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Abstract The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p

Abstract Background Persistent human papillomavirus (HPV) infection is considered the primary etiological factor for invasive cervical cancer. Understanding the epidemiology of circulating potential high-risk (HR) and HR HPV strains is essential in updating epidemiological knowledge and recommendations on genotype-specific vaccination development. This study determined the prevalence and factors associated with Potential HR/HR HPV among women attending selected reproductive health clinics in Lake Victoria Basin. Methods A cross-sectional facility-based survey made up of 434 women aged 16–68 years was carried out in two selected facilities. Structured questionnaires were administered to collect participant clinical and social characteristics. Cervical specimens were collected and HPV genotyping was carried out using RIATOL HPV genotyping qPCR assay. Descriptive statistics followed by logistic binary regression was done using R version 4.3.2. Results The overall prevalence of potential HR/HR HPV among women attending the selected reproductive health clinics was reported at 36.5% (158/434). Specifically, in the rural setting, Gobei Health Center, the prevalence was 41.4% (41/99) while in the urban setting-JOOTRH, it was 34.6% (117/335). The most prevalent potential HR/HR HPV are 52, 67, 16, 31, 39, 45, and 31 among women. Age was the main factor associated with HPV infection with women between the age of 30–39 having the highest risk (AOR = 0.3, CI:0.2–0.7, p

Artificial intelligence (AI) can enhance, enable, or replace traditional open innovation (OI) practices, changing the scope and efficiency of both outside-in and inside-out OI. This article provides a comprehensive framework to analyze AI's influence on OI, supported by illustrative examples, and outlines the key implications for organizations and researchers. The co-evolutionary relationship between AI and OI will be a central focus in both research and practice moving forward. [ABSTRACT FROM AUTHOR]

Abstract Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

Objectives This study aims to design and fabricate a modular phantom for hyperthermia applications, addressing interpatient variability in thermal regulation mechanisms like sweating rate, metabolic heat production, and blood redistribution.Materials & methods The phantom can be constructed in various weights and dimensions by connecting identical units. Each unit consists of an agar-based block, an ethyl cellulose-based top layer, a heat source, deep and superficial water circulation, and a sweating mechanism. Agar and ethyl cellulose gels mimic the thermal properties of human tissues and fat respectively. The blocks are wrapped in PVC foil to prevent water evaporation. A heating wire, coiled around an embedded aluminum tubing simulates metabolic heat production. A superficial water circulation mimics skin capillaries. A water pump ensures a steady flow rate throughout the tubing system. Sweat production is simulated using a water pump and perforated tubing. A programmed controller maintains core temperature in a normal operating mode and simulates an anesthetized patient in anesthesia mode.Results Temperature uniformity and regulation were assessed under varying environmental conditions. The phantom effectively regulated its core temperature at 37.0 °C +/- 0.7 °C with an ambient temperature ranging between 21 °C and 30 °C. Activating the water circulation reduced the maximum temperature gradient within the phantom from 4.70 °C to 1.92 °C.Conclusion The versatile phantom successfully models heat exchange processes. Its thermal properties, dimensions, and heat exchange rates can be tuned to mimic different patient models. These are promising results as an effective tool for hyperthermia device validation and verification, representing human physiological responses.

Summary: The chorioallantoic membrane (CAM) model is an increasingly attractive model for the study of human tumors. However, concise techniques for the use of pancreatic ductal adenocarcinoma BxPC-3 xenografts in CAM assays are not yet available. Here, we present a protocol for the induction of BxPC-3 xenograft tumors with high grafting efficiency. We describe steps for embryo incubation, egg handling, and grafting, each of which has been optimized to prevent fungal contamination and minimize mortality. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background The objective of this international multicenter study was to investigate both early and late outcomes of cardiac resynchronization therapy (CRT) in patients with a systemic right ventricle (SRV) and to identify predictors for congestive heart failure readmissions and mortality. Methods and Results This retrospective international multicenter study included 13 centers. The study population comprised 80 adult patients with SRV (48.9% women) with a mean age of 45±14 (range, 18-77) years at initiation of CRT. Median follow-up time was 4.1 (25th-75th percentile, 1.3-8.3) years. Underlying congenital heart disease consisted of congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries in 63 (78.8%) and 17 (21.3%) patients, respectively. CRT resulted in significant improvement in functional class (before CRT: III, 25th-75th percentile, II-III; after CRT: II, 25th-75th percentile, II-III; P=0.005) and QRS duration (before CRT: 176±27; after CRT: 150±24 milliseconds; P=0.003) in patients with pre-CRT ventricular pacing who underwent an upgrade to a CRT device (n=49). These improvements persisted during long-term follow-up with a marginal but significant increase in SRV function (before CRT; 30%, 25th-75th percentile, 25-35; after CRT: 31%, 25th-75th percentile, 21-38; P=0.049). In contrast, no beneficial change in the above-mentioned variables was observed in patients who underwent de novo CRT (n=31). A quarter of all patients were readmitted for heart failure during follow-up, and mortality at latest follow-up was 21.3%. Conclusions This international experience with CRT in patients with an SRV demonstrated that CRT in selected patients with SRV dysfunction and pacing-induced dyssynchrony yielded consistent improvement in QRS duration and New York Heart Association functional status, with a marginal increase in SRV function.

