An Autonomous Oscillation Times and Executes Centriole Biogenesis.

The accurate timing and execution of organelle biogenesis is crucial for cell physiology. Centriole biogenesis is regulated by Polo-like kinase 4 (Plk4) and initiates in S-phase when a daughter centriole grows from the side of a pre-existing mother. Here, we show that a Plk4 oscillation at the base of the growing centriole initiates and times centriole biogenesis to ensure that centrioles grow at the right time and to the right size. The Plk4 oscillation is normally entrained to the cell-cycle oscillator but can run autonomously of it-potentially explaining why centrioles can duplicate independently of cell-cycle progression. Mathematical modeling indicates that the Plk4 oscillation can be generated by a time-delayed negative feedback loop in which Plk4 inactivates the interaction with its centriolar receptor through multiple rounds of phosphorylation. We hypothesize that similar organelle-specific oscillations could regulate the timing and execution of organelle biogenesis more generally.

Cellular Mechanisms of NETosis.

Neutrophils are critical to innate immunity, including host defense against bacterial and fungal infections. They achieve their host defense role by phagocytosing pathogens, secreting their granules full of cytotoxic enzymes, or expelling neutrophil extracellular traps (NETs) during the process of NETosis. NETs are weblike DNA structures decorated with histones and antimicrobial proteins released by activated neutrophils. Initially described as a means for neutrophils to neutralize pathogens, NET release also occurs in sterile inflammation, promotes thrombosis, and can mediate tissue damage. To effectively manipulate this double-edged sword to fight a particular disease, researchers must work toward understanding the mechanisms driving NETosis. Such understanding would allow the generation of new drugs to promote or prevent NETosis as needed. While knowledge regarding the (patho)physiological roles of NETosis is accumulating, little is known about the cellular and biophysical bases of this process. In this review, we describe and discuss our current knowledge of the molecular, cellular, and biophysical mechanisms mediating NET release as well as open questions in the field.

Regulation of centrosome size by the cell-cycle oscillator in Drosophila embryos.

Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. In early C. elegans embryos, mitotic centrosome size appears to be set by the limiting amount of a key component. In Drosophila syncytial embryos, thousands of mitotic centrosomes are assembled as the embryo proceeds through 13 rounds of rapid nuclear division, driven by a core cell cycle oscillator. These divisions slow during nuclear cycles 11-13, and we find that centrosomes respond by reciprocally decreasing their growth rate, but increasing their growth period-so that they grow to a relatively consistent size at each cycle. At the start of each cycle, moderate CCO activity initially promotes centrosome growth, in part by stimulating Polo/PLK1 recruitment to centrosomes. Later in each cycle, high CCO activity inhibits centrosome growth by suppressing the centrosomal recruitment and/or maintenance of centrosome proteins. Thus, in fly embryos, mitotic centrosome size appears to be regulated predominantly by the core cell cycle oscillator, rather than by the depletion of a limiting component.

Centrioles generate a local pulse of Polo/PLK1 activity to initiate mitotic centrosome assembly.

Mitotic centrosomes are formed when centrioles start to recruit large amounts of pericentriolar material (PCM) around themselves in preparation for mitosis. This centrosome "maturation" requires the centrioles and also Polo/PLK1 protein kinase. The PCM comprises several hundred proteins and, in Drosophila, Polo cooperates with the conserved centrosome proteins Spd-2/CEP192 and Cnn/CDK5RAP2 to assemble a PCM scaffold around the mother centriole that then recruits other PCM client proteins. We show here that in Drosophila syncytial blastoderm embryos, centrosomal Polo levels rise and fall during the assembly process-peaking, and then starting to decline, even as levels of the PCM scaffold continue to rise and plateau. Experiments and mathematical modelling indicate that a centriolar pulse of Polo activity, potentially generated by the interaction between Polo and its centriole receptor Ana1 (CEP295 in humans), could explain these unexpected scaffold assembly dynamics. We propose that centrioles generate a local pulse of Polo activity prior to mitotic entry to initiate centrosome maturation, explaining why centrioles and Polo/PLK1 are normally essential for this process.

Upper bound for broadband radiofrequency field disruption of magnetic compass orientation in night-migratory songbirds.

