Qualitative study exploring the design of a patient-reported symptom-based risk stratification system for suspected head and neck cancer referrals: protocol for work packages 1 and 2 within the EVEREST-HN programme.

INTRODUCTION: Between 2009/2010 and 2019/2020, England witnessed an increase in suspected head and neck cancer (sHNC) referrals from 140 to 404 patients per 100 000 population. 1 in 10 patients are not seen within the 2-week target, contributing to patient anxiety. We will develop a pathway for sHNC referrals, based on the Head and Neck Cancer Risk Calculator. The evolution of a patient-reported symptom-based risk stratification system to redesign the sHNC referral pathway (EVEREST-HN) Programme comprises six work packages (WPs). This protocol describes WP1 and WP2. WP1 will obtain an understanding of language to optimise the SYmptom iNput Clinical (SYNC) system patient-reported symptom questionnaire for sHNC referrals and outline requirements for the SYNC system. WP2 will codesign key elements of the SYNC system, including the SYNC Questionnaire, and accompanying behaviour change materials. METHODS AND ANALYSIS: WP1 will be conducted at three acute National Health Service (NHS) trusts with variation in service delivery models and ensuring a broad mixture of social, economic and cultural backgrounds of participants. Up to 150 patients with sHNC (n=50 per site) and 15 clinicians (n=5 per site) will be recruited. WP1 will use qualitative methods including interviews, observation and recordings of consultations. Rapid qualitative analysis and inductive thematic analysis will be used to analyse the data. WP2 will recruit lay patient representatives to participate in online focus groups (n=8 per focus group), think-aloud technique and experience-based codesign and will be analysed using qualitative and quantitative approaches. ETHICS AND DISSEMINATION: The committee for clinical research at The Royal Marsden, a research ethics committee and the Health Research Authority approved this protocol. All participants will give informed consent. Ethical issues of working with patients on an urgent cancer diagnostic pathway have been considered. Findings will be disseminated via journal publications, conference presentations and public engagement activities.

Challenges to well-being in critical care.

BACKGROUND: Paediatric critical care (PCC) is a high-pressure working environment. Staff experience high levels of burnout, symptoms of post-traumatic stress, and moral distress. AIM: To understand challenges to workplace well-being in PCC to help inform the development of staff interventions to improve and maintain well-being. STUDY DESIGN: The Enhanced Critical Incident Technique (ECIT) was used. ECIT encompasses semi-structured interviews and thematic analysis. We identified 'critical incidents', challenges to well-being, categorized them in a meaningful way, and identified factors which helped and hindered in those moments. Fifty-three nurses and doctors from a large UK quaternary PCC unit were consented to take part. RESULTS: Themes generated are: Context of working in PCC, which examined staff's experiences of working in PCC generally and during COVID-19; Patient care and moral distress explored significant challenges to well-being faced by staff caring for increasingly complex and chronically ill patients; Teamwork and leadership demonstrated the importance of team-belonging and clear leadership; Changing workforce explored the impact of staffing shortages and the ageing workforce on well-being; and Satisfying basic human needs, which identified absences in basic requirements of food and rest. CONCLUSIONS: Staff's experiential accounts demonstrated a clear need for psychologically informed environments to enable the sharing of vulnerabilities, foster support, and maintain workplace well-being. Themes resonated with the self-determination theory and Maslow's hierarchy of needs, which outline requirements for fulfilment (self-actualization). RELEVANCE TO CLINICAL PRACTICE: Well-being interventions must be informed by psychological theory and evidence. Recommendations are flexible rostering, advanced communication training, psychologically-informed support, supervision/mentoring training, adequate accommodation and hot food. Investment is required to develop successful interventions to improve workplace well-being.

A Role for Two-Pore Channel Type 2 (TPC2)-Mediated Regulation of Membrane Contact Sites During Zebrafish Notochord Biogenesis?

