Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology.

The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Actin filaments (F-actin) are the major structural component of dendritic spines, and therefore, actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Studies of the past decade identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission, and behavior, and they emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. Here, we report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperates with cofilin1 in spines and that its helical folded domain is relevant for this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that is essential for synaptic cofilin1 activity.

Pictorial Representation of Illness and Self-Measure to assess the perceived burden in patients with chronic inflammatory vulvar diseases: an observational study.

BACKGROUND: Chronic inflammatory vulvar diseases can have a huge detrimental impact on patient welfare. A few studies have addressed this issue so far, mainly measuring patients' quality of life or sexual dysfunction. OBJECTIVE: To assess the burden of suffering in patients with chronic inflammatory vulvar diseases using the Pictorial Representation of Illness and Self-Measure (PRISM), a visual, non-verbal instrument. We also assessed (i) the concordance between PRISM and the Dermatology Life Quality Index (DLQI), (ii) whether some variables, both patient-related and disease-related, affect the patient's suffering and quality-of-life impairment. METHODS: We evaluated for inclusion in this cross-sectional study all patients who attended our Vulva Unit over a 9-month period with histologically proven lichen sclerosus (LS), lichen planus (LP), lichen simplex chronicus (LSC), eczema, plasma cell vulvitis and psoriasis (at least five for each disease). Demographics and disease-related subjective and objective scores were recorded. The PRISM and DLQI were administered. RESULTS: We included 87 patients affected with LS, 13 with LSC and seven with LP. Median PRISM values (0-273 mm) ranged from 95 to 120 mm, depending on the disease, and median DLQI scores (0-30) were five for all three groups. Neither PRISM nor DLQI scores differed significantly among the three groups. Moderate coherence was found between PRISM and DLQI (ρ = 0.5455, P < 0.001). Global subjective score was the only variable significantly associated with the degree of suffering and quality-of-life impairment. CONCLUSIONS: Pictorial Representation of Illness and Self-Measure proved to be a valuable, highly reliable tool for measuring the perceived burden in these patients. In spite of a moderate correlation, PRISM resulted more sensitive in capturing patient distress than DLQI.

Seeking Formula for Misinformation Treatment in Public Health Crises: The Effects of Corrective Information Type and Source.

An increasing lack of information truthfulness has become a fundamental challenge to communications. Insights into how to debunk this type of misinformation can especially be crucial for public health crises. To identify corrective information strategies that increase awareness and trigger actions during infectious disease outbreaks, an online experiment (N = 700) was conducted, using a U.S. sample. After initial misinformation exposure, participants' exposure to corrective information type (simple rebuttal vs. factual elaboration) and source (government health agency vs. news media vs. social peer) was varied, including a control group without corrective information. Results show that, if corrective information is present rather than absent, incorrect beliefs based on misinformation are debunked and the exposure to factual elaboration, compared to simple rebuttal, stimulates intentions to take protective actions. Moreover, government agency and news media sources are found to be more successful in improving belief accuracy compared to social peers. The observed mediating role of crisis emotions reveals the mechanism underlying the effects of corrective information. The findings contribute to misinformation research by providing a formula for correcting the increasing spread of misinformation in times of crisis.

Diagnosis of leprosy in a Nigerian migrant: implementation of surveillance measures in the current migration context.

BACKGROUND: In Italy, leprosy diagnosis is reported in immigrants from endemic countries or Italians who have stayed in endemic areas. We report the first leprosy case to be observed in a migrant from Nigeria in the Rimini district (Emilia-Romagna, Northern Italy). METHODS: After describing the tasks of the various health Institutions in the Italian integrated system for diagnosis, treatment, and surveillance of leprosy, we describe the management and outcomes of the leprosy case and of the patient's contacts. RESULTS: In April 2017, Multibacillary Lepromatose Leprosy was diagnosed in a 29-year-old Nigerian man who arrived in Rimini in July 2014 after a 2-year stay in Libya. The local Public Health Service implemented the epidemiological investigation and identified the patient's close contacts. The management of the case and the surveillance of the 13 identified contacts, 7 Italians and 6 migrants, highlighted some critical issues. The late diagnosis of the case, due to the lack of knowledge of exotic diseases by general practitioners and other health and social professionals, and the loss at follow up of the close contacts (5 out of 6 migrants), represented important obstacles to the full success of surveillance measures. CONCLUSIONS: Although in Italy there is a well codified system of notification and surveillance of leprosy, the recognising of cases and the tracing and follow up of contacts are made difficult by the particular conditions of the involved people. This represents a new challenge for the Italian Public Health Authorities which, in the current context of immigration, often uncontrolled, must know how to respond to the new needs, in close collaboration with the State Institutions responsible for registering migrants and those health and social professionals who could facilitate the access of foreign people to health services.

