Background: Isolated splenic metastases from endometrial cancer, which is a relatively common malignancy, are extremely rare findings; to date, only 14 cases have been reported in the literature. Case Summary: We report a patient with isolated splenic metastases of endometrial cancer 3 years after radical surgery of the primary tumor. The patient was successfully treated by splenectomy and six cycles of paclitaxel. Fifty months after splenectomy, she was alive and well, and with no evidence of disease. Conclusion: Isolated spleen metastasis of endometrial cancer is very rare. Radical surgery and adjuvant therapy may offer excellent long-term survival. The spleen is not a common site for metastasis of solid, non-hematological tumors, primarily due to its specific anatomy and microenvironment. Most metastases to the spleen generally occur due to multivisceral metastatic cancer dissemination but are rare as a solitary lesion  from ovaHerein, we report a patient with isolated splenic metastasis of endometrial cancer 3 years after radical surgery of the primary tumor. A literature search of online databases and search engines was performed  completed by an internet-based search. The keywords used were “endometrial, cancer, spleen, metastases”. All references of included articles were manually screened to find relevant articles.A 62-year-old woman was admitted to our hospital for vague abdominal symptoms, dyspepsia, and mild pain in the left hypochondrium.The patient had a history of total hysterectomy with bilateral salpingo-oophorectomy 32 months prior due to stage pT1apN0 papillary serous form of endometrial adenocarcinoma, without subsequent adjuvant therapy. The patient was treated in another institution and referred to our institution—tertiary abdominal surgery center. We had only written data about her treatment—without adjuvant therapy after the first operation.Clinical examination was normal, except slight tenderness in the left hypochondrium with no clinical visceromegaly registered.The laboratory data  were within normal ranges. Tumor markers levels were also normal .Ultrasonography of the abdomen revealed an enlarged spleen  with two hypoechogenic, cystic-like, well-demarcated lesions located on the lower (76 mm × 62 mm) and upper (37 mm × 37 mm) poles of the spleen. T1-weighted magnetic resonance imaging also showed two well-circumscribed round hypointense lesions, similar to dimensions registered on ultrasonography located on the upper and lower poles of the spleen. Lesions were bright and hyperintense on T2-weighted magnetic resonance imaging, with peripheral signal enhancing and small endophytic lobulization of the bigger lesion, mimicking some form of the membranous component.The suspicion of spleen hydatid disease was raised by the radiologist. Immunohistochemistry and immunofluorescence serology were performed, and they were both negative. We indicated surgery under the tentative diagnosis of a cystic neoplasm of the spleen, possibly metastatic from previously treated endometrial cancer.Left subcostal laparotomy revealed an enlarged spleen surrounded with dense adhesions .Total abdominal exploration was carried out, but it yielded no other pathological findings. There was no regional lymphadenopathy. The patient underwent a classic splenectomy. Spleen dimensions were 14 cm × 12 cm × 9 cm, and it weighed 650 g. The spleen capsule was intact, but a large part of the parenchyma was involved by two solid and partly colliquated necrotic tumors with irregular borders. The dimensions were similar to the preoperative measurements. Surgical biopsies were fixed in 10% formaldehyde overnight, processed in paraffin wax, and cut at 4 μm. The sections were stained with hematoxylin and eosin, periodic acid—Schiff (PAS)—Alcian Blue, van Gieson, and immunohistochemical avidin biotin complexes. Microscopic examination of the splenic tumor confirmed metastatic adenocarcinoma compatible with endometrial origin .The immunohistochemical examination was positive for p53  and vime2) every 21 d.Subsequently, the patient was administered paclitaxel  . In our Furthermore, other than conventional radiological techniques, 18-fluorodeoxyglucose positron emission tomography scanning can be used for confirmation of diagnosis . Serum lTreatment of isolated splenic metastasis includes several procedures. A splenectomy is indicated if there are isolated metastases or to reduce the tumor burden before chemotherapy . Piura eIsolated spleen metastases of endometrial cancer represent a very rare condition. Radical surgery and adjuvant therapy may offer excellent long-term survival. Further studies analyzing the patients with isolated splenic metastasis are necessary for better understanding of the pathogenesis, clinical course, and treatment of this rare condition.


Blood smears showed 10% suspected blasts, 17% myelocytes, and 17% metamyelocytes with thrombocytopenic crisis. The HbF level was 5.8%. BCR-ABL gene tested negative. The patient was diagnosed with juvenile myelomonocytic leukemia. Considering that HSCT could not be done in our center and lack other financial possibilities to seek treatment abroad, the family agreed to do the palliative treatment. The patient was treated with oral 6-mercaptopurine and subcutaneous cytarabine. Four weeks after receiving 6-mercaptopurine, the white blood cell count decreased to 10.6 × 103/μL and the spleen size was half of the original size. The patient continued chemotherapy until week 15, chemotherapy was stopped, but 16 weeks after the diagnosis of JMML, he developed severe thrombocytopenia, endophthalmitis, and sepsis and passed away. As a conclusion, in JMML cases in developing countries without HSCT, palliative chemotherapy is acceptable, and palliative care is an important aspect.Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy in children, with an incidence of 1.2 per million children per year. At this moment, we present a case report and a brief literature review of JMML in a child, primarily focused on its applicability in low-middle income countries. A 3.5-year-old male was referred to our tertiary center due to pallor, enlarging abdomen and neck mass, recurrent fever, and chronic diarrhea. Initial laboratory workup showed hemoglobin of 6.4 g/dl, white blood cell of 315.62 × 10 Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy in children with features characteristic of myelodysplastic and myeloproliferative disorders . In 2008JMML affects young children, with a median age at diagnosis of 20–24 months and a significant male predominance 2.5 : 1) ., 10.9, 1μL, blasts in peripheral blood <20%, splenomegaly, absence of BRC-ABL gene) and two items in category 3 (circulating myeloid precursors and increased HbF with age). This patient also had the epidemiologic characteristics of JMML, i.e., male sex and age less than six years old. The pathogenesis of JMML involves hyperactivation of signal transduction along the RAS pathway, with a resultant selective hypersensitivity of JMML cells to GM-CSF. Unfortunately, we could not perform laboratory tests to find aberrations in the RAS pathway.This patient fulfilled all items in category 1  is the only curative regimen for most patients with JMML. HSCT can achieve long-treatment-free survival in about 50% of patients, but it still has