PurposePrevious studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign.MethodsThis study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections.ResultsAfter booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer.ConclusionOur study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.

Abstract Cutaneous warts are benign skin lesions caused by the human papillomavirus (HPV). Even though they are considered benign, they can have a considerable impact on the quality of life and cause serious illness in certain immunocompromised populations. Studies have shown that the efficacy of wart treatment is dependent on the causative HPV type. Therefore, in this article, we aim to determine the HPV genotype-specific prevalence in cutaneous warts of a Flemish population as part of the Omnivirol-Salycilic acid randomized controlled trial. Swab samples of cutaneous warts (n = 269) were collected during enrollment. The DNA extraction was performed on the automated NucliSENS® easyMAG® system (bioMérieux). The samples were analyzed with two separate in-house PCR assays capable of detecting the most prevalent cutaneous HPV types (i.e. wart-associated HPV qPCR) as well as the most relevant mucosal types (i.e. RIATOL qPCR assay). In total, the type-specific prevalence of 30 distinct HPV genotypes was determined. The beta-globin gene was used as a cellularity control and for viral load quantification. Data concerning wart persistence, previous treatment, wart type, and other relevant wart and patient characteristics was collected through a baseline questionnaire. The study population consisted mostly of persistent warts considering that 98% (n = 263) of the sampled skin lesions were older than six months and 92% (n = 247) had undergone previous treatment. The most prominent wart type was the mosaic verruca plantaris (42%, n = 113). The most prevalent HPV types were cutaneous HPV types 27 (73%, n = 195), 57 (63%, n = 169), and 2 (42%, n = 113). Only 2% (n = 6) of the lesions was HPV negative. The highest median viral loads were observed with HPV27 and 57 (i.e. 6.29E+04 and 7.47E+01 viral copies per cell respectively). The multivariate analysis found significant associations between wart persistence and certain wart types, the number of warts, and HPV genotypes. Based on these findings, persistent warts are more likely to: (1) be verruca vulgaris, verruca plantaris simple or mosaic, (2) to manifest as multiple warts, (3) and to be negative for HPV type 2 or 4. These characteristics can be useful in the clinical setting for future risk stratification when considering treatment triage and management. Trial registration: NCT05862441, 17/05/2023 (retrospectively registered).

Abstract Background In the Netherlands, general practitioners (GPs) play a key role in provider-initiated HIV testing, but opportunities for timely diagnosis are regularly missed. We implemented an educational intervention to improve HIV testing by GPs from 2015 to 2020, and observed a 7% increase in testing in an evaluation using laboratory data. The objective for the current study was to gain a deeper understanding of whether and how practices and perceptions of GPs’ HIV/sexually transmitted infection (STI) testing behaviour changed following the intervention. Methods We performed a mixed-methods study using questionnaires and semi-structured interviews to assess self-reported changes in HIV/STI testing by participating GPs. Questionnaires were completed by participants at the end of the final educational sessions from 2017 through 2020, and participating GPs were interviewed from January through March 2020. Questionnaire data were analysed descriptively, and open question responses were categorised thematically. Interview data were analysed following thematic analysis methods. Results In total, 101/103 participants completed questionnaires. Of 65 participants that were included in analyses on the self-reported effect of the programme, forty-seven (72%) reported it had changed their HIV/STI testing, including improved STI consultations, adherence to the STI consultation guideline, more proactive HIV testing, and more extragenital STI testing. Patients’ risk factors, patients’ requests and costs were most important in selecting STI tests ordered. Eight participants were interviewed and 15 themes on improved testing were identified, including improved HIV risk-assessment, more proactive testing for HIV/STI, more focus on HIV indicator conditions and extragenital STI testing, and tools to address HIV during consultations. However, several persistent barriers for optimal HIV/STI testing by GPs were identified, including HIV-related stigma and low perceived risk. Conclusions Most GPs reported improved HIV/STI knowledge, attitude and testing, but there was a discrepancy between reported changes in HIV testing and observed increases using laboratory data. Our findings highlight challenges in implementation of effective interventions, and in their evaluation. Lessons learned from this intervention may inform follow-up initiatives to keep GPs actively engaged in HIV testing and care, on our way to zero new HIV infections.