Quantifying Triplet State Formation in Zinc Dipyrrin Complexes.

Photocatalysis is a promising method to harness solar energy and use it to form fuels and other high-value chemicals, but most sensitizers used in photocatalytic reactions are complexes of rare and expensive metals such as ruthenium and iridium. Zinc dipyrromethene complexes have potential to be a more earth-abundant alternative, but their photophysical properties are largely unexplored. In this study, triplet state formation was quantified in two zinc dipyrromethene complexes, with and without heavy atoms, by transient absorption spectroscopy. Without heavy atoms, the triplet quantum yield was 16% in toluene and 27% in THF. With the addition of heavy I atoms, the triplet quantum yield increased to 62-63% and was insensitive to solvent polarity. The fact that in the absence of heavy atoms the triplet yield is affected by solvent polarity and in the presence of heavy atoms it is not suggests that triplet formation occurs through different pathways in the two complexes. These triplet yields meet or exceed those of successful organic photosensitizers, illustrating the potential for zinc dipyrromethene complexes as photosensitizers.

Clearance in vulvar lichen sclerosus: a realistic treatment endpoint or a chimera?

BACKGROUND: According to the current guidelines, the aim of vulvar lichen sclerosus (VLS) treatment was to improve symptoms and signs, not to cure. OBJECTIVE: To assess (i) the rate of patients with VLS who achieved complete clearance of symptoms or objective features, or both, with a 12-week pharmacological treatment and (ii) the predictive value of therapeutic response to the demographic and clinical features. METHODS: We retrospectively included patients with VLS who had undergone any topical treatment for 12 weeks; demographics, history, VLS-related symptoms and objective features recorded at baseline and on completion of treatment were collected and elaborated. The primary study endpoint was to assess the rate of patients achieving complete clearance of global subjective score (GSS), or in global objective score (GOS), and in both scores. RESULTS: One hundred and ninety-six patients were included; 24 (12.2%) were asymptomatic at baseline, and nine (4.6%) dropped out. After treatment, 78 patients (47.3%) achieved GSS = 0, 40 (21.4%) achieved GOS = 0, and 23 (13.9%) achieved complete clearance of both symptoms and signs. Lower symptom scores at baseline and shorter disease duration were associated with the achievement of symptom clearance at the end of the treatment. Earlier disease onset, diagnosis and beginning of study treatment as well as lower baseline GOS were significantly associated with complete recovery of VLS signs and clearance of both symptoms and signs. CONCLUSION: A relevant part of patients who undergo a 12-week topical treatment is not completely cured of VLS. It may be hypothesized that these patients, in spite of a significant improvement, may still have substantial residual disease and, as a result, its effect on their quality of life.

Clobetasol propionate vs. mometasone furoate in 1-year proactive maintenance therapy of vulvar lichen sclerosus: results from a comparative trial.

BACKGROUND: Twice-weekly proactive application of mometasone furoate 0.1% ointment (MMF) over 52 weeks was found to be an effective and safe therapy option in maintaining vulvar lichen sclerosus (VLS) remission and in preventing relapse. OBJECTIVE: To assess and compare the effectiveness and safety of two different topical corticosteroids, clobetasol propionate 0.05% ointment (CP) and MMF, administered twice weekly as a maintenance therapy of VLS previously stabilized with a topical corticosteroid course. METHODS: Forty-eight patients affected with VLS who had responded to therapy with either CP or MMF in an earlier 12-week randomized active treatment phase trial were enroled in a 52-week maintenance phase (MP) to apply their previous treatment twice weekly. The main efficacy parameters were the relapse rate, the mean time of relapse, and the change in symptom and sign severity throughout MP. RESULTS: By the end of the 52-week MP, 2 (8.33%) subjects among the CP patients and 1 (4.17%) among the MMF patients experienced a relapse; among relapsing patients the mean time to relapse was 30 weeks. Neither subjective nor objective scores changed significantly during MP among CP and MMF patients. No significant differences were found in any of the assessed efficacy endpoints between CP and MMF. Both treatments were well tolerated and the proactive regimen was judged as convenient by patients. CONCLUSIONS: Proactive application of the ultra-potent CP and the potent MMF was found to be an effective, safe and suitable maintenance treatment for long-term management of VLS. There were no differences between the two corticosteroids.