a high relapse rate of 30–40% . In the 2 or low dose, i.e., cytarabine in a 40 mg/m2 dose for five days has been used to control the JMML symptoms before HSCT [2 and cytarabine 2 g/m2 daily for five consecutive days have been adopted by some centers [AML protocols for intensive chemotherapy can induce temporary remission in JMML, but this approach is also very toxic. The European Working Group of MDS (EWOG-MDS) trial reported no significant difference in event survival rate and mortality of AML-type chemotherapy compared to less intensive treatment . For manore HSCT . In aggr centers . JMML so centers . Various centers . Sakashi centers . Due to Jin Kang et al. in Korea proposed a novel regimen for newly diagnosed JMML lacking access to transplantation. They offered a standard regimen in 3-week intervals consisting of a combination of chemotherapy  and differentiation therapy (isotretinoin). If the disease relapsed or progressed, they continued to salvage the regimen of chemotherapy  and differentiation therapy (low-dose Ara-C) in 3-4 weeks intervals. This regimen was safe and effective, but the study was only done on 5 JMML patients . Another2, i.e., on days 1–7 of a 28-day cycle as a bridging therapy before HSCT and reported a good response and favorable toxicity [The Food and Drug Administration (FDA) currently approved azacitidine for JMML therapy in March 2022. Azacitidine has been shown to induce complete clinical remission in some JMML patients. A study by Niemeyer et al. stated that azacitidine monotherapy is a suitable option for children with newly diagnosed JMML . Fabri etoxicity  and the 6/mm3, and HbF >10% are related to short survival [Age, platelet count, and percentage of HbF at diagnosis are the main prognostic factors in JMML. Age >2 years at diagnosis, platelet count <33 × 10survival . This pasurvival .In a terminal illness with limited available therapy, palliative care is appropriate. Palliative care is a patient-centered approach that aims to improve the quality of life of patients and their families through the prevention and relief of suffering using early identification and treatment of pain and other physical, psychosocial, and spiritual problems . PalliatOur patient's history suggested he had been suffering from JMML for about one year before he reached the Estella Clinic for Children with Cancer and Blood Diseases. He came from a small town about 400 km or 10 hours car drive away from Manado. After making the diagnosis of JMML, when he was in cachectic condition, he was treated with a simple palliative chemotherapy course: 6 MP orally daily plus cytarabine subcutaneously weekly. He improved significantly, both clinically and in laboratory values. After two months, he came home with his family and had a good quality of life until, in the end, low WBC counts and low platelets led to his death four months after the start of palliative chemotherapy. His home health care was provided by his parents and a local health care provider. At the end of his life, with use of antibiotics and analgetics, he passed away with minimal pain and breathing difficulty. In retrospect, the increases of 20% of 6-MP and cytarabine was maybe not indicated, since his WBC had come down already. Also, a check of his hematological data should have been performed at least before starting the third course of cytostatic drugs in order to prevent neutropenia and sepsis.Unfortunately, access to pediatric palliative care in low- or middle-income countries is limited and primarily focused on adult patients. Lack of knowledge about the principles of palliative care and misperceptions about palliative care are significant barriers that limit the development of palliative services in low- and middle-income countries . Therefo


The measurement of serum neurofilament light chain (sNfL) is of growing importance in the field of neurology. In the management of multiple sclerosis, it can serve as a useful marker to assess disease activity and treatment response. This paper compares two available methods, namely the Single Molecule Array (Simoa) and the Ella microfluid platform, to measure longitudinal sNfL levels of 42 highly active multiple sclerosis patients treated with alemtuzumab over a period of 36 months. In order to assess the methods agreement, Bland–Altman plots and Passing–Bablok regression were analyzed. Here, we show that despite the fact that Ella measures around 24% higher values than Simoa, both are equally suitable for longitudinal sNfL monitoring. Neurofilaments are an essential component of the cytoskeleton in neurons; they rise after neuronal damage not only in cerebrospinal fluid (CSF), but also in blood, indicating neuroaxonal injury independent of the causal pathway .In recent years, growing attention has been paid to serum neurofilament light chain (sNfL) as a reliable quantification and longitudinal follow-up evaluation marker of neuroaxonal damage. As a biomarker in clinical practice, it is suggested to use sNfL both to quantify disease activity and to monitor the treatment response in neurological diseases such as multiple sclerosis (MS) ,3,4. It Since different ultrasensitive immunoassays to measure sNfL are available, the questions arises of whether these methods are interchangeable ,14. Two Based on patient data from highly active MS patients treated with the induction therapy alemtuzumab, we compared the two methods and investigated, for the first time, whether Ella and Simoa are equally suitable for longitudinal monitoring of sNfL level response to alemtuzumab treatment.p < 0.001) higher compared to Simoa measurement . Measurements with both platforms presented similar intra-assay CVs on Ella  and Simoa . In order to assess the comparability of the two methods, Bland–Altman plots  was significantly  are significantly different, indicating a systematic difference between the methods. Since the influence of biological covariates cannot be excluded, we additionally analyzed different subpopulations  as described above and present the data in We monitored the sNfL levels of 42 patients during alemtuzumab treatment . At baseMonitoring of sNfL levels is increasingly important in neurological diseases in clinical practice . EspeciaThe results demonstrate that Simoa and Ella measurements do not agree. Ella shows about 24% higher values than Simoa. Although similar anti-NfL antibodies and blockers are used in both techniques, different calibrators are discussed as potential reasons for differences in sNfL levels . Our data are in line with a previous study which showed that Ella overestimates Simoa’s results by about 17% . In thisWe think that both methods are very helpful in the monitoring of neurological diseases, in addition to clinical examination and standard diagnostic tests. In MS, definition of disease activity and treatment response is important for individualizing patient care. Alemtuzumab is known as an induction therapy that induces T and B cell lysis by the monoclonal antibody against CD52, especially in highly active MS patients. The sNfL evaluation by both methods demonstrates correlation with clinical and subclinical disease activity markers in our cohort. Serum NfL levels rapidly decreased after the first alemtuzumab infusion cycle and remained at a low steady state level after initial