We have previously shown that in the developing trunk of zebrafish embryos, two-pore channel type 2 (TPC2)-mediated Ca2+ release from endolysosomes plays a role in the formation of the skeletal slow muscle. In addition, TPC2-mediated Ca2+ signaling is required for axon extension and the establishment of synchronized activity in the primary motor neurons. Here, we report that TPC2 might also play a role in the development of the notochord of zebrafish embryos. For example, when tpcn2 was knocked down or out, increased numbers of small vacuoles were formed in the inner notochord cells, compared with the single large vacuole in the notochord of control embryos. This abnormal vacuolation was associated with embryos displaying attenuated body axis straightening. We also showed that TPC2 has a distinct pattern of localization in the notochord in embryos at ∼24 hpf. Finally, we conducted RNAseq to identify differentially expressed genes in tpcn2 mutants compared to wild-type controls, and found that those involved in actin filament severing, cellular component morphogenesis, Ca2+ binding, and structural constituent of cytoskeleton were downregulated in the mutants. Together, our data suggest that TPC2 activity plays a key role in notochord biogenesis in zebrafish embryos.

Actin-mediated endocytosis in the E-YSL helps drive epiboly in zebrafish.

In zebrafish, a punctate band of F-actin is reported to develop in the external yolk syncytial layer (E-YSL) during the latter part of epiboly in zebrafish embryos. Here, electron microscopy (EM) and fluorescence confocal microscopy were conducted to investigate dynamic changes in the E-YSL membrane during epiboly. Using scanning EM, we report that the surface of the E-YSL is highly convoluted, consisting of a complex interwoven network of branching membrane surface microvilli-like protrusions. The region of membrane surface protrusions was relatively wide at 30% epiboly but narrowed as epiboly progressed. This narrowing was coincident with the formation of the punctate actin band. We also demonstrated using immunogold transmission EM that actin clusters were localized at the membrane surface mainly within the protrusions as well as in deeper locations of the E-YSL. Furthermore, during the latter part of epiboly, the punctate actin band was coincident with a region of highly dynamic endocytosis. Treatment with cytochalasin B led to the disruption of the punctate actin band and the membrane surface protrusions, as well as the attenuation of endocytosis. Together, our data suggest that, in the E-YSL, the region encompassing the membrane surface protrusions and its associated punctate actin band are likely to be an integral part of the localized endocytosis, which is important for the progression of epiboly in zebrafish embryos.

The Effects of Oral Lavender Therapy on Wounding in Chimpanzees (Pan troglodytes).

Lavender administration in humans has been shown to promote calmness without the side effects often observed with benzodiazepines. Studies in both humans and rodents have found that ingestion of oral lavender capsules resulted in significantly decreased anxiety. Additionally, mice developed an anti-conflict effect and humans increased socially inclusive behaviors. Given the safety of oral lavender oil and the observed benefits, we administered daily lavender capsules to six chimpanzees who exhibited conflict-instigating behaviors in an effort to further decrease our already low levels of wounding. We compared the total number of wounds in 25 chimpanzees housed with the six lavender-treated chimpanzees in five different social groups (1) prior to administration of daily oral lavender capsules to (2) total wounds during daily oral lavender capsule treatment. We hypothesized that lavender therapy treatment would reduce overall wounding in the social groups. Surprisingly, overall wounding was higher during the lavender treatment period (p = 0.01), yet the percentage of wounds requiring treatment significantly decreased during the lavender therapy period (36% vs. 21%, p = 0.02).

Locomotion as a Measure of Well-Being in Captive Chimpanzees (Pan troglodytes).

Locomotion in non-human primates, including walking, climbing, and brachiating among other types of movement (but not pacing), is a species-typical behavior that varies with age, social housing conditions, and environmental factors (e.g., season, food availability, physical housing conditions). Given that captive primates are typically observed to engage in lower levels of locomotor behaviors than their wild counterparts, increases in locomotion are generally considered to be indicative of improved welfare in captivity. However, increases in locomotion do not always occur with improvements in welfare, and sometimes occur under conditions of negative arousal. The use of time spent in locomotion as a welfare indicator in studies of well-being is relatively limited. We conducted focal animal observations on 120 captive chimpanzees across a series of studies and found higher percentages of time spent in locomotion (1) upon transfer to a new enclosure type, (2) in larger groups with wider within-group age ranges, and fewer males, and (3) with participation in an experimental medication choice paradigm. We also found that, among geriatric chimpanzees, those housed in nongeriatric groups exhibited more locomotion than those living in geriatric groups. Lastly, locomotion was significantly negatively correlated with several indicators of poor welfare and significantly positively correlated with behavioral diversity, one indicator of positive welfare. Overall, the increases in time spent in locomotion observed in these studies were part of an overall behavioral pattern indicative of enhanced welfare, suggesting that an increase in time spent in locomotion itself may be an indicator of enhanced welfare. As such, we suggest that levels of locomotion, which are typically assessed in most behavioral experiments, may be used more explicitly as indicators of welfare in chimpanzees.