Physical exercise for late-life major depression.

BACKGROUND: Interventions including physical exercise may help improve the outcomes of late-life major depression, but few studies are available. AIMS: To investigate whether augmenting sertraline therapy with physical exercise leads to better outcomes of late-life major depression. METHOD: Primary care patients (465 years) with major depression were randomised to 24 weeks of higher-intensity, progressive aerobic exercise plus sertraline (S+PAE), lower-intensity, non-progressive exercise plus sertraline (S+NPE) and sertraline alone. The primary outcome was remission (a score of ≤10 on the Hamilton Rating Scale for Depression). RESULTS: A total of 121 patients were included. At study end, 45% of participants in the sertraline group, 73% of those in the S+NPE group and 81% of those in the S+PAE group achieved remission (P = 0.001). A shorter time to remission was observed in the S+PAE group than in the sertraline-only group. CONCLUSIONS: Physical exercise may be a safe and effective augmentation to antidepressant therapy in late-life major depression.

Continuous vs. tapering application of the potent topical corticosteroid mometasone furoate in the treatment of vulvar lichen sclerosus: results of a randomized trial.

BACKGROUND: Topical corticosteroids are the first-line treatment for vulvar lichen sclerosus (VLS). However, evidence on the most appropriate treatment regimen is lacking. OBJECTIVES: To compare the effectiveness and tolerability of tapering vs. continuous application of mometasone furoate (MMF) 0·1% ointment in the treatment of active VLS. METHODS: Sixty-four patients with VLS who enrolled in a 12-week active treatment phase were randomized to apply MMF either (i) once daily for 5 days per week for 4 weeks, then on alternate days for 4 weeks, then twice weekly for 4 weeks (group A) or (ii) for five consecutive days per week for the entire treatment duration (group B). The efficacy parameters were the response rate, the proportion of patients achieving an improvement from baseline of ≥ 75% in subjective and objective scores, and the mean reduction in subjective and objective scores. RESULTS: By the end of the active treatment phase, 27 patients (84%) were considered to be responders in group A, and 25 patients (78%) in group B; 69% and 47% of patients in group A and 62% and 28% in group B achieved ≥ 75% improvement in subjective and objective scores, respectively. The decreases in mean symptom and sign scores were significant compared with baseline with both regimens. No significant differences were found in any of the assessed efficacy end points between the two treatment protocols. Both regimens were well tolerated. CONCLUSIONS: Both tapering and continuous application of MMF showed similar efficacy and tolerability in the treatment of active VLS, without any difference in patient adherence to therapy.

Avocado and soybean extracts as active principles in the treatment of mild-to-moderate vulvar lichen sclerosus: results of efficacy and tolerability.

OBJECTIVE: Limited evidence is available on the effectiveness of treatments alternative to corticosteroids for vulvar lichen sclerosus (VLS). The present study aimed to assess the efficacy and tolerability of avocado and soybean extracts (ASE) as active principles of both a topical product and a nutritional supplement in the treatment of active mild-to-moderate VLS. MATERIALS AND METHODS: Twenty-three patients were enrolled. Treatment consisted of a topical product containing ASE and other lenitive and anti-oxidant principles administered twice daily for 24 weeks, in association with a dietary supplement containing ASE, vitamin E and para-aminobenzoic acid for the first 12 weeks. The primary efficacy endpoint was the rate of patients achieving an improvement from baseline in global subjective score (GSS) and global objective score (GOS) of ≥ 75%. Secondary efficacy endpoint was the rate of patients achieving GSS50 and GOS50. Tertiary efficacy endpoint was the mean reduction in subjective and objective scores throughout the treatment. RESULTS: By the end of the 24-week treatment, 12 (70.5% of symptomatic patients) and 13 patients (72.2%) achieved an improvement of at least 75% in subjective and objective global scores, respectively; 100% and 88.9% reached GSS50 and GOS50, respectively. Mean symptom and sign scores decreased significantly after treatment. The treatment was well tolerated. CONCLUSIONS: Our results provide evidence that the topical and dietary supplements used in the study, which contain active principles exerting anti-inflammatory, anti-fibrotic, emollient and lenitive actions, are effective alternatives in the treatment of symptoms and signs of mild-to-moderate VLS.

First randomized trial on clobetasol propionate and mometasone furoate in the treatment of vulvar lichen sclerosus: results of efficacy and tolerability.