treatment ,11. SincBoth devices offer advantages that can be favorable for certain users. The lower limit of quantification (LLOQ) is 2.70 pg/mL for Ella and 0.174 pg/mL for Simoa . For patA new assay was recently developed for the ADVIA Centaur XP immunoassay system from Siemens Healthineers. It shows very promising results and might become a good alternative to the methods presented here . As far In summary, Ella measures 24% higher sNfL values than Simoa. The difference depends on the measurement range and can be determined using a regression line. Moreover, both methods were equally able to show the qualitative course of sNfL for highly active multiple sclerosis patients treated with alemtuzumab. While Simoa is well suited for measuring particularly small sNfL values, Ella is more cost efficient for larger routine diagnostics.For this study, we analyzed the data collected from 42 patients diagnosed with highly active RRMS . They reThroughout the first infusion course, 12 mg alemtuzumab was infused on five consecutive days. During the second course (12 months later), alemtuzumab was applied on three consecutive days. Serum samples were collected regularly over the treatment period of 36 months. Clinical parameters including relapse activity were recorded at three monthly visits. A cerebral MRI was performed every 12 months.We used the Simple Plex Human NF-L Cartridge measured on an Ella instrument  and Simoa NF-light Advantage Kit for Simoa and measurement on a HD-X analyser  to assess sNfL. After blood collection, serum samples were frozen and stored at −80 °C. For both devices, samples were measured directly after thawing according to the manufacturer’s recommendations on the same day and under identical laboratory conditions. A dilution of 1:2 and 1:4 was used for Ella and Simoa, respectively. Separate standard curves were generated prior to all measurements, and both high and low controls were included.The intra-assay coefficients of variation (CV) of manufacturer-provided controls were automatically calculated in duplicate (Simoa) or internal triplicate (Ella). Associated quantitative variables are presented as mean and 95% confidence interval (CI). Median sNfL values were compared by Wilcoxon rank test.2 + CV_Simoa2) × 1/2, as suggested in previous studies [For Bland–Altman plots and Passing–Bablok regression, sNfL values differing by more than three standard deviations from the mean of the particular method were considered as outliers and were removed prior to statistical analysis. Furthermore, we included additional data of the same patients over a total period of 113 months. The acceptance interval for the Bland–Altman plot was defined to be 0 ± 1.96 × (CV_Ella studies . Accordi studies ,24. This


The WHO recommends oral calcium supplementation (1.5–2.0 g) in pregnant women to reduce the risk of pre-eclampsia living in areas with low dietary calcium intake. Although maternal mortality is high in Nepal and eclampsia causes at least 20% of maternal deaths, implementing WHO recommendations would be a major undertaking.This review aimed to assess whether the current evidence supports the blanket supplementation of calcium to prevent pre-eclampsia among pregnant women in Nepal.We used a structured approach to appraise the evidence for calcium supplementation in Nepal. We identified what may influence the impact of calcium supplementation in Nepal and conducted a situation analysis in the country covering maternal mortality, pre-eclampsia occurrence, and existing government policy provisions for supplementation. We also consulted with experts and government officials to explore their perspectives and experience on supplementation. We then used AMSTAR (A MeaSurement Tool to Assess Systematic Reviews) to appraise the Cochrane Systematic Review of calcium supplementation. Finally, we used these data in a GRADE –Evidence to Decision framework to reach a policy recommendation.Our assessment of the Cochrane Review showed that the recommendation made by the WHO is based on weak evidence and trial findings that are not consistent between studies. The Cochrane Review found low certainty of the evidence for benefit . Conversely, there is a high certainty of the evidence of undesirable effects  although this is uncommon. The likely absolute reduction in maternal deaths projected to Nepal was estimated to be low, while the implementation costs were high. Stakeholders also raised several concerns regarding feasibility, acceptability, appropriate dosing, and risk communication.This review concludes that the blanket supplementation of calcium cannot be recommended in Nepal. A better approach may be to identify high-risk pregnant women and manage their antenatal visits and delivery to prevent mortality from pre-eclampsia. The World Health Organization (WHO) currently recommends oral calcium supplementation 1.5–2.0 g) for pregnant women in areas with low dietary calcium intake to reduce the risk of pre-eclampsia  compared with 4 fewer cases of pre-eclampsia  syndrome. HELLP is a serious condition, which when undiagnosed and untreated may pose substantial health risks for both mother and foetus. It is estimated that HELLP syndrome occurs in 0.5–0.9% of pregnancies, and it increases to 10–20% in pregnancy cases with severe pre-eclampsia . The eviclampsia . ConsideStakeholders also raised the issue of a potential negative impact of calcium supplementation on the number of women completing the existing iron supplementation programme in Nepal and difficulties in integrating the two schemes. Therefore, we concluded that the undesirable effects were categorised as LARGE, principally due to the increased incidence of HELLP.The trials including a relatively small number of participants  showed a greater effect on pre-eclampsia reduction, whereas trials incorporating a large sample size of over 1,000 participants showed no effect. Therefore, we concluded that there is a low certainty of evidence regarding the desirable effects.In contrast, the supplementation trials that assessed undesirable effects, including HELLP syndrome, were robust with a relatively large sample size. Taking into account the low certainty evidence of benefit of calcium supplementation but high certainty evidence of undesirable effects, we concluded the overall certainty of the evidence to be moderate. This is primarily because of small study effects (publication bias), inconsistent trials observed for desirable effects, and increased risk of HELLP syndrome reported in high-quality trials.A calcium supplementation programme would aim to reduce pre-eclampsia and maternal mortality as the main beneficial outcomes, with adverse events such as HELLP syndrome as the principal harm. Since both pre-eclampsia and HELLP syndrome can result in maternal mortality, these two outcomes would be expected to have similar value judgements among diverse stakeholders, and the ratio between the two outcomes becomes the important factor. For example, a substantial reduction in maternal mortality due to calcium supplementation may result in a minimal increased risk of HELLP syndrome being considered acceptable. However, if the increased risk of HELLP syndrome outweighs the population-level benefit gained from supplementation, the risk would be considered unacceptable. Stakeholders