The Ethanol Extract of Evodiae Fructus and Its Ingredient, Rutaecarpine, Inhibit Infection of SARS-CoV-2 and Inflammatory Responses.

COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the effectiveness of the current vaccines. Thus, there is still an urgent need to develop potent non-vaccine therapeutics against this infectious disease. We recently established a series of detecting platforms to screen a large library of Chinese medicinal herbs and phytochemicals. Here, we reveal that the ethanolic extract of Evodiae Fructus and one of its components, rutaecarpine, showed promising potency in inhibiting the activity of 3C-like (3CL) protease, blocking the entry of the pseudo-typed SARS-CoV-2 (including wild-type and omicron) into cultured cells. In addition, inflammatory responses induced by pseudo-typed SARS-CoV-2 were markedly reduced by Evodiae Fructus extract and rutaecarpine. Together our data indicate that the herbal extract of Evodiae Fructus and rutaecarpine are potent anti-SARS-CoV-2 agents, which might be considered as a treatment against COVID-19 in clinical applications.

Intensive care nurse practitioners in Australia: A description of a service model in an adult tertiary intensive care unit.

BACKGROUND: Although well-established internationally, nurse practitioners (NPs) in Australian adult intensive care units (ICUs) are rare. Australian literature clearly highlights the importance of creating ICU NP roles to meet emerging demands. An ICU NP model of care at a metropolitan hospital in Sydney provides care in four core practice areas: complex case management, vascular access, tracheostomy management, and intrahospital transport of critically ill patients. The ICU NPs also provide training and assessment for ICU nurses and medical officers in these same core practice areas and can efficiently meet service gaps in crisis such as the most recent COVID-19 pandemic. RESULTS: The ICU NP program described is an innovative model of care that has demonstrated potential benefits to patients and their families. Potential benefits to the healthcare system including supporting advanced practice nursing development in regional and rural Australia and in addressing future ICU workforce issues are also identified. This model of care provides a clear role and structure for the integration of NPs in the adult ICU. Research to evaluate the impact of the role is required and is underway. CONCLUSIONS: This model is being used to develop a national adult ICU NP fellowship training program for ICU transitional NPs preparing for endorsement or endorsed NPs who require additional ICU-specific training. This immersive clinical training program combined with didactic learning modules offers a framework to support the implementation of the adult ICU NP role as well as a framework for NP fellowship programs in other specialties.

Neuroanatomical correlates of individual differences in the object choice task in chimpanzees (Pan troglodytes).

Declarative and imperative joint attention or joint engagement are important milestones in human infant development. These have been shown to be a significant predictor of later language development and are impaired in some individuals with, or at risk for, a diagnosis of autism spectrum disorder. Comparatively, while chimpanzees and other great apes have been reported to engage in imperative joint attention, evidence of declarative joint attention remains unclear based on existing studies. Some have suggested that differences in methods of assessing joint attention may have an influence on performance in nonhuman primates. Here, we report data on a measure of receptive joint attention (object choice task) in a sample of captive chimpanzees. Chimpanzees, as a group, performed significantly better than chance. By contrast, when considering individual performance, there was no significant difference in the number of those who passed and those who failed. Using quantitative genetic analyses, we found that performance on the object choice task was not significantly heritable nor were there any significant effects of sex, rearing history, or colony. Lastly, we found significant differences in gray matter covariation, between those who passed or failed the task. Those who passed contributed more to gray matter covariation in several brain regions within the social brain network, consistent with hypotheses regarding the importance of these regions in human and nonhuman primate social cognition.