BACKGROUND: A 3-month topical application of clobetasol propionate (CP) represents the recommended and accepted first-line treatment for vulvar lichen sclerosus (VLS); however, to date, no randomized controlled trials have compared the efficacy and safety of CP with other topical corticosteroids. OBJECTIVE: To compare the effectiveness and tolerability of two different topical corticosteroids, CP 0·05% ointment and mometasone furoate (MMF) 0·1% ointment, in the treatment of VLS. METHODS: Fifty-four patients with VLS were enrolled in a 12-week active treatment phase (ATP) and randomized to apply either CP or MMF in a tapering regimen. The main efficacy parameters were the response rate, the rate of patients achieving an improvement from baseline of ≥ 75% in the subjective and objective scores, and the mean reduction in subjective and objective scores throughout the treatment. RESULTS: By the end of the 12-week ATP, 24 (89%) patients were considered to be responders among the CP patients and 24 (89%) among the MMF patients; 59% and 37% of patients in the CP group and 67% and 48% in the MMF group achieved an improvement of at least 75% in subjective and objective scores, respectively. The decrease in mean symptom and sign scores was significant compared with baseline with both treatments. No significant differences were found in any of the assessed efficacy endpoints between CP and MMF. Both treatments were well tolerated. CONCLUSIONS: Clobetasol propionate and MMF appeared similarly efficacious and well tolerated for the treatment of VLS and both may represent the first-line treatment for the disease.

Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.

BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.

Borrelia burgdorferi bba66 gene inactivation results in attenuated mouse infection by tick transmission.

The impact of the Borrelia burgdorferi surface-localized immunogenic lipoprotein BBA66 on vector and host infection was evaluated by inactivating the encoding gene, bba66, and characterizing the mutant phenotype throughout the natural mouse-tick-mouse cycle. The BBA66-deficient mutant isolate, Bb(ΔA66), remained infectious in mice by needle inoculation of cultured organisms, but differences in spirochete burden and pathology in the tibiotarsal joint were observed relative to the parental wild-type (WT) strain. Ixodes scapularis larvae successfully acquired Bb(ΔA66) following feeding on infected mice, and the organisms persisted in these ticks through the molt to nymphs. A series of tick transmission experiments (n = 7) demonstrated that the ability of Bb(ΔA66)-infected nymphs to infect laboratory mice was significantly impaired compared to that of mice fed upon by WT-infected ticks. trans-complementation of Bb(ΔA66) with an intact copy of bba66 restored the WT infectious phenotype in mice via tick transmission. These results suggest a role for BBA66 in facilitating B. burgdorferi dissemination and transmission from the tick vector to the mammalian host as part of the disease process for Lyme borreliosis.

The bba64 gene of Borrelia burgdorferi, the Lyme disease agent, is critical for mammalian infection via tick bite transmission.

The spirochetal agent of Lyme disease, Borrelia burgdorferi, is transmitted by bites of Ixodes ticks to mammalian reservoir hosts and humans. The mechanism(s) by which the organism is trafficked from vector to host is poorly understood. In this study, we demonstrate that a B. burgdorferi mutant strain deficient in the synthesis of the bba64 gene product was incapable of infecting mice via tick bite even though the mutant was (i) infectious in mice when introduced by needle inoculation, (ii) acquired by larval ticks feeding on infected mice, and (iii) able to persist through tick molting stages. This finding of a B. burgdorferi gene required for pathogen transfer and/or survival from the tick to the susceptible host represents an important breakthrough toward understanding transmission mechanisms involved for the Lyme disease agent.

Can we trust measures of trust? a comparison of results from open and closed questions.

Many public opinion surveys compare trust in a number of different information and (mediated) knowledge sources, typically using closed questions with a set of answer categories that are imposed by researchers. We aim to validate these categories by quantitatively comparing survey responses about trustworthy sources using open and closed questions, and by qualitatively analyzing the open answers. The results show that answer options typically used for closed questions in academic research are generally valid and closely match categories that respondents come up with unprimed. In some cases, answers to open questions can be non-exhaustive, particularly when sources are considered trustworthy but are not salient for respondents. Open questions, however, may still be useful for exploratory research or more detailed investigations of media diets on the outlet-level. Qualitative approaches to open questions can also give more insight into motivations for distrust, e.g. perceptions of inconsistency or a fundamental rejection of the shared factual basis of an issue. In addition, our results indicate that respondents' interpretation of answer categories may change reported levels of trust: those that think of more specific outlets tend to report higher general media trust. This study provides new insights into how question design, and particularly the choice of answer options, may influence reported levels and sources of trust, and how qualitative and quantitative approaches to trust measurement can be combined.