expressed concerns regarding risk communication associated with the adverse effect of calcium supplementation. Their key question was how the message regarding the dosage should be conveyed to pregnant women as based on the evidence that higher doses are associated with the undesirable effect (HELLP syndrome). We therefore judged that there was no important uncertainty for this outcome.Given the high certainty of the evidence of increased incidence of HELLP syndrome (undesirable effect) and the small effect size of the desirable effects, coupled with very low certainty of the evidence, the weight of evidence favours the control (no supplementation), rather than the intervention . Therefore, we judged that the balance of effects probably favours the comparison (no supplementation).We calculated the approximate cost estimates required for calcium supplementation in the country based on extrapolation of costs from a pilot calcium supplementation programme conducted in Nepal . We calcThe certainty of the evidence is low regarding resource requirements. A full health economic evaluation is not available. The data we applied to the cost estimates are derived from a pilot supplementation programme implemented in a district with technical support from the USAID-funded Maternal and Child Health Integrated Program , which bThe Cochrane systematic review did not include cost-effectiveness evaluations of calcium supplementation. A retrospective analysis of the pilot calcium study in Nepal reported only a marginal increase in cost-effectiveness when compared against a scenario without any intervention for managing pre-eclampsia and eclampsia . As per Primary prevention of pre-eclampsia, such as increasing ANC coverage, routine screening of blood pressure, identifying high-risk women, and examining proteinuria in existing health facilities, may be more cost-effective if these preventive services could be strengthened. Based on the minimal available evidence on cost-effectiveness, we considered the evidence to favour the comparison (no supplementation).Blanket supplementation of calcium is unlikely to increase health equity because those who face barriers to access the health facility may also not be able to receive calcium. Women without access to health facilities are generally those in the lowest socioeconomic groups and most likely to have malnutrition, including low-calcium diets during pregnancy.A blanket supplementation programme may also create health inequity by supplementing women with an adequate dietary calcium intake as well as those with low-calcium diets.Therefore, we judged that a blanket calcium supplementation programme probably reduces health equity.Evidence from a small pilot study in Nepal indicated that calcium supplements (1 g/day) are acceptable to pregnant women attending ANC clinics with a compliance rate of 67.3% completing the full course  [Stakeholders also raised concerns regarding risk communication to pregnant women. When the high-certainty evidence indicating an increased risk of HELLP syndrome is clearly communicated, it was thought that the pregnant women would be unlikely to accept the supplements.Stakeholders questioned the high dose (1.5–2 g) of calcium supplemented in the trials, which exceeds the recommended daily dietary allowance of 1,000 mg for pregnant women in Nepal.There is no national data on dietary calcium intake among pregnant women, but a small study conducted in two districts reported an average intake of 353 mg/day in Nepal . ExtrapoThe supplementation does not seem to be feasible in the current context of Nepal because the intervention requires trained human resources, health infrastructure for transportation and storage capacity, and a regular monitoring mechanism. Universal supplementation of calcium would therefore be resource-intensive compared to the iron/folate supplementation programme, which is implemented nationwide. Calcium supplementation in Nepal would require considering the capacity development needs of health facilities to manage calcium-associated adverse effects and its potential impact on iron absorption. A qualitative study conducted in Western Kenya reported increased workload on the part of the health providers when adding calcium supplementation to an existing iron supplementation programme . LikewisAs a result, such schedules may make it difficult for the women to take supplements as some women reported not being able to find a suitable time for taking supplements and others reported the schedules as inconvenient to follow . All sucTherefore, feasibility is categorised as probably not feasible.Based on the GRADE-EtD evaluation presented in We consider that there is a high risk of harm due to increased incidence of HELLP syndrome and potentially reduced compliance with existing iron supplementation, which is not justified by the possibility of a small, if any, absolute reduction in maternal mortality due to pre-eclampsia. In addition, the high resource costs of such a programme would be better applied to strengthening ANC services, including pre-eclampsia screening.There is no relevant data about the prevalence of pre-eclampsia in the low-calcium diet subgroup in Nepal or about the prevalence of low-calcium diets. Therefore, it was not possible to conduct a Nepal-specific subgroup analysis.This analysis does not recommend initiating the implementation of the supplementation.Given the weight of evidence against blanket calcium supplementation in Nepal, we would recommend that further research should focus on alternative approaches to reducing maternal deaths due to pre-eclampsia. This should include research on approaches to strengthening antenatal screening services with blood pressure tests and dipstick proteinuria screening tests integrated into routine ANC. Any further trials of calcium supplementation in Nepal should test targeted calcium supplementation in women with low-calcium diets, rather than blanket supplementation. Such trials should include a cost-effectiveness evaluation, given the high resource costs associated with calcium supplementation. Reduction of pre-eclampsia in Nepal is clearly an urgent priority, and alternative interventions to blanket calcium supplementation should be designed and rigorously tested. Moreover, research should prioritise collaboration with the targeted communities to understand their requirements and practices of seeking ANC and their access and utilisation of health services to prevent pre-eclampsia.Blanket calcium supplementation in pregnant women is not an appropriate intervention in Nepal based upon this comprehensive context-specific evidence review. Blanket calcium supplementation is unlikely to result in a significant reduction in maternal mortality due to eclampsia, whereas it may cause increased mortality due to HELLP syndrome. Early identification of high-risk pregnant women during their ANC visits in health facilities and case-by-case management of pre-eclampsia would provide an alternative to blanket supplementation. Countries should aim to generate evidence on the calcium intake among women of reproductive age and pregnant women from nationwide surveys. National policy documents regarding calcium supplementation should be revisited based on the available current country-specific evidence.