Neuromasts and Olfactory Organs of Zebrafish Larvae Represent Possible Sites of SARS-CoV-2 Pseudovirus Host Cell Entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the acute respiratory disease coronavirus disease 2019 (COVID-19), which has resulted in millions of deaths globally. Here, we explored the mechanism of host cell entry of a luciferase-ZsGreen spike (SARS-CoV-2)-pseudotyped lentivirus using zebrafish embryos/larvae as an in vivo model. Successful pseudovirus entry was demonstrated via the expression of the luciferase (luc) gene, which was validated by reverse transcription-PCR (RT-PCR). Treatment of larvae with chloroquine (a broad-spectrum viral inhibitor that blocks membrane fusion) or bafilomycin A1 (a specific inhibitor of vacuolar proton ATPases, which blocks endolysosomal trafficking) significantly reduced luc expression, indicating the possible involvement of the endolysosomal system in the viral entry mechanism. The pharmacological inhibition of two-pore channel (TPC) activity or use of the tpcn2dhkz1a mutant zebrafish line also led to diminished luc expression. The localized expression of ACE2 and TPC2 in the anterior neuromasts and the forming olfactory organs was demonstrated, and the occurrence of endocytosis in both locations was confirmed. Together, our data indicate that zebrafish embryos/larvae are a viable and tractable model to explore the mechanism of SARS-CoV-2 host cell entry, that the peripheral sense organs are a likely site for viral host cell entry, and that TPC2 plays a key role in the translocation of the virus through the endolysosomal system. IMPORTANCE Despite the development of effective vaccines to combat the COVID-19 pandemic, which help prevent the most life-threatening symptoms, full protection cannot be guaranteed, especially with the emergence of new viral variants. Moreover, some resistance to vaccination remains in certain age groups and cultures. As such, there is an urgent need for the development of new strategies and therapies to help combat this deadly disease. Here, we provide compelling evidence that the peripheral sensory organs of zebrafish possess several key components required for SARS-CoV-2 host cell entry. The nearly transparent larvae provide a most amenable complementary platform to investigate the key steps of viral entry into host cells, as well as its spread through the tissues and organs. This will help in the identification of key viral entry steps for therapeutic intervention, provide an inexpensive model for screening novel antiviral compounds, and assist in the development of new and more effective vaccines.

The Extracts of Polygonum cuspidatum Root and Rhizome Block the Entry of SARS-CoV-2 Wild-Type and Omicron Pseudotyped Viruses via Inhibition of the S-Protein and 3CL Protease.

COVID-19, resulting from infection by the SARS-CoV-2 virus, caused a contagious pandemic. Even with the current vaccines, there is still an urgent need to develop effective pharmacological treatments against this deadly disease. Here, we show that the water and ethanol extracts of the root and rhizome of Polygonum cuspidatum (Polygoni Cuspidati Rhizoma et Radix), a common Chinese herbal medicine, blocked the entry of wild-type and the omicron variant of the SARS-CoV-2 pseudotyped virus into fibroblasts or zebrafish larvae, with IC50 values ranging from 0.015 to 0.04 mg/mL. The extracts were shown to inhibit various aspects of the pseudovirus entry, including the interaction between the spike protein (S-protein) and the angiotensin-converting enzyme II (ACE2) receptor, and the 3CL protease activity. Out of the chemical compounds tested in this report, gallic acid, a phytochemical in P. cuspidatum, was shown to have a significant anti-viral effect. Therefore, this might be responsible, at least in part, for the anti-viral efficacy of the herbal extract. Together, our data suggest that the extracts of P. cuspidatum inhibit the entry of wild-type and the omicron variant of SARS-CoV-2, and so they could be considered as potent treatments against COVID-19.

Polygoni multiflori radix extracts inhibit SARS-CoV-2 pseudovirus entry in HEK293T cells and zebrafish larvae.

BACKGROUND: Globally, COVID-19 has caused millions of deaths and led to unprecedented socioeconomic damage. There is therefore, in addition to vaccination, an urgent need to develop complementary effective treatments and/or protective and preventative therapies against this deadly disease. METHODS: Here, a multi-component testing platform was established to screen a library of herbal extracts from traditional Chinese medicine (TCM), to identify potent herbal extracts/phytochemicals as possible therapeutics for COVID-19. We utilized assays for spike protein (S-protein) binding to angiotensin-converting enzyme II (ACE2); the enzymatic inhibition of 3CL protease; and entry of the SARS-CoV-2 pseudovirus into cultured HEK293T cells and zebrafish larvae. RESULTS: Over a thousand herbal extracts were screened and approximately 20 positive hits were identified. Among these, we found that the water and ethanol extracts of Polygoni Multiflori Radix (PMR) significantly inhibited S-protein binding to ACE2, 3CL protease activity, and viral entry into the cell and fish models. The water extract was more effective than the ethanol extract, with IC50 values of 25 to 500 µg/ml. In addition, the polysaccharide-depleted fraction of the former, and epigallocatechin gallate (EGCG) which was found in both extracts, displayed significant antiviral activity. CONCLUSIONS: Our results indicate that the water and ethanol extracts of PMR have an inhibitory effect on SARS-CoV-2 pseudovirus host-cell entry. Furthermore, EGCG might be an active component of PMR, which blocks SARS-CoV-2 entry to cells. Taken together, our findings suggest that PMR might be considered as a potential treatment for COVID-19.