Night-migratory songbirds have a light-dependent magnetic compass sense, the mechanism of which is thought to depend on the photochemical formation of radical pairs in cryptochrome (Cry) proteins located in the retina. The finding that weak radiofrequency (RF) electromagnetic fields can prevent birds from orienting in the Earth's magnetic field has been regarded as a diagnostic test for this mechanism and as a potential source of information on the identities of the radicals. The maximum frequency that could cause such disorientation has been predicted to lie between 120 and 220 MHz for a flavin-tryptophan radical pair in Cry. Here we show that the magnetic orientation capabilities of Eurasian blackcaps (Sylvia atricapilla) are not affected by RF noise in the frequency bands 140 to 150 MHz and 235 to 245 MHz. From a consideration of its internal magnetic interactions, we argue that RF field effects on a flavin-containing radical-pair sensor should be approximately independent of frequency up to 116 MHz and that birds' sensitivity to RF disorientation should fall by about two orders of magnitude when the frequency exceeds 116 MHz. Taken together with our earlier finding that 75 to 85 MHz RF fields disrupt the magnetic orientation of blackcaps, these results provide compelling evidence that the magnetic compass of migratory birds operates by a radical pair mechanism.

Centriole distal-end proteins CP110 and Cep97 influence centriole cartwheel growth at the proximal end.

Centrioles are composed of a central cartwheel tethered to nine-fold symmetric microtubule (MT) blades. The centriole cartwheel and MTs are thought to grow from opposite ends of these organelles, so it is unclear how they coordinate their assembly. We previously showed that in Drosophila embryos an oscillation of Polo-like kinase 4 (Plk4) helps to initiate and time the growth of the cartwheel at the proximal end. Here, in the same model, we show that CP110 and Cep97 form a complex close to the distal-end of the centriole MTs whose levels rise and fall as the new centriole MTs grow, in a manner that appears to be entrained by the core cyclin-dependent kinase (Cdk)-Cyclin oscillator that drives the nuclear divisions in these embryos. These CP110 and Cep97 dynamics, however, do not appear to time the period of centriole MT growth directly. Instead, we find that changing the levels of CP110 and Cep97 appears to alter the Plk4 oscillation and the growth of the cartwheel at the proximal end. These findings reveal an unexpected potential crosstalk between factors normally concentrated at opposite ends of the growing centrioles, which might help to coordinate centriole growth. This article has an associated First Person interview with the first authors of the paper.

Endocuff With or Without Artificial Intelligence-Assisted Colonoscopy in Detection of Colorectal Adenoma: A Randomized Colonoscopy Trial.

INTRODUCTION: Both artificial intelligence (AI) and distal attachment devices have been shown to improve adenoma detection rate and reduce miss rate during colonoscopy. We studied the combined effect of Endocuff and AI on enhancing detection rates of various colonic lesions. METHODS: This was a 3-arm prospective randomized colonoscopy study involving patients aged 40 years or older. Participants were randomly assigned in a 1:1:1 ratio to undergo Endocuff with AI, AI alone, or standard high-definition (HD) colonoscopy. The primary outcome was adenoma detection rate (ADR) between the Endocuff-AI and AI groups while secondary outcomes included detection rates of polyp (PDR), sessile serrated lesion (sessile detection rate [SDR]), and advanced adenoma (advanced adenoma detection rate) between the 2 groups. RESULTS: A total of 682 patients were included (mean age 65.4 years, 52.3% male), with 53.7% undergoing diagnostic colonoscopy. The ADR for the Endocuff-AI, AI, and HD groups was 58.7%, 53.8%, and 46.3%, respectively, while the corresponding PDR was 77.0%, 74.0%, and 61.2%. A significant increase in ADR, PDR, and SDR was observed between the Endocuff-AI and AI groups (ADR difference: 4.9%, 95% CI: 1.4%-8.2%, P = 0.03; PDR difference: 3.0%, 95% CI: 0.4%-5.8%, P = 0.04; SDR difference: 6.4%, 95% CI: 3.4%-9.7%, P < 0.01). Both Endocuff-AI and AI groups had a higher ADR, PDR, SDR, and advanced adenoma detection rate than the HD group (all P < 0.01). DISCUSSION: Endocuff in combination with AI further improves various colonic lesion detection rates when compared with AI alone.

Clinical profile, treatment and quality of life of patients with psoriatic arthritis in Malaysia: A population-based cross-sectional study.