The systematic review set out in this protocol is part of a broader evidence synthesis which intends to produce two systematic reviews to address a significant gap in the evidence base identified by Luchenski et al. (2018) and by White and Narayanan (2021). This review (the focus of this protocol) will be of the experiences of adults experiencing homelessness when accessing and using psychosocial interventions. This review of qualitative data will use thematic synthesis to analyse these experiences as faced by this population when accessing and using psychosocial interventions. These foci vary between countries and over time, though increasingly it is recognised that both might have explanatory power  face significant barriers accessing services, and often fall through the cracks between different services they need to access Dobson, . They caPsychosocial interventions are aimed at reducing or preventing harms caused by homelessness, and addressing issues that increase the risk of an individual becoming homeless. These interventions are increasingly used with this population for several reasons. First, there is growing evidence of their effectiveness more generally, and it is assumed they must therefore be effective for people experiencing homelessness. However, this assumption may not be valid, given that people experiencing homelessness face significant challenges when accessing, maintaining, and benefiting from services compared to the general population. All things being equal, it is reasonable to assume that given these challenges, evidence about the effectiveness in general of these interventions is not directly translatable to this specific population of people experiencing homelessness. The purpose of the review proposed here is to systematically identify and synthesise evidence of these challenges, so that policy makers and practitioners can take them into account when designing and delivering psychosocial interventions for adults experiencing homelessness. Secondly, because these types of intervention are often used to address clinical needs  with which people experiencing homelessness often present. Finally, a number of health bodies  recommend their use.1.21.2.1Psychosocial interventions for mental and substance use disorders: a framework for establishing evidence‐based standards. This report was the outcome of detailed work by a committee of 16 experts established by the Institute of Medicine in the United States. In the report, Mary England and colleagues state that psychosocial interventions are ‘interpersonal or informational activities, techniques, or strategies that target biological, behavioral, cognitive, emotional, interpersonal, social, or environmental factors’  focused on mental health or substance use. Several include social change as well as psychological change as an objective, and also all exclude interventions that are wholly or mostly pharmacological in approach. But the extant literature also identifies huge variation in these interventions, including differences in setting, intensity, whether the intervention is group or individual based, and the treatment goals of the intervention. For this review, we propose to use the definition provided by England et al.  and outl1.2.2Psychosocial interventions are often used to address problematic substance use, poor mental health, and offending behaviours, as well wider social determinants of health such as housing instability and homelessness, worklessness, and poor skills or education. As adults experiencing homelessness may be dealing with more than one of these issues at any given time, many will access services that include psychosocial interventions. It is therefore essential to understand what barriers adults experiencing homelessness might face when accessing these interventions, and what might facilitate improved access. It is also important to understand what factors adults experiencing homelessness perceive in relation to the effectiveness for them, of these interventions.1.2.3Interpersonal relationships. This assumes that an individual's interactions with other people affect their sense of security, self, motivations, physical health, and behaviours. The idea is that an individual's current relationships drive homelessness, substance use, and mental health issues. Psychosocial interventions drawing on this approach focusing on improving interpersonal functioning, providing effective tools for dealing with relationship problems. They also involve providing supportive, non‐judgement support. Family therapy is an example of an intervention that draws on this theory of change.Habituation. Habituation assumes that, over time, certain behaviours change from being reward‐driven to be automatized, highly stimulus bound, inflexible, and insensitive to the associated outcomes (positive or negative). Psychosocial interventions drawing on this approach aim to disrupt of change these habits, using approaches such as exposure therapy or contingency rewards.Meta cognitive awareness refers to a set of activities which involve thinking about one's thinking and responding accordingly to what is happening in the moment in one's life. Psychosocial interventions drawing on metacognitive awareness approaches focus on cognitive processes and related dysfunctional beliefs or specific cognitive biases. The aim is to help individuals understand how their cognitive biases might lead to, or prolong, homelessness, substance use, and mental health issues, and to provide alternative ways of responding to these thoughts and thereby reduce these symptoms. Motivational interviewing is an example of an intervention that draws on this theory of change.Broadly speaking, the main mechanism of change underpinning these interventions is psychological, focusing on the individual's psychological development and interaction with their social environment. There is no single theory of change underpinning these types of interventions; some are more explicitly based on formal theories, others less so. England et al.  and otheIt is possible that some individual interventions might draw on more than one of these theories of change. As the review team develops and critically assesses these theories of change, it will need to identify which specific interventions draw on which theory, and whether any draw on more than one theory of change.1.31.3.1As noted above in the initial introduction, and elsewhere in the background sections, homelessness is a significant and growing policy issue in a number of high income countries around the world. It is increasingly recognised that homelessness has a devastating effect on those experiencing it and on the wider community, and that is costly to the public purse. There is ongoing uncertainty as to which interventions are most effective at preventing and reducing homelessness and the harms associated with homelessness, particularly in relation to people experiencing severe and multiple disadvantage homelessness.Psychosocial interventions increasingly play a role in policy and practice responses to homelessness and the harms caused by homelessness. There is some evidence about the effectiveness of these interventions generally, but not specifically in relation to adults experiencing homelessness. There is also a limited but growing evidence base factors affecting access and use of psychosocial intervention, but there is no evidence specifically related to adults experiencing homelessness. For example, Troup et al.  recentlyThere is also a significant gap in the current evidence base in terms of the voice of people with lived experience of homelessness, as it largely treats people with lived experience as passive research participants. This proposed review aims to elevate the voice of people with lived experience in three ways. First, there will be an ‘experts by experience’ review process that will run alongside the technical peer review process. This will enable the review team to gain views on relevance and appropriateness of the review and its outcomes to the users of services. Secondly, the team proposes to work with a panel of people with lived experience to co‐produce the discussion, recommendations, and conclusions of the published review. Thirdly, this review focuses specifically on the experiences of people experiencing homelessness as they access and use psychosocial interventions and thus aims to hear directly the voice of homeless people as collected in the included studies. We will use the Guidance for Reporting Involvement of Patients and the Public (GRIPP2)  will use meta‐analysis to synthesise the effectiveness of different psychosocial interventions in (1) reducing problematic substance use; (2) improving mental health; and (3) improving housing stability for adults experiencing homelessness. Housing is recognised as a significant social determinant of health  was used in the development of the criteria for considering studies for this review. The following paragraphs set out the 3.1.1There are a number of definitions of homelessness available, reflecting differences between countries and over time. There are also different forms of homelessness, taking into account the length of time someone has been experiencing homelessness, distinctions between living on the street or in their vehicles, or having a temporary place to stay.Homelessness is defined as those individuals who are in inadequate accommodation (environments which are unhygienic and/or overcrowded), who are sleeping rough (sometimes defined as street homeless or unsheltered), those in temporary accommodation (such as shelters and hostels), those in insecure accommodation (such as those facing eviction or in abusive or unsafe environments), and people whose accommodation is inappropriate .We propose to draw on the definition of homelessness used by Keenan et al.  in a recOur focus is on adults (men and women aged 18 years and over), undertaken in any high‐income country and published in English. Studies of families or children will be excluded from the review. In many countries (particularly the UK), there are different legal