Localized TPC1-mediated Ca2+ release from endolysosomes contributes to myoseptal junction development in zebrafish.

In the trunk of developing zebrafish embryos, adjacent myotome blocks transmit contractile force via myoseptal junctions (MJs), which are dynamic structures that connect the actin cytoskeleton of skeletal muscle cells to extracellular matrix components via transmembrane protein complexes in the sarcolemma. Here, we report that the endolysosomal ion channel, two-pore channel type 1 (TPC1, encoded by tpcn1), generates highly localized non-propagating Ca2+ transients that play a distinct and required role in the capture and attachment of superficial slow skeletal muscle cells at MJs. Use of antisense morpholinos or CRISPR/Cas9 gene editing to disrupt tpcn1 gene expression resulted in abnormal MJ phenotypes, including slow skeletal muscle cells detaching from or crossing the myosepta. We also report that TPC1-decorated endolysosomes are dynamically associated with MJs in a microtubule-dependent manner, and that attenuating tpcn1 expression or TPC1 function disrupted endolysosomal trafficking and resulted in an abnormal distribution of ß-dystroglycan (encoded by dag1; a key transmembrane component of the dystrophin-associated protein complex). Taken together, our data suggest that localized TPC1-generated Ca2+ signals facilitate essential endolysosomal trafficking and membrane contact events, which help form and maintain MJs following the onset of slow skeletal muscle cell contractile activity. This article has an associated First Person interview with the first author of the paper.

Understanding what wellbeing means to medical and nursing staff working in paediatric intensive care: an exploratory qualitative study using appreciative inquiry.

AIMS AND OBJECTIVES: To explore what wellbeing means to medical and nursing staff working in a large paediatric intensive care (PIC). DESIGN: Exploratory qualitative design using an appreciative inquiry framework. SETTING: PIC unit; primary, secondary and tertiary. PARTICIPANTS: 46 nurses and doctors working on PIC. INTERVENTIONS: A set of images were used together with open-ended questions to prompt staff to discuss what wellbeing means to them. Interviews were audiorecorded and transcribed. Data were analysed thematically. RESULTS: Images depicting nature, children and groups of adults were selected most. Meanings of wellbeing for PIC staff can be understood through three themes: (1) Being nurtured and supported at work, (2) Importance of nature and (3) Social support independent of work. The first theme considered the importance of being listened to at work as well as staff highlighting the value of being in control at work. Within the second theme, being active in nature and outdoors as well as the importance of being in the present moment was illustrated. Within the final theme, staff expressed the value of having support independent of work and highlighted the importance of spending time with family. CONCLUSIONS: This study provides a unique insight into how individuals working in PIC experience wellbeing and what wellbeing means to them. Understanding how healthcare professionals in PIC settings experience wellbeing and what wellbeing means to them will enable researchers to develop interventions designed to enhance staff wellbeing based on lived experience.

Transmembrane H+ fluxes and the regulation of neural induction in Xenopus laevis.

It has previously been reported that in ex vivo planar explants prepared from Xenopus laevis embryos, the intracellular pH (pHi) increases in cells of the dorsal ectoderm from stage 10.5 to 11.5 (i.e. 11-12.5 hpf). It was proposed that such increases (potentially due to H+ being extruded, sequestered, or buffered in some manner), play a role in regulating neural induction. Here, we used an extracellular ion-selective electrode to non-invasively measure H+ fluxes at eight locations around the equatorial circumference of intact X. laevis embryos between stages 9-12 (˜7-13.25 hpf). We showed that at stages 9-11, there was a small H+ efflux recorded from all the measuring positions. At stage 12 there was a small, but significant, increase in the efflux of H+ from most locations, but the efflux from the dorsal side of the embryo was significantly greater than from the other positions. Embryos were also treated from stages 9-12 with bafilomycin A1, to block the activity of the ATP-driven H+ pump. By stage 22 (24 hpf), these embryos displayed retarded development, arresting before the end of gastrulation and therefore did not display the usual anterior and neural structures, which were observed in the solvent-control embryos. In addition, expression of the early neural gene, Zic3, was absent in treated embryos compared with the solvent controls. Together, our new in vivo data corroborated and extended the earlier explant-derived report describing changes in pHi that were suggested to play a role during neural induction in X. laevis embryos.