Psoriatic arthritis (PsA) is a major comorbidity of psoriasis and may lead to irreversible joint damage and disability. This study aims to describe the clinical profile, treatment and quality of life (QoL) of patients with PsA in Malaysia. This is a multicentre retrospective cross-sectional study of psoriasis patients who were notified to the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018. Of 21 735 psoriasis patients, 2756 (12.7%) had PsA. The male to female ratio was 1:1. The mean age of psoriasis onset for PsA patients was 34.73 ± 14.44 years. They had a higher rate of family history of psoriasis (26% vs. 22.4%, p < 0.001), scalp (82.7% vs. 81.0%, p = 0.04) and nail involvement (73.3% vs. 53.3%, p < 0.001), obesity (62.6% vs. 54.4%, p < 0.001), dyslipidaemia (23.8% vs. 15.4%, p < 0.001), hypertension (31.1% vs. 22.7%, p < 0.001) and diabetes mellitus (20.9% vs. 15.2%, p < 0.001) compared to non-PsA patients. More than half (54.3%) had severe psoriasis [(body surface area >10% and/or Dermatology Life Quality Index (DLQI) >10)]. Most had oligo-/monoarthropathy (40.3%), followed by distal interphalangeal arthropathy (31.3%), symmetrical polyarthropathy (28.3%), spondylitis/sacroiliitis (8.2%) and arthritis mutilans (3.2%). Nearly 40% of PsA patients received systemic treatment, but only 1.6% received biologic agents. QoL was more significantly affected in PsA than in non-PsA patients (mean DLQI 10.12 ± 7.16 vs. 9.52 ± 6.67, p < 0.001). One in eight patients with psoriasis in Malaysia had PsA. They had a higher incidence of comorbidities, severe disease, impaired QoL and were more likely to receive systemic and biological treatment compared to non PsA patients.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

The Effect of Spin Relaxation on Magnetic Compass Sensitivity in ErCry4a.

This study explores the impact of thermal motion on the magnetic compass mechanism in migratory birds, focusing on the radical pair mechanism within cryptochrome photoreceptors. The coherence of radical pairs, crucial for magnetic field inference, is curbed by spin relaxation induced by intra-protein motion. Molecular dynamics simulations, density-functional-theory-based calculations, and spin dynamics calculations were employed, utilizing Bloch-Redfield-Wangsness (BRW) relaxation theory, to investigate compass sensitivity. Previous research hypothesized that European robin's cryptochrome 4a (ErCry4a) optimized intra-protein motion to minimize spin relaxation, enhancing magnetic sensing compared to the plant Arabidopsis thaliana's cryptochrome 1 (AtCry1). Different correlation times of the nuclear hyperfine coupling constants in AtCry1 and ErCry4a were indeed found, leading to distinct radical pair yields in the two species, with ErCry4a showing optimized sensitivity. However, this optimization is likely negligible in realistic spin systems with numerous nuclear spins. Beyond insights in magnetic sensing, the study presents a detailed method employing molecular dynamics simulations to assess spin relaxation effects on chemical reactions with realistically modelled protein motion, relevant for studying radical pair reactions at finite temperature.

Nanomanipulation of Ligand Nanogeometry Modulates Integrin/Clathrin-Mediated Adhesion and Endocytosis of Stem Cells.

Nanosubstrate engineering can be a biomechanical approach for modulating stem cell differentiation in tissue engineering. However, the study of the effect of clathrin-mediated processes on manipulating this behavior is unexplored. Herein, we develop integrin-binding nanosubstrates with confined nanogeometries that regulate clathrin-mediated adhesion- or endocytosis-active signaling pathways for modulating stem fates. Isotropically presenting ligands on the nanoscale enhances the expression of clathrin in cells, thereby facilitating uptake of dexamethasone-loaded nanoparticles (NPs) to boost osteogenesis of stem cells. In contrast, anisotropic ligand nanogeometry suppresses this clathrin-mediated NP entry by strengthening the association between clathrin and adhesion spots to reinforce mechanotransduced signaling, which can be abrogated by the pharmacological inhibition of clathrin. Meanwhile, inhibiting focal adhesion formation hinders cell spreading and enables a higher endocytosis efficiency. Our findings reveal the crucial roles of clathrin in both endocytosis and mechanotransduction of stem cells and provide the parameter of ligand nanogeometry for the rational design of biomaterials for tissue engineering.

Experiences of receiving an mHealth application with proactive nursing support among community-dwelling older adults: a mixed-methods study.