frameworks that apply to homeless families and children, and thereby their access to different types of services, and different outcomes expected.The review will include studies where it appears that a substantial number of participants are homeless or described as at risk of becoming homeless. As the review is based on an evidence and gap map (EGM) focused on people who are homeless, we should safely assume that the populations included in the studies in the EGM entirely or mainly comprise people who are in fact homeless.3.1.2Given the varying definitions of what constitutes psychosocial interventions, whether interventions are labelled as psychosocial in approach, and the significant operational differences in whether and how these interventions are structured and delivered, it is important to be clear about the types of interventions that we will cover.The review is focused on formal psychosocial interventions used with adults experiencing homelessness. Interventions based solely or mainly on pharmacological approaches or approaches other than psychosocial, will be excluded. The National Institute for Health and Care Excellence (NICE) provides some help here, stating that formal psychosocial interventions include: contingency management, behavioural couples therapy, community reinforcement approach, social behaviour network therapy, cognitive behavioural relapse prevention‐based therapy, and psychodynamic therapy NICE, .We draw on this and have developed a typology of psychosocial interventions to help focus this review. As part of the scoping work to develop this protocol, the typology Table  was discThe typology categorises specific interventions as either low intensity or high intensity, drawing on the distinction made by the Welsh Government  between The typology further categories interventions by their type, as detailed here below in text and in the table that follows.Talking therapies are a type of psychosocial intervention that primarily involves the service user discussing issues around their thoughts, feelings, or behaviours with a professional therapist. These interventions might be delivered in group or one‐to‐one settings.Behavioural incentives are a type of psychosocial intervention that use extrinsic rewards or negative consequences to change an individual's behaviour. Finally, self‐help interventions are a group of psychosocial interventions in which individuals work through therapeutic materials or processes on their own, or with minimal input from a professional therapist. This can involve working in a group with others also going through the same process.3.1.3Eligible studies will include those that use individual and group interviews, focus groups, observation, or other qualitative‐related methods focused on the experiences, views, or opinions of adults experiencing homelessness.3.1.4Types of study will include those where empirical data presenting the experiences, views, or opinions of people who are homeless or at risk of homelessness when accessing or using psychosocial interventions, and are directly presented either as direct quotes or summaries, or as reports of participant experience by researchers.3.1.5Eligible studies will include data reported either as part of a mixed methods study or collected in a qualitative empirical study identified in process evaluations of psychosocial interventions focused on people who are homeless.3.2the Homelessness Implementation Studies Evidence and Gaps Map ; andhand searches (set out in the section ‘searching other sources’ below).Studies considered for inclusion in this review will be identified in three ways:3.2.1here. A further update to the Implementation EGM will commence in early 2022.Studies included in this review will be based on an existing Implementation EGM which was last updated in early 2021 by The Campbell Collaboration .n = 275 EGM studies.)The EGM includes systematic reviews and evidence reviews, as well as primary studies. The review team will unpack any systematic review or evidence review, and cross check the unpacked primary studies against the EGM. The review team will undertake a title and abstract review on any unpacked primary study that is not included in the EGM. . The Campbell EGM team also searched the websites of government departments  as well as state or county governments in Australia, Canada, the United States, the United Kingdom, and major cities in these countries. In addition, the websites of homelessness agencies, such as Crisis, Homeless Link, Shelter in the United Kingdom and Mission Australia and other relevant databases from around the world as listed in Supporting Information: Appendix In addition to the above, to build the EGM, the Campbell team undertook additional website searches for grey literature, including those of bilateral and multilateral organisations. A major source of these studies is the Canadian Homeless Hub.  which was disseminated through Manchester Metropolitan University and the Centre for Homelessness Impact social media channels, inviting people with lived experience, researchers, commissioners, service providers and wider stakeholders to submit relevant grey literature evidence for consideration in both these parallel reviews. Specifically, the call was for evidence that is:○gives voice to people with experience of homelessness;○measures the impact of interventions ;○identifies the experiences of accessing and using, interventions;empirical, based on research that:is about psychosocial interventions aimed at preventing or reducing homelessness, mental ill‐health, and problematic substance use;is not published in a book or academic journal; andis specific to the UK, or England, Northern Ireland, Scotland or Wales.In January/February 2022 the review team undertaking the review set out in this protocol issued a hand search key journals, using similar search terms and date ranges as White et al.  title/abstract, (ii) full‐text using the inclusion/exclusion criteria for this review (the inclusion and exclusion criteria are listed in the Supporting Information: Appendix). All screening will be undertaken by two reviewers, and any disagreements will be discussed with another member of the review team. Twenty‐five percent (25%) of final screening decisions will be sampled by a third reviewer. Final decisions about inclusion will be made by all members of the review team.3.33.3.1Descriptive data will be extracted from eligible studies in two ways. Some relevant descriptive data will have already been extracted by the Campbell team when developing the EGM and we propose to use these where available. For descriptive data that is not included in the EGM, data will be extracted from studies by two reviewers.–Publication details –Geographical location—this data is available from the EGM–Setting–Intervention details, including basis, focus, typology classification, explicit theory of change–Participant details, including classification –Number of service users involved in the study–Research aim and design–Service/intervention outcomesDescriptive data will cover the details of the study, description of the theory of change underpinning the intervention, description of the intervention, qualitative data collection method used, qualitative analysis method used, and confidence in the study's findings  for thematic synthesis analysis of participant experience data, and subsequently used for Stages two and three of the thematic synthesis analysis.3.3.2Eligible studies that are included in the Implementation EGM have already been assessed using Campbell's Critical Appraisal Tool for Primary Studies   to identified any areas of disagreement. In any case where the coders disagree, a third researcher will then review the outcome of this discussion to develop a consensus. At the third stage of analysis, two researchers will independently examine and then discuss the key descriptive themes. These will then be drawn out and translated, to infer analytical and more abstract themes. At this stage, the analytical themes will be explored through the lens of the theory of change developed during the design stage of the two reviews, recognising the distinction between ‘data’ driven descriptive themes, and ‘theory’ driven analytic themes  access and (b) use psychosocial interventions. The current evidence clearly demonstrates that adults experiencing homelessness have significantly higher levels of mental ill‐health, problematic substance use, and housing instability compared to the general population, and are also less likely to be able to access services  to reduce the impact of, and negative effects from, these experiences. By focusing this review on the experiences of adults experiencing homelessness, the review aims to elevate the voice of? homeless people and thereby address a fundamental limitation of many systematic reviews—that of treating service users as passive research participants rather than as citizens who may actively participate in their own recovery. As part of the broader evidence synthesis , the review team will use extracted data on theories change underpinning the interventions covered by the included studies to help understand the causal mechanisms and pathways by which psychosocial interventions are intended or expected to lead to positive change in the core outcomes for adults experiencing homelessness. The review team hopes that these theories will enable synthesis of the effectiveness and experiences reviews, so as to provide in‐depth insight into what works, why, how, for whom, and in what contexts, for psychosocial interventions with this population.3.3.6The NIHR evidence synthesis research grant covers an 18‐month period from October 2021 to May 2023. To comply with the grant requirements, we plan to submit the final review by no later than May 2023.3.3.7Dependent on additional funding.Lead: Chris O'LearyContent: Chris O'Leary and Esther CorenSystematic review methods: Esther CorenInformation retrieval: Anton Roberts and Chris O'LearyThe authors declare that there are no conflicts of interest.Supporting information.Click here for additional data file.


