference fringe analysis uses tunable light sources. Originally developed to solve the problem of phase shifting in large aperture systems, the technique has evolved to the simultaneous measurement of multiple surfaces and optical thickness of optical assemblies and components. Here we review the principles and current state of the art for swept-wavelength interferometry for optical testing, including recent advances in digital holographic refocusing and environmental robustness using model-based data analysis. Applications for swept-wavelength interferometry span the full optical metrology space; we provide examples of the measurement of glass substrates for rigid data storage drives to planar waveguides for augmented and mixed reality.

Optical instruments have long played a role in manufacturing, and strong arguments favor accelerated adoption of fast, non-contact measurements of surfaces, shapes and positions as an enabler for industry 4.0. High-precision techniques such as optical interferometry have advanced considerably and have found applications ranging from semiconductor wafer lithography to automotive engine production. Even though there are clear benefits, there are obstacles to the more widespread adoption of optical techniques for dimensional measurements. Many of these obstacles are technical--such as vibration sensitivity and metrological traceability; but others reflect the cultural gaps between academia, makers of optical instruments, standards organizations and end users. In this talk, I propose that understanding these cultural differences can assist in advancing optical methods for the most critical needs of data-driven manufacturing.

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.

Stem‐cell‐based therapy may be used to replace damaged or lost neurons in the cochlear nerve of patients suffering from severe‐to‐profound sensorineural hearing loss. In order to achieve functional recovery in future clinical trials, knowledge about survival of grafted cells and their differentiation into functional neurons is a prerequisite. This calls for non‐invasive in vivo visualization of cells and long‐term monitoring of their survival and fate after cochlear transplantation. We have investigated if molecular optical imaging enables visualization of exogenous cells in the intact cochlea of guinea pig cadaver heads. Transduced (stem) cells, stably co‐expressing fluorescent (copGFP) and bioluminescent (Luc2) reporter molecules, were injected into the internal auditory meatus or directly into the cochlea through the round window. After injection of the cells into the internal auditory meatus, a bright bioluminescent signal was observed in the cavum conchae of the auricle, indicating that light generated by Luc2 is passing through the tympanic membrane and the external auditory meatus. Similar results were obtained after injection of the cells through the round window membrane, either directly into the scala tympani or in Rosenthal's canal within the modiolus of the basal cochlear turn. Imaging of the auditory bulla demonstrated that the bioluminescent signal passes through the tympanic membrane and crevices in the bony wall of the bulla. After opening the auditory bulla, the bioluminescent signal was emanating from the round window. This is the first study demonstrating that bioluminescence imaging enables visualization of luciferase‐expressing cells injected into the intact guinea pig cochlea. Anat Rec, 303:427–440, 2020. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Rationale: Strontium isotope analysis can be applied to the calcined human otic capsule in the petrous part (pars petrosa ossis temporalis; PP) to gain information on childhood mobility in archaeological and forensic contexts. However, only a thin layer of the otic capsule, the inner cortex, demonstrates virtually no remodelling. This paper proposes an improved sampling method for the accurate sampling of the inner cortex of the otic capsule to ensure that 87Sr/86Sr ratios related to early childhood are obtained. Methods: Calcined rib and diaphyseal fragments and PP from ten cremation deposits are sampled for strontium isotope analysis, whereby our improved sampling strategy is applied to sample the inner cortex of the otic capsule. This allows inter- and intraskeletal 87Sr/86Sr comparison within an Iron Age collection from Oss, The Netherlands. Results: Forty percent (4/10) of the calcined PP that were evaluated for this study show marked differences in 87Sr/86Sr (0.00035–0.00065) between the inner cortex and the bone sample surrounding this layer, the external cortex that has higher remodelling rates. Differences in 87Sr/86Sr between various skeletal elements also aided in the identification of the minimum number of individuals. Conclusions: Our study demonstrates the problematic nature of the external cortex and stresses the need for a precise sampling method of the correct areas of the otic capsule. This can only be obtained by cutting the calcined PP midmodiolarly to enable adequate combustion degree assessment, and the correct identification and sampling of the inner cortex of the otic capsule.

Candida auris is an emerging multidrug-resistant fungal pathogen responsible for nosocomial outbreaks of invasive candidiasis. Although several studies on the pathogenicity of this species have been reported, the knowledge on C. auris virulence is still limited. This study aims to analyze the pathogenicity of C. auris, using one aggregating isolate and eleven non-aggregating isolates from different clinical origins (blood, urine and oropharyngeal specimens) in two alternative host models of candidiasis: Caenorhabditis elegans and Galleria mellonella. Furthermore, possible associations between virulence, aggregation, biofilm-forming capacity, and clinical origin were assessed. The aggregating phenotype isolate was less virulent in both in vivo invertebrate infection models than non-aggregating isolates but showed higher capacity to form biofilms. Blood isolates were significantly more virulent than those isolated from urine and respiratory specimens in the G. mellonella model of candidiasis. We conclude that both models of candidiasis present pros and cons but prove useful to evaluate the virulence of C. auris in vivo. Both models also evidence the heterogeneity in virulence that this species can develop, which may be influenced by the aggregative phenotype and clinical origin.