BACKGROUND: As the population ages, a plethora of digital and mobile health applications for assistance with independent living have emerged. Still unknown, however, is how older adults sustain the use of these applications. AIM: This study sought to explore the experiences of older adults following their participation in a programme that combined the use of an mHealth application with proactive telecare nursing support. METHODS: We employed a concurrent mixed-methods design for this study. The quantitative strand included a survey, whereas the qualitative strand included open-ended questions as part of the survey to understand the participants' experiences. Participants for this study were community-dwelling older adults who had taken part in an interventional study that sought to examine the effects of mHealth and nurse support. A convenience sampling approach was employed to recruit potential participants for this study. FINDINGS: Fifty-five older adults participated. The majority expressed positive attitudes and satisfaction with the app and the nurses' support. The app and nurses' support helped participants to understand their health status and obtain health information. Reasons to halt app usage included technical issues and limited social support. CONCLUSION: Mobile apps with professional follow-up support could potentially support older adults in the community, although emerging concerns need to be addressed to sustain long-term usage of these apps.

A Multilayered Mesoporous Gold Nanoarchitecture for Ultraeffective Near-Infrared Light-Controlled Chemo/Photothermal Therapy for Cancer Guided by SERS Imaging.

Surface-enhanced Raman scattering (SERS) imaging has emerged as a promising tool for guided cancer diagnosis and synergistic therapies, such as combined chemotherapy and photothermal therapy (chemo-PTT). Yet, existing therapeutic agents often suffer from low SERS sensitivity, insufficient photothermal conversion, or/and limited drug loading capacity. Herein, a multifunctional theragnostic nanoplatform consisting of mesoporous silica-coated gold nanostar with a cyclic Arg-Gly-Asp (RGD)-coated gold nanocluster shell (named RGD-pAS@AuNC) is reported that exhibits multiple "hot spots" for pronouncedly enhanced SERS signals and improved near-infrared (NIR)-induced photothermal conversion efficiency (85.5%), with a large capacity for high doxorubicin (DOX) loading efficiency (34.1%, named RGD/DOX-pAS@AuNC) and effective NIR-triggered DOX release. This nanoplatform shows excellent performance in xenograft tumor model of HeLa cell targeting, negligible cytotoxicity, and good stability both in vitro and in vivo. By SERS imaging, the optimal temporal distribution of injected RGD/DOX-pAS@AuNCs at the tumor site is identified for NIR-triggered local chemo-PTT toward the tumor, achieving ultraeffective therapy in tumor cells and tumor-bearing mouse model with 5 min of NIR irradiation (0.5 W cm-2 ). This work offers a promising approach to employing SERS imaging for effective noninvasive tumor treatment by on-site triggered chemo-PTT.

Blue-light imaging or narrow-band imaging for proximal colonic lesions: a prospective randomized tandem colonoscopy study.

BACKGROUND AND AIMS: Blue-light imaging (BLI) is a new image-enhanced endoscopy with a wavelength filter similar to narrow-band imaging (NBI). We compared the 2 with white-light imaging (WLI) on proximal colonic lesion detection and miss rates. METHODS: In this 3-arm prospective randomized study with tandem examination of the proximal colon, we enrolled patients aged ≥40 years. Eligible patients were randomized in 1:1:1 ratio to receive BLI, NBI, or WLI during the first withdrawal from the proximal colon. The second withdrawal was performed using WLI in all patients. Primary outcomes were proximal polyp (pPDRs) and adenoma (pADRs) detection rates. Secondary outcomes were miss rates of proximal lesions found on tandem examination. RESULTS: Of 901 patients included (mean age, 64.7 years; 52.9% men), 48.1% underwent colonoscopy for screening or surveillance. The corresponding pPDRs of the BLI, NBI, and WLI groups were 45.8%, 41.6, and 36.6%, whereas the corresponding pADRs were 36.6%, 33.8%, and 28.3%. There was a significant difference in pPDR and pADR between BLI and WLI groups (difference, 9.2% [95% confidence interval {CI}, 3.3-16.9] and 8.3% [95% CI, 2.7-15.9]) and between NBI and WLI groups (difference, 5.0% [95% CI, 1.4-12.9] and 5.6% [95% CI, 2.1-13.3]). Proximal adenoma miss rates were significantly lower with BLI (19.4%) than with WLI (27.4%; difference, -8.0%; 95% CI, -15.8 to -.1) but not between NBI (27.2%) and WLI. CONCLUSIONS: Both BLI and NBI were superior to WLI on detecting proximal colonic lesions, but only BLI had lower proximal adenoma miss rates than WLI. (Clinical trial registration number: NCT03696992.).