Latency is one of the key parameters of Internet services. However, it is difficult to correctly assess a service by its latency. Many latency measurements are blocked en route by routers and firewalls. For this reason, the service latency is not fully known. This work proposes a method to assess Internet services including the blocked latency measurements. Survival theory is applied to process latency values. The results show that the omission of blocked latencies from statistical processing severely underestimates the service latency. Two Internet service providers were compared as an example. Their latency difference was 9 ms using the traditional approach. The survival latency resulted in a difference of 17 ms. The method of survival latency can be used to increase revenues in e-commerce and to improve the experience of online gaming. There are many types of Internet services, including content delivery network (CDN), software as a service (SaaS), platform as a service (PaaS), Infrastructure as a service (IaaS), and ISP (Internet service provider) connection service. The quality of Internet services is assessed by various measures. These include latency, which is a crucial service parameter. Service latency is mainly given by the geographical distribution of the service cache servers, backbone connection, and peering to other networks. It is stated that latency is the key goal for future Internet development .This work deals with service assessment by latency, which is difficult to correctly implement. Service latency is assessed by a set of observation points  that mimic the service users. Geographical placement of the observation points affects the service assessment as latency is naturally dependent on the distance. A proper distribution of the observation points mitigates the effect of geographical distance. However, this does not solve the problem of incorrect service assessment, as some latency measurements from the observation points are blocked en route. The blocked latency values carry important information and their omission from the statistical processing is detrimental to the result. Blocking of latency measurements is due to the policy of intermediate devices  and cannot be regulated. Therefore, it will always be present in Internet communication.The idea presented in this work is to assess a service by both observed and unobserved latency. The observed latency is the measured true latency. The unobserved latency  is lost due to measurement blocking en route. Therefore, it is only partially known. Survival theory is applied to process blocked latency measurements . There iThere will always be some censoring present in a larger number of patients. This also holds for a larger number of observation points as some latency measurements will be blocked. It has to be noted that the scale of the patient’s lifetime in years and service latency in milliseconds are completely different.This work finds its use in the general assessment of Internet services. Different services offering the same functionality can be assessed for contracting purposes. Contact points of the same service can be assessed for their automatic selection for users. Furthermore, when services or their contact points are compared, it is important to know the magnitude of the latency difference. This information also helps when other factors are present, such as the cost of service optimization.An example application is CDN service comparison for contracting purposes. CDN services distribute website content closer to visitors for faster page loading . In geneIt has to be noted that the simplified selection of CDN services based on the number of contact points in a country is not correct. It is also not correct to select a service contact point that is geographically closest to the user. Such a selection is not related to the lowest latency. In fact, latency depends on the actual connection between the user and the service contact point. Using the method of survival latency, a set of CDN service contact points can be periodically evaluated and sorted by the lowest latency for users in a country or region. A user is then automatically assigned the true best latency contact point to connect.The rest of the article is structured as follows: The next section gives an overview of the related work. The ‘Traditional service assessment’ section explains the problem of biased service assessment by latency. The method of survival latency is described in the ‘Survival latency method’ section. Implementation of the method using the RIPE Atlas is described in the ‘Implementation’ section. The ‘Example’ section includes an unbiased service comparison.The importance of latency for Internet services has been studied in a number of works . In addiService latency is reduced by the presence of contact points that are geographically distributed. With CDN, service users are directed to the nearby contact point, which is a server that offers the service. This redirection is based on the domain name system and global routing. With domain names, the IP address of the service contact point is returned for the service, and the client contacts it on its own. Anycast BGP (Border Gateway Protocol) routing announces the service IP address from more locations, and the client is automatically routed to the service contact point.CDN providers differ in the number of their contact points, ranging from tens to thousands . The geoSurvival theory has already been applied in different fields, including digital communication. In In To the best of the author’s knowledge, survival theory has not been applied in Internet service assessment to handle the problem of blocked latency measurements.Traditional service assessment is demonstrated by etc.). These delay contributors lower the speed of data transmission to 4/9 of the speed of light in a vacuum, which is 133 km/ms . In the case of ISP connection service assessment, the observation points mimic the services as the end hosts access them.With a larger number of observation points, a number of latency measurements will be blocked en route. tmax, inf), where tmax is the highest unobserved latency. It has to be noted that the maximum unobserved latency is considered, not the latency measured for the responsive router closest to the service.The idea of survival latency is to include the blocked latency measurements in the service latency statistics. Survival theory handles the problem of observed and unobserved data to obtain an unbiased result. The survival functionl. L is a random variable expressing the latency and F(l) = P(L ≤ l) is the cumulative distribution function.The survival function includes both observed and unobserved values. It is obtained using the Kaplan-Meier estimator , which ini is the number of latency values at risk up to latency li, di is the number of latency values observed at li, and li is the time equal to at least one latency observed.A service can be assessed by the mean or median survival latency. Median survival latency is the latency with a survival probability of 0.5. However, the median may not be significant for service assessment  as it does not interpret the skewness of the latency values. The mean survival latency is a better metric when the magnitude of the latency difference is important to know. The importance of mean survival for service assessment is demonstrated in In the sample, the mean survival latency was calculated using the whole area under the survival function curve. However, real data have outliers that have a strong effect on the mean survival and thus on the magnitude of the latency difference. Larger latencies (both observed and unobserved) may be a result of temporary outages and their inclusion would be incorrect for service assessment. Such latencies cannot simply be removed from the input data using a latency threshold. The reason is that it is not known which unobserved latency will cross the threshold line and which not. Therefore, the mean survival is found using the restricted mean survival (RMST), which isl for the integral to exclude large latency values caused by temporary network problems. The limit selection is further discussed in the section ‘Implementation’.The restricted mean survival uses the limit The steps of the survival latency method are the following: (i) Measure observed latency to service. (ii) Measure unobserved latency to service. (iii) Estimate the survival latency function and calculate the restricted mean. The input prerequisite is a set of latency observation points that are distributed over the service area.The above steps are processed for each service compared. The time for service assessment is determined by the number of observation points. Therefore, the number of available points can be reduced to limit the measurement time. A service is first approached by an echo message to obtain the observed latency. The observation points, whose latency measurement was blocked, then measure the latency to the routers en route. Parallel processing is possible.Independent censoring–The observed latency is independent of the unobserved latency. By the nature of latency blocking in the Internet, there is a positive correlation between observed and unobserved latency. The