BackgroundData on cellular response and the decay of antibodies and T cells in time are scarce in lung transplant recipients (LTRs). Additionally, the development and durability of humoral and cellular immune responses have not been investigated in patients on the waitlist for lung transplantation (WLs). Here, we report our 6-month follow-up of humoral and cellular immune responses of LTRs and WLs, compared with controls.MethodsHumoral responses to two doses of the mRNA-1273 vaccination were assessed by determining spike (S)-specific IgG antibodies and neutralizing antibodies. Cellular responses were investigated by interferon gamma (IFN-γ) release assay (IGRA) and IFN-γ ELISpot assay at 28 days and 6 months after the second vaccination.ResultsIn LTRs, the level of antibodies and T-cell responses was significantly lower at 28 days after the second vaccination. Also, WLs had lower antibody titers and lower T-cell responses compared with controls. Six months after the second vaccination, all groups showed a decrease in antibody titers and T-cell responses. In WLs, the rate of decline of neutralizing antibodies and T-cell responses was significantly higher than in controls.ConclusionOur results show that humoral and cellular responses in LTRs, if they develop, decrease at rates comparable with controls. In contrast, the inferior cellular responses and the rapid decay of both humoral and cellular responses in the WL groups imply that WLs may not be protected adequately by two vaccinations and repeat boostering may be necessary to induce protection that lasts beyond the months immediately post-transplantation.

Abstract Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4+ and CD8+ memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 μg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th)1 (IL-2, TNF-α, and IFN-γ) and Th2 (IL-4, IL-5, IL-13) cytokines, and low levels of Th17 (IL-17A, IL-22) and Th9 (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th1 cytokines upon re-stimulation, with lower levels or absence of Th2, Th17, and Th9 cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th1 and Th2 cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells.

Abstract Influenza virosomes serve as antigen delivery vehicles and pre-existing immunity toward influenza improves the immune responses toward antigens. Here, vaccine efficacy was evaluated in non-human primates with a COVID-19 virosome-based vaccine containing a low dose of RBD protein (15 µg) and the adjuvant 3M-052 (1 µg), displayed together on virosomes. Vaccinated animals (n = 6) received two intramuscular administrations at week 0 and 4 and challenged with SARS-CoV-2 at week 8, together with unvaccinated control animals (n = 4). The vaccine was safe and well tolerated and serum RBD IgG antibodies were induced in all animals and in the nasal washes and bronchoalveolar lavages in the three youngest animals. All control animals became strongly sgRNA positive in BAL, while all vaccinated animals were protected, although the oldest vaccinated animal (V1) was transiently weakly positive. The three youngest animals had also no detectable sgRNA in nasal wash and throat. Cross-strain serum neutralizing antibodies toward Wuhan-like, Alpha, Beta, and Delta viruses were observed in animals with the highest serum titers. Pro-inflammatory cytokines IL-8, CXCL-10 and IL-6 were increased in BALs of infected control animals but not in vaccinated animals. Virosomes-RBD/3M-052 prevented severe SARS-CoV-2, as shown by a lower total lung inflammatory pathology score than control animals.

Abstract Living myocardial slices (LMS) are beating sections of intact human myocardium that maintain 3D microarchitecture and multicellularity, thereby overcoming most limitations of conventional myocardial cell cultures. We introduce a novel method to produce LMS from human atria and apply pacing modalities to bridge the gap between in-vitro and in-vivo atrial arrhythmia studies. Human atrial biopsies from 15 patients undergoing cardiac surgery were dissected to tissue blocks of ~ 1 cm2 and cut to 300 µm thin LMS with a precision-cutting vibratome. LMS were placed in a biomimetic cultivation chamber, filled with standard cell culture medium, under diastolic preload (1 mN) and continuous electrical stimulation (1000 ms cycle length (CL)), resulting in 68 beating LMS. Atrial LMS refractory period was determined at 192 ± 26 ms. Fixed rate pacing with a CL of 333 ms was applied as atrial tachyarrhythmia (AT) model. This novel state-of-the-art platform for AT research can be used to investigate arrhythmia mechanisms and test novel therapies.