Magnetic field effects on radical pair reactions: estimation of B1/2 for flavin-tryptophan radical pairs in cryptochromes.

Magnetic field effects on the yields of radical pair reactions are often characterised by the "half-field" parameter, B1/2, which encodes useful information on spin relaxation, radical recombination kinetics and electron-electron couplings as well as electron-nuclear hyperfine interactions. Here we use a variety of spin dynamics simulation methods to estimate the hyperfine-only values of B1/2 for the flavin-tryptophan radical pair, [FAD˙- TrpH˙+], thought to be the detector in the magnetic compass sense of migratory songbirds. The main findings are: (a) in the absence of fast recombination and spin relaxation, [FAD˙- TrpH˙+] radical pairs in solution and in the putative magnetoreceptor protein, cryptochrome, have B1/2 ≈ 1.89 mT and 2.46 mT, respectively. (b) The widely used expression for B1/2 due to Weller et al. (Chem. Phys. Lett, 1983, 96, 24-27) is only applicable to small, short-lived (∼5 ns), rapidly tumbling radical pairs in solution, and is quantitatively unreliable in the context of magnetoreception. (c) In the absence of molecular tumbling, the low-field effect for [FAD˙- TrpH˙+] is predicted to be abolished by the anisotropic components of the hyperfine interactions. Armed with the 2.46 mT "base value" for cryptochrome, measurements of B1/2 can be used to understand the impact of spin relaxation on its performance as a magnetic compass sensor.

Oncologist-led BRCA counselling improves access to cancer genetic testing in middle-income Asian country, with no significant impact on psychosocial outcomes.

BACKGROUND: Identifying patients with BRCA mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming. METHODS: The Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer. RESULTS: Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1 or BRCA2, and there was no difference between psychosocial measures for carriers in both arms. CONCLUSION: The MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.

Impact of BRCA1/2 cascade testing on anxiety, depression, and cancer worry levels among unaffected relatives in a multiethnic Asian cohort.

Cascade testing for families with BRCA pathogenic variants is important to identify relatives who are carriers. These relatives can benefit from appropriate risk management and preventative strategies arising from an inherited increased risk of breast, ovarian, prostate, melanoma, and pancreatic cancers. Cascade testing has the potential to enable cost-effective cancer control even in low- and middle-income settings, but few studies have hitherto evaluated the psychosocial impact of cascade testing in an Asian population, where the cultural and religious beliefs around inheritance and destiny have previously been shown to influence perception and attitudes toward screening. In this study, we evaluated the short- and long-term psychosocial impact of genetic testing among unaffected relatives of probands identified through the Malaysian Breast Cancer Genetics Study and the Malaysian Ovarian Cancer Study, using validated questionnaires (Hospital Anxiety and Depression Scale and Cancer Worry Scale) administered at baseline, and 1-month and 2-year post-disclosure of results. Of the 305 unaffected relatives from 98 independent families who were offered cascade testing, 256 (84%) completed predictive testing and family history of cancers was the only factor significantly associated with uptake of predictive testing. We found that the levels of anxiety, depression, and cancer worry among unaffected relatives decreased significantly after result disclosure and remained low 2-year post-result disclosure. Younger relatives and relatives of Malay descent had higher cancer worry at both baseline and after result disclosure compared to those of Chinese and Indian descent, whereas relatives of Indian descent and those with family history of cancers had higher anxiety and depression levels post-result disclosure. Taken together, the results from this Asian cohort highlight the differences in psychosocial needs in different communities and inform the development of culture-specific genetic counseling strategies.

NETosis proceeds by cytoskeleton and endomembrane disassembly and PAD4-mediated chromatin decondensation and nuclear envelope rupture.