explanation is that latency measurements are typically blocked by routers  closer to the destination. Therefore, this assumption is invalid.Non-prognostic censoring–An unobserved latency value does not carry prognostic information about the true latency. This assumption is considered valid for Internet communication. We do not have any information about the true latency increase towards the service given the unobserved value, which is the maximum value obtained from the responsive routers on the path.The use of the Kaplan-Meier estimator is conditioned by non-informative censoring . Non-infThere are two other assumptions associated with the Kaplan-Meier survival analysis : (i) SurAn implementation is presented to apply the method of survival latency in a real scenario. In particular, the implementation shows that the omission of blocked latency measurements underestimates the service latency. This is detrimental to service comparisons or their optimal setup. In a proper implementation, the latency observation points that mimic the service users must be geographically located in the targeted service area. It may be sufficient to delimit the service area by country borders for national-related services. For international services, a group of target countries or whole continents can be used. The area may also be delimited by other means, such as a country region, a circle with a given radius, or a general polygon. Worldwide coverage is also possible if there is such interest.In the implementation, the latency observation points that mimic the service users belong to the RIPE Atlas . The AtlISP connection service of a national operator (Vodafone CZ) is used to demonstrate the service assessment by latency. The latency of the ISP connection is determined by the technology used and by the ISP peering to other networks. Peering is typically implemented in the country of the end host.ping tool is used to collect the observed latency values. Second, the traceroute tool is used to collect the unobserved latency values. The unobserved latency is the highest latency measured on the path if the destination was not reached, as shown in Latency is measured from the end host to the observation points. First, the M is obtained graphically as S(M) = 0.5 from data collected in a country. The tail of the function also demonstrates the need for a maximum latency restriction to exclude erroneous latencies caused by temporal network problems. This is further implemented by restricted mean survival. There were in total 252 latency values, of which 189 were observed and 63 were unobserved. The table below the figure gives an overview of the censoring. The row ‘At risk’ gives the number of remaining latency values in the survival analysis by the end of the interval. The row ‘Censored’ shows the number of unobserved latency values that occurred by the end of the interval. The censored values are also shown as crosses along the curve. It is apparent that the censoring starts to occur with higher latency values. The reason is that the latency measurements are typically blocked further en route, closer to the destination. The row ‘Events’ gives the number of observed latency values that occurred by the end of the interval. The median survival latency for the service is 19 ms and the blue shaded area shows 95% confidence intervals. The function shows a typical tail for latency values in Internet communication. The tail is trimmed for clarity of presentation.The survival latency function  for the This section demonstrates the final outcome of the survival latency method, which is unbiased service comparison. The example works with the data from the implementation part that were given for an ISP connection service. These data are extended by additional measurements of a different ISP connection service. The magnitude of the difference in latency between the two ISP connection services is calculated to demonstrate the biased and unbiased comparison.l in The latency of each ISP connection service was assessed using the same set of observation points. The limit Both columns show that the ISP connection service of end host B is better. However, when considering the magnitude of the difference, the traditional latency severely underestimates the result. The mean survival latency difference is almost twice the mean traditional latency difference. The true magnitude of the difference is important when other factors are to be considered, such as the service price.Internet services differ in quality, and latency is one of the key parameters. Naively, service latency is assessed by a single observation point. Such service assessment is biased as the geographical distance between the observation point and the service affects the latency. A set of distributed observation points is used to mitigate the effect of geographical distance. However, some latency measurements from the observation points will be blocked en route, given the policy of intermediate devices, which is detrimental to the service assessment.The idea of this work was to consider both observed and unobserved (censored) latency for an unbiased service assessment. Survival theory, originally used in healthcare, was used to calculate the restricted mean survival latency. The method can be applied if specific assumptions are met, including non-informative censoring. The validity of the assumptions for Internet communication was discussed.In addition to service comparison, this work can be used for service optimization or new service setup. A service provider may consider the geographic placement of their servers in an area to achieve a low latency. The magnitude of the difference in latency between different geographic configurations can be used to select the best latency option at a cost. The cost is the number of servers needed and their operation at the selected locations . An examThe method of survival latency was demonstrated by an implementation that evaluates the ISP connection services. This type of service was selected for implementation as it has a straightforward application for general users who are interested in an unbiased assessment of their ISPs.The raw data and implementation source code are available at Dan Komosny is a professor at Brno University of Technology, Czech Republic. He received his PhD. degree in Teleinformatics in 2003. His research is focused on IP networks and cybergeography. He lectures courses on operating systems and data networks. He also runs Cisco Networking Academy courses.10.7717/peerj-cs.1072/supp-1Supplemental Information 1Click here for additional data file.


Unlike earlier claims, Kanzi's performance actually vastly exceeds random chance, suggesting that non-human primates can also understand word order grammatical rules, which may be attributed to homologous instead of divergent brain circuitry (Schoenemann).■ (2) Investigating Word Order Emergence: Constraints From Cognition and Communication, which also investigated reversibility, but focused on human gesture production of reversible and irreversible events . It is known from previous studies that in gesturing the word order does not just follow the speakers' native spoken languages  The fourth paper investigated less related but closely associated species and explored the influence of common cultural selection procedure.Did Dog Domestication Contribute to Language Evolution? based on a comprehensive review of biological, neurological, and archaeological studies, raised the hypothesis of a parallel human-canine domestication: in the reciprocal influences between the two species, selected controlling of reactive aggression and prosocial behavior may have provided the critical cultural and physiological bases for more complex forms of human languages to emerge .■ (4) 2.The second set of studies (three papers) investigated human individuals who use two linguistic varieties. These papers may shed light on how microscopic changes happening in bilingual and bi-dialectal minds collectively modulate the evolutionary process of co-evolving languages and dialects.Two of the papers investigated the influences of bilingual or bi-dialectal experiences on cross-linguistic behaviors.Different Neural Responses for Unfinished Sentence as a Conventional Indirect Refusal Between Native and Non-native Speakers: An Event-Related Potential Study investigated the pragmatic processing of conventions interculturally . The authors identified event-related potential (ERP) components related to increased pragmatic processing load induced by the non-nativeness of the language. Interestingly, the ERP responses were also found to be modulated by individual mentalizing ability, in line with the above-mentioned inter-species studies (4).■ (5) Effects of Familiarity and Dialect Experience on the Description of Tonal Variant found that variation of sociophonetic factors across Chinese tonal dialects can predict the bi-dialectal listeners' descriptive decisions on tone height variants, and suggested that individuals' cross-dialectal perception may influence cultural coevolution of cross-dialect tonal variation (Liu and Gibbon).■ (6) Different from these two papers and previous studies on bilingualism, the third paper directly tapped into the process of