Are conspecific social videos rewarding to chimpanzees (Pan troglodytes)? A test of the social motivation theory.

Many claim that social stimuli are rewarding to primates, but few, if any, studies have explicitly demonstrated their reward value. Here, we examined whether chimpanzees would produce overt responses for the opportunity to view conspecific social, compared to dynamic (video: Experiment 1) and static (picture: Experiment 2) control content. We also explored the relationships between variation in social reward and social behavior and cognition. We provided captive chimpanzees with access to a touchscreen during four, one-hour sessions (two 'conspecific social' and two 'control'). The sessions consisted of ten, 15-second videos (or pictures in Experiment 2) of either chimpanzees engaging in a variety of behaviors (social condition) or vehicles, humans, or other animals engaged in some activity (control condition). For each chimpanzee, we recorded the number of responses to the touchscreen and the frequency of watching the stimuli. Independent t-tests revealed no sex or rearing differences in touching and watching the social or control videos (p>0.05). Repeated measures ANOVAs showed chimpanzees touched and watched the screen significantly more often during the social compared to control video sessions. Furthermore, although chimpanzees did not touch the screen more often during social than control picture sessions in Experiment 2, they did watch the screen more often. Additionally, chimpanzees that previously performed better on a task of social cognition and engaged in more affiliative behavior watched a higher percentage of social videos during the touchscreen task. These results are consistent with the social motivation theory, and indicate social stimuli are intrinsically rewarding, as chimpanzees made more overt responses for the opportunity to view conspecific social, compared to control, content.

Development of an IgG-Fc fusion COVID-19 subunit vaccine, AKS-452.

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.

Systematic literature review of current treatments for stage I-III Merkel cell carcinoma.

Aim: There is a need to evaluate current treatments for stages I-III of Merkel cell carcinoma (MCC). Materials & methods: A systematic literature review was conducted to understand how patients with stage I-III MCC are treated and assess efficacy, safety, health-related quality of life and economic impact of current therapies. Embase was searched using the following inclusion criteria: publications from 2014 to 2019, in English, with adult patients (≥18 years) with early-stage MCC (i.e., stages I-III) and any interventions/comparators. Publications were excluded if they included only patients with stage IV MCC, had no distinction between early and advanced or metastatic MCC or had no extractable data. Results: A total of 18 retrospective studies were included. Few studies had evidence that surgery plus adjuvant radiotherapy significantly increased survival versus surgery alone in early MCC. Limited safety data were reported in three studies. None of the studies reported data on health-related quality of life or economic impact of treatment in patients with early-stage MCC. Conclusion: Although surgery plus adjuvant radiotherapy was a common treatment, no clear standard of care exists for stages I-III MCC and treatment outcomes need to be improved. All studies were retrospective with a high variability in sample sizes; hence, findings should be interpreted with caution.

Caring Dads intervention for fathers who have perpetrated abuse within their families: Quasi-experimental evaluation of child protection outcomes over two years.

BACKGROUND: In Canada, two of the most common forms of maltreatment substantiated by child protective services are child exposure to domestic violence and child physical abuse. Fathers are identified as the parent responsible for a substantial proportion of this maltreatment. OBJECTIVE: This study examined whether providing a group-based intervention program for fathers was associated with greater engagement of fathers in child protection case management and with lower rates of subsequent father-perpetrated abuse. PARTICIPANTS: A quasi-experimental design compared child protection outcomes in families in which fathers were referred to an intervention program (Caring Dads) and either completed the group (n = 85) or remained on a waitlist for future service (n = 100). METHODS: Data were collected from a retrospective review of administrative files over two years, starting from the time of referral to Caring Dads. RESULTS: Initial comparisons found no significant differences in intervention and comparison group fathers in demographic characteristics, child protection concerns, and all but one area of risk and needs. Completing intervention, as compared to being waitlisted, was associated with a greater number of contacts between child protection workers and fathers over two years (M = 30.3 vs. M = 16.7), a difference that was significant and large in size (d = 0.81) and with lower rates of verified re-referral due to fathers' maltreatment (20.5% vs. 36.0%), a difference that was significant and between small and medium in size (V = 0.17). CONCLUSIONS: Current results suggest that there may be significant benefits of involving fathers in child protection-linked intervention.