Neutrophil extracellular traps (NETs) are web-like DNA structures decorated with histones and cytotoxic proteins that are released by activated neutrophils to trap and neutralize pathogens during the innate immune response, but also form in and exacerbate sterile inflammation. Peptidylarginine deiminase 4 (PAD4) citrullinates histones and is required for NET formation (NETosis) in mouse neutrophils. While the in vivo impact of NETs is accumulating, the cellular events driving NETosis and the role of PAD4 in these events are unclear. We performed high-resolution time-lapse microscopy of mouse and human neutrophils and differentiated HL-60 neutrophil-like cells (dHL-60) labeled with fluorescent markers of organelles and stimulated with bacterial toxins or Candida albicans to induce NETosis. Upon stimulation, cells exhibited rapid disassembly of the actin cytoskeleton, followed by shedding of plasma membrane microvesicles, disassembly and remodeling of the microtubule and vimentin cytoskeletons, ER vesiculation, chromatin decondensation and nuclear rounding, progressive plasma membrane and nuclear envelope (NE) permeabilization, nuclear lamin meshwork and then NE rupture to release DNA into the cytoplasm, and finally plasma membrane rupture and discharge of extracellular DNA. Inhibition of actin disassembly blocked NET release. Mouse and dHL-60 cells bearing genetic alteration of PAD4 showed that chromatin decondensation, lamin meshwork and NE rupture and extracellular DNA release required the enzymatic and nuclear localization activities of PAD4. Thus, NETosis proceeds by a stepwise sequence of cellular events culminating in the PAD4-mediated expulsion of DNA.

The Synergistic Effect of Nurse Proactive Phone Calls With an mHealth App Program on Sustaining App Usage: 3-Arm Randomized Controlled Trial.

BACKGROUND: Although mobile health application (mHealth app) programs have effectively promoted disease self-management behaviors in the last decade, usage rates have tended to fall over time. OBJECTIVE: We used a case management approach led by a nurse and supported by a health-social partnership team with the aim of sustaining app usage among community-dwelling older adults and evaluated the outcome differences (i.e, self-efficacy, levels of depression, and total health service usages) between those who continued to use the app. METHODS: This was a 3-arm randomized controlled trial. A total of 221 older adults with hypertension, diabetes, or chronic pain were randomized into 3 groups: mHealth (n=71), mHealth with interactivity (mHealth+I; n=74), and the control (n=76). The mHealth application was given to the mHealth and mHealth+I groups. The mHealth+I group also received 8 proactive calls in 3 months from a nurse to encourage use of the app. The control group received no interventions. Data were collected at preintervention (T1), postintervention (T2), and at 3 months' postintervention (T3) to ascertain the sustained effect. RESULTS: A total of 37.8% of mHealth+I and 18.3% of mHealth group participants continued using the mHealth app at least twice per week until the end of the sixth month. The difference in app usage across the 2 groups between T2 and T3 was significant (χ21=6.81, P=.009). Improvements in self-efficacy (ß=4.30, 95% CI 0.25-8.35, P=.04) and depression levels (ß=-1.98, 95% CI -3.78 to -0.19, P=.03) from T1 to T3 were observed in the mHealth group participants who continued using the app. Although self-efficacy and depression scores improved from T1 to T2 in the mHealth+I group, the mean values decreased at T3. Health service usage decreased for all groups from T1 to T2 (ß=-1.38, 95% CI -1.98 to -0.78, P<.001), with a marginal increase at T3. CONCLUSIONS: The relatively low rates of mHealth app usage at follow-up are comparable to those reported in the literature. More work is needed to merge the technology-driven and in-person aspects of mHealth. TRIAL REGISTRATION: ClinicalTrials.gov NCT03878212; https://clinicaltrials.gov/ct2/show/NCT03878212. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1159/000509129.

An unexpected visitor and a sword play: a randomized controlled trial of collective narrative therapy groups for primary carers of people with schizophrenia.

BACKGROUND: Most family carer support programs focus on supporting carers with caregiving-related knowledge and skills to help their family members who suffer from schizophrenia in their recovery process while carers' inner resources and preferred identities are less emphasized in the existing studies. AIMS: The present study uses collective narrative therapy groups (CNTG) to promote the inner strengths and agency of family carers and help them to explore their preferred identities while caring for family members with schizophrenia. METHOD: To ensure an evidence-based intervention, 89 Chinese family carers of people with schizophrenia took part in this three-wave longitudinal program evaluation study using a randomized controlled trial design. RESULTS: Compared with the control group, family carers in CNTG reported better family relationships, a lesser caregiving burden, and more perceived inner resources. Repeated one-way ANOVA revealed that CNTG improved family relationships, the caregiving burden, the level of hope and inner resources in the posttest, and a statistically significantly better mental health condition in the follow-up. CONCLUSION: This study shows that collective narrative psychotherapy is effective in supporting family carers of people with schizophrenia in Hong Kong. Based on the research findings, we discuss the strengths of the program and its implications for practitioners.