Contains fulltext : 232443.pdf (Publisher’s version ) (Closed access) BACKGROUND: In the Netherlands, access to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has been unrestricted for chronic infection since 2015. We evaluated whether the nationwide incidence of HCV infections in individuals with HIV has changed since 2015. METHODS: In this retrospective cohort study, data from the ATHENA cohort of people with HIV aged 18 years or older attending any of the 24 HIV treatment centres in the Netherlands between 2000 and 2019 were assessed. We used parametric proportional hazards models with a piecewise exponential survival function to model HCV primary infection and reinfection incidence per 1000 person-years. FINDINGS: Of the 23 590 individuals without previous HCV infection, 1269 cases of HCV primary infection were documented (incidence 5·2 per 1000 person-years [95% CI 5·0-5·5]). The highest incidence was observed in men who have sex with men (MSM; 7·7 per 1000 person-years [7·3-8·2]) and was lower in people who inject drugs (PWID; 1·7 per 1000 person-years [0·7-4·1]) and other key populations (1·0 per 1000 person-years [0·8-1·2]). In MSM, incidence increased in 2007 to 14·3 per 1000 person-years and fluctuated between 8·7 and 13·0 per 1000 person-years from 2008 to 2015. In 2016, incidence declined to 6·1 cases per 1000 person-years and remained steady between 4·1 and 4·9 per 1000 person-years from 2017 to 2019. Of the 1866 individuals with a previous HCV infection, 274 reinfections were documented (incidence 26·9 per 1000 person-years [95% CI 23·9-30·3]). The highest incidence rate was observed in MSM (38·5 per 1000 person-years [33·9-43·7]) and was lower in PWID (10·9 per 1000 person-years [3·5-33·8]) and other key populations (8·9 per 1000 person-years [6·3-12·5]). In MSM, reinfection incidence fluctuated between 38·0 and 88·9 per 1000 person-years from 2006 to 2015, reaching 55·6 per 1000 person-years in 2015. In 2016, reinfection incidence declined to 41·4 per 1000 person-years, followed by further decreases to 24·4 per 1000 person-years in 2017 and 11·4 per 1000 person-years in 2019. INTERPRETATION: The sharp decline in HCV incidence in MSM with HIV shortly after restrictions on DAAs were lifted suggests a treatment-as-prevention effect. HCV incidence was already low in PWID and other groups before unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but high rate of reinfection, stressing the need for additional preventive measures. FUNDING: Dutch Ministry of Health, Welfare, and Sport.

Candida auris is an emerging multidrug-resistant fungal pathogen responsible for nosocomial outbreaks of invasive candidiasis. Although several studies on the pathogenicity of this species have been reported, the knowledge on C. auris virulence is still limited. This study aims to analyze the pathogenicity of C. auris, using one aggregating isolate and eleven non-aggregating isolates from different clinical origins (blood, urine and oropharyngeal specimens) in two alternative host models of candidiasis: Caenorhabditis elegans and Galleria mellonella. Furthermore, possible associations between virulence, aggregation, biofilm-forming capacity, and clinical origin were assessed. The aggregating phenotype isolate was less virulent in both in vivo invertebrate infection models than non-aggregating isolates but showed higher capacity to form biofilms. Blood isolates were significantly more virulent than those isolated from urine and respiratory specimens in the G. mellonella model of candidiasis. We conclude that both models of candidiasis present pros and cons but prove useful to evaluate the virulence of C. auris in vivo. Both models also evidence the heterogeneity in virulence that this species can develop, which may be influenced by the aggregative phenotype and clinical origin. This work was supported by the Euskal Herriko Unibertsitatea [PIF 16/39]; Euskal Herriko Unibertsitatea [PIF17/167]; Eusko Jaurlaritza [GIC15/78 IT-990-16]; Ministerio de Economia y Competitividad [SAF2017-86188-P].

Additional file 6. Translation METC document.