Osteoarthritis (OA) can be debilitating and is related to impaired resolution of synovial inflammation. Current treatments offer temporary relief of clinical signs, but have potentially deleterious side effects. Bone marrow mononuclear cells (BMNC) are a rich source of macrophage progenitors that have the ability to reduce OA symptoms in people and inflammation in experimentally-induced synovitis in horses. The objective of this study was to evaluate the ability of intra-articular BMNC therapy to improve clinical signs of naturally occurring equine OA. Horses presenting with clinical and radiographic evidence of moderate OA in a single joint were randomly assigned to 1 of 3 treatment groups: saline (negative control), triamcinolone (positive control), or BMNC (treatment group). Lameness was evaluated subjectively and objectively, joint circumference measured, and synovial fluid collected for cytology and growth factor/cytokine quantification at 0, 7, and 21 days post-injection. Data were analyzed using General Estimating Equations with significance set at p

Aim: In oncology, thermal therapy is the application of external heat to fight cancer cells. The goal of whole-body thermal treatment (WBTT) is to raise the patient’s core temperature to 39–42 °C, and represents the only thermal treatment modality that can act on both the primary tumor and distant metastases. However, WBTT carries potential risks for toxicity when applied without accurate thermometry and monitoring. Methods: ElmediX has developed a medical device, HyperTherm, to deliver long-term controlled and accurate WBTT (41.5 °C, up to 8 h). The safety of the device and thermal treatment protocol was initially evaluated in minipigs, and we present the confirmation of tolerability of WBTT in dogs with advanced cancer, in combination with a reduced dose of radiotherapy or chemotherapy. Results: Thermometry in liver, rectum, and tumor confirmed a homogeneous heating of these body parts. Monitoring of clinical parameters showed acceptable and reversible changes in liver, cardiac, muscle and coagulation parameters, as was expected. Combination of WBTT with both radiotherapy and chemotherapy only caused some low-grade adverse events. Conclusion: We conclude that our findings support the safe use of HyperTherm-mediated WBTT for canine patients with advanced malignancies. They also tend to support a genuine therapeutic potential for long-term WBTT which needs to be confirmed on a larger dog patient population. Combined with previously reported safety results in minipigs, these contribute to support the ongoing clinical evaluation of WBTT in advanced human cancer patients.

Background The use of heat to treat various diseases is called hyperthermia treatment (HT). Since the 1970s, the anti-cancer effects of HT have been investigated. Different HT techniques can be categorized as local, regional and whole-body hyperthermia treatment (WBHT). We aim to provide a summary of recent research done on HT to treat cancer.Methods In July 2020 ClinicalTrials.gov were systematically searched for all trials including hyperthermia and cancer registered between 2000 and 2020. Studies were excluded when they did not concern hyperthermal treatment, when they were not oncological studies, when they were observational or other non-interventional studies.Results Of 1654 identified trials, 235 were included. Of these 235 studies, 123 described the use of HIPEC (52.3%), 44 other types of regional HT (18.7%), 45 local HT (19.1%) and 15 WBHT (6.4%). A steady increase (720%) in research to hyperthermic intraperitoneal chemotherapy (HIPEC) can be observed in the last decade. Although HIPEC is the most researched HT modality, an evolution in other HT technologies could be observed during the past decade.Conclusions Research to HT to treat cancer has expanded fast. Some techniques, for example HIPEC start to be used outside of research context, but overall, more research is needed to establish a clear effect of these HT techniques.

The first exposure to influenza is presumed to shape the B-cell antibody repertoire, leading to preferential enhancement of the initially formed responses during subsequent exposure to viral variants. Here, we investigated whether this principle remains applicable when there are large genetic and antigenic differences between primary and secondary influenza virus antigens. Because humans usually have a complex history of influenza virus exposure, we conducted this investigation in influenza-naive cynomolgus macaques. Two groups of six macaques were immunized four times with influenza virus-like particles (VLPs) displaying either one (monovalent) or five (pentavalent) different hemagglutinin (HA) antigens derived from seasonal H1N1 (H1N1) strains. Four weeks after the final immunization, animals were challenged with pandemic H1N1 (H1N1pdm09). Although immunization resulted in robust virus-neutralizing responses to all VLP-based vaccine strains, there were no cross-neutralization responses to H1N1pdm09, and all animals became infected. No reductions in viral load in the nose or throat were detected in either vaccine group. After infection, strong virus-neutralizing responses to H1N1pdm09 were induced. However, there were no increases in virus-neutralizing titers against four of the five H1N1 vaccine strains; and only a mild increase was observed in virus-neutralizing titer against the influenza A/Texas/36/91 vaccine strain. After H1N1pdm09 infection, both vaccine groups showed higher virus-neutralizing titers against two H1N1 strains of intermediate antigenic distance between the H1N1 vaccine strains and H1N1pdm09, compared with the naive control group. Furthermore, both vaccine groups had higher HA-stem antibodies early after infection than the control group. In conclusion, immunization with VLPs displaying HA from antigenically distinct H1N1 variants increased the breadth of the immune response during subsequent H1N1pdm09 challenge, although this phenomenon was limited to intermediate antigenic variants.

Background: In previous years, several cutaneous disorders have been associated with human papillomavirus (HPV); however, the exact role of HPV remains largely unknown. The lack of optimization and standardization of the pre-analytical phase forms a major obstacle. The aim of this study was to develop an accurate/patient-friendly sampling method for skin disorders, with cutaneous warts as a case study. Methods: Various sample processing techniques, pre-treatment protocols and DNA extraction methods were evaluated. Several sampling methods were examined, that is, skin scrapings, swabs and a tape-based method. Quantification of DNA yield was achieved by beta-globin real-time polymerase chain reaction (qPCR), and a wart-associated HPV genotyping qPCR was used to determine the HPV prevalence. Results: All samples tested positive for beta-globin. Skin scrapings had significantly higher yield than both swab and tape-based methods ( p 0.05). No significant difference in DNA yield was found between cotton and flocked swabs ( p > 0.05). All swabs were HPV positive, and although there were some discrepancies in HPV prevalence between both swabs, an overall good strength of agreement was found [κ = 0.77, 95% CI (0.71–0.83)]. Conclusion: Although skin scrapings produced the highest DNA yield, patient discomfort was an important limitation of this method. Considering that in combination with our optimized DNA extraction procedure, all samples gave valid results with the less invasive swab methods preferred. Standardization of the pre-analytical phase is the first step in establishing a link between HPV and specific skin disorders and may have significant downstream diagnostic as well as therapeutic implications.

Summary: Background: Indicator-condition (IC) guided HIV testing is a feasible and cost-effective strategy to identify undiagnosed people living with HIV (PLHIV), but remains insufficiently implemented. We aimed to promote IC-guided HIV testing in seven ICs. Methods: Relevant departments in five hospitals of the Amsterdam region participated. HIV testing among adult patients without known HIV infection but with an IC was assessed using electronic health records during pre-intervention (January 2015–June 2020) and intervention (July 2020–June 2021) periods. The multifaceted intervention included audit and feedback. The primary endpoint was HIV testing ≤3 months before or after IC diagnosis and the effect of the intervention was evaluated using segmented Poisson regression. Findings: Data from 7986 patients were included, of whom 6730 (84·3%) were diagnosed with an IC in the pre-intervention period and 1256 (15·7%) in the intervention period. The proportion HIV tested ≤3 months before or after IC diagnosis increased from 36.8% to 47.0% (adjusted risk ratio [RR]= 1.16, 95% CI=1.03–1.30, p=0.02). For individual ICs, we observed significant increases in HIV testing among patients with cervical cancer or intraepithelial neoplasia grade 3 (adjusted RR=3.62, 95% CI=1.93–6.79) and peripheral neuropathy (adjusted RR=2.27 95% CI=1.48–3.49), but not the other ICs. Eighteen of 3068 tested patients were HIV positive (0.6%). Interpretation: Overall IC-guided testing improved after the intervention, but not for all ICs. Variations in effect by IC may have been due to variations in implemented developments, but the effect of separate elements could not be assessed. Funding: HIV Transmission Elimination Amsterdam (H-TEAM) initiative, Aidsfonds (grant number: P-42702).

Open innovation has become well established as a new imperative for organizing innovation. In line with the increased use in industry, it has also attracted a lot of attention in academia. However, understanding the full benefits and possible limits of open innovation still remains a challenge. We draw on strategic management theory to describe some of these benefits and limits. More specifically, we develop a dynamic capabilities framework as a way to better understand the strategic management of open innovation, which can then help to better explain both success and failure in open innovation. With this background, as guest editors we introduce select papers published in this Special Section of California Management Review that were originally presented at the fifth annual World Open Innovation Conference, held in San Francisco, California, in December of 2018.

Abstract Background Persistent high-risk (hr) human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Cervical cancer is a major public health problem in Sub-Saharan Africa including South Africa. This study investigated the prevalence of and factors associated with hr-HPV infection among women attending a tertiary hospital in Gauteng Province, South Africa. Methods Cervical samples were collected from 526 participants aged ≥ 18 years using a Cervex Brush® Combi and tested for hr-HPV types on the Abbott m2000 analyzer using the Abbott RealTime HR HPV assay. Samples that tested hr-HPV deoxyribonucleic acid (DNA)-positive were further tested for hr-HPV E6/E7 messenger ribonucleic acid (mRNA) using the APTIMA® HPV assay on the Panther system (Hologic, Inc.). Sociodemographic data were collected using a self-administered questionnaire. Binomial regression analysis was used to assess factors associated with hr-HPV infection. Results Overall hr-HPV DNA prevalence was 48.1% (95%CI: 43.8–52.4%). Of the hr-HPV DNA-positives, 24.5% (95%CI: 19.3–30.1) had HPV-16; 12.3% (95%CI: 8.5–16.9) had HPV-18 and 87.4% (95%CI: 82.6–91.2) had other 12 h-HPVs. Of the samples positive for hr-HPV DNA, 84.2% (95%CI: 79.1–88.5) (213/253) were positive for hr-HPV E6/E7 mRNA. Advanced age was an important factor linked to hr-HPV E6/E7 mRNA positivity. Based on multivariate binomial regression analysis, unemployment (PR: 1.50; 95%CI: 1.23–1.83) and being married (PR: 0.61; 95%CI: 0.47–0.81) were identified as statistically significant (p

Abstract Background The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC. Methods The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16(INK4a) immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology. Results Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests (DNA, p16 and mRNA). Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific (92.5%; 62/67). The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67. Conclusions Single hrHPV DNA PCR and p16(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.

Objective Cardiac surgery may cause temporarily impaired ventricular performance and myocardial injury. We aim to characterise the response to perioperative injury for patients undergoing repair or pulmonary valve replacement (PVR) for tetralogy of Fallot (ToF).Methods We enrolled children undergoing ToF repair or PVR from four tertiary centres in a prospective observational study. Assessment—including blood sampling and speckle tracking echocardiography—occurred before surgery (T1), at the first follow-up (T2) and 1 year after the procedures (T3). Ninety-two serum biomarkers were expressed as principal components to reduce multiple statistical testing. RNA Sequencing was performed on right ventricular (RV) outflow tract samples.Results We included 45 patients with ToF repair aged 4.3 (3.4 – 6.5) months and 16 patients with PVR aged 10.4 (7.8 – 12.7) years. Ventricular function following ToF repair showed a fall-and-rise pattern for left ventricular global longitudinal strain (GLS) (−18±4 to −13±4 to −20±2, p < 0.001 for each comparison) and RV GLS (−19±5 to −14±4 to 20±4, p < 0.002 for each comparison). This pattern was not seen for patients undergoing PVR. Serum biomarkers were expressed as three principal components. These phenotypes are related to: (1) surgery type, (2) uncorrected ToF and (3) early postoperative status. Principal component 3 scores were increased at T2. This increase was higher for ToF repair than PVR. The transcriptomes of RV outflow tract tissue are related to patients’ sex, rather than ToF-related phenotypes in a subset of the study population.Conclusions The response to perioperative injury following ToF repair and PVR is characterised by specific functional and immunological responses. However, we did not identify factors relating to (dis)advantageous recovery from perioperative injury.Trial registration number Netherlands Trial Register: NL5129.

Our brain is continuously challenged by daily experiences. Thus, how to avoid systematic erasing of previously encoded memories? While it has been proposed that a dual-learning system with ‘slow’ learning in the cortex and ‘fast’ learning in the hippocampus could protect previous knowledge from interference, this has never been observed in the living organism. Here, we report that increasing plasticity via the viral-induced overexpression of RGS14414 in the prelimbic cortex leads to better one-trial memory, but that this comes at the price of increased interference in semantic-like memory. Indeed, electrophysiological recordings showed that this manipulation also resulted in shorter NonREM-sleep bouts, smaller delta-waves and decreased neuronal firing rates. In contrast, hippocampal-cortical interactions in form of theta coherence during wake and REM-sleep as well as oscillatory coupling during NonREM-sleep were enhanced. Thus, we provide the first experimental evidence for the long-standing and unproven fundamental idea that high thresholds for plasticity in the cortex protect preexisting memories and modulating these thresholds affects both memory encoding and consolidation mechanisms.