Candida parapsilosis is a frequent cause of fungal bloodstream infections, especially in critically ill neonates or immunocompromised patients. Due to the formation of biofilms, the use of indwelling catheters and other medical devices increases the risk of infection and complicates treatment, as cells embedded in biofilms display reduced drug susceptibility. Therefore, biofilm formation may be a significant clinical parameter, guiding downstream therapeutic choices. Here, we phenotypically characterized 120 selected isolates out of a prospective collection of 215 clinical C. parapsilosis isolates, determining biofilm formation, major emerging colony morphotype, and antifungal drug susceptibility of the isolates and their biofilms. In our isolate set, increased biofilm formation capacity was independent of body site of isolation and not predictable using standard or modified European Committee on Antimicrobial Susceptibility Testing (EUCAST) drug susceptibility testing protocols. In contrast, biofilm formation was strongly correlated with the appearance of non-smooth colony morphotypes and invasiveness into agar plates. Our data suggest that the observation of non-smooth colony morphotypes in cultures of C. parapsilosis may help as an indicator to consider the initiation of anti-biofilm-active therapy, such as the switch from azole- to echinocandin- or polyene-based strategies, especially in case of infections by potent biofilm-forming strains. This work was funded in part by grants or scholarships from the ZabaldUz program (Universidad del País Vasco/Euskal Herriko Unibertsitatea) to IDlP, the Consejería de Educación, Universidades e Investigación (GIC15/78 IT-990-16) of Gobierno Vasco-Eusko Jaurlaritza to GQ, the Ministerio de Economía y Competitividad (grants SAF2013-47570-P and SAF2017-86188-P, the latter co-financed by FEDER) of the Spanish government to P.G. and G.Q., and the FP7-PEOPLE-2013-ITN—Marie-Curie Action: “Initial Training Networks”: Molecular Mechanisms of Human Fungal Pathogen Host Interaction, ImResFun, MC-ITN-606786, to O.B. and U.G.

Additional file 2. Chemotherapy administration.

Additional file 1. Eligibility criteria RFA.

Additional file 4. SPIRIT checklist.

Additional file 5. Translation grant.

ObjectivesTo present an overview of effectiveness and training characteristics of physical training on aerobic fitness, compared with alternative or no training, in adults aged over 65 years with various health statuses, providing a basis for guidelines for aerobic training of vulnerable older adults that can be used in geriatric rehabilitation.DesignAn umbrella review of systematic reviews that included both randomised controlled trials and other types of trials.Data sourcesMEDLINE, Embase, CINAHL and the Cochrane Library were searched on 9 September 2019.Eligibility criteria for selecting studiesWe included systematic reviews reporting on physical training interventions that are expected to improve aerobic fitness, presenting results for adults aged 65 years and older, describing at least one of the FITT-characteristics: Frequency, Intensity, Time or Type of exercise, and measuring aerobic fitness at least before and after the intervention.Data extraction and synthesisTwo independent reviewers extracted the data and assessed the risk of bias. A narrative synthesis was performed.ResultsWe included 51 papers on 49 reviews. Positive effect of training on aerobic fitness was reported by 33 reviews, 11 reviews remained inconclusive and 5 reviews reported no effect. Training characteristics varied largely. Frequency: 1–35 sessions/week, Intensity: light–vigorous, Time: ConclusionPhysical fitness training can be effective for vulnerable older adults. Exercise characteristics from current existing guidelines are widely applicable, although lower frequencies and intensities are also beneficial. For some conditions, adjustments are advised.PROSPERO registration numberCRD42020140575.

Tiny Earth (TE) is a popular international citizen science program aimed at improving public awareness on the growing antimicrobial resistance problem of which MicroMundo Albacete is a Spanish node. With a protocol that is focused on the isolation of antibiotics-producing actinomycetes from soil, 70% of the high school students in MicroMundo Albacete 2020 isolated colonies with antagonistic activity against Gram-positive tester bacteria. However, no activity was found against Gram-negative bacteria. Here, we further adapted the protocol toward a more targeted screening that also enables isolation of antagonistic bacteria against Gram negatives using two different reverse-antibiosis approaches involving a spraying technique or flipping soil sample disks upside down. Exploiting the soil samples from MicroMundo Albacete 2020, the new approaches yielded isolation of actinomycete bacteria with antagonistic activity against Gram-negative as well as Gram-positive tester bacteria. We propose that (educational) science programs which aim to search for antibiotic-producing bacteria may implement these approaches in their protocol to promote a successful and stimulating outcome of the experiment for the participating students.

Slow dissolution of the borosilicate container of triple-point-of-water (TPW) cell is widely recognized as the main cause of long-term drift in observed triple point temperature. We add to the available experimental data a comparison of two large batches of TPW cells (67 cells in total) of various ages (from 1 year to 64 years), manufacturers (NRC, VSL, Fluke, Isotech, etc.), and materials (borosilicate glass and fused-silica) which was undertaken in 2018. After measuring the TPW temperatures realized by all 67 cells, 12 borosilicate cells were opened and their water was analyzed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) in order to correlate their impurity content with their respective age and their realized TPW temperature. No direct correlation was observed between the TPW cells age/impurity content and their measured triple-point temperature for neither borosilicate cells nor fused silica cells (Pearson's correlation coefficient rxy is within the range -0.60≤ rxy≤+0.40 for all the pairs considered). For fused-silica cells, the results indicate that after the isotopic variation in the water source is taken into account, the long-term drift due to the dissolution of glass envelope, if any, is negligibly small: (+0.4(±0.6) μK.yr-1 reported herein). Given that all the fused-silica cells realize the TPW temperature within 100 μK of NRC and VSL national reference cells and since the analyzed time period of 15 years is equal to the average lifespan of a TPW cell, we conclude that fused-silica TPW cells are superior to those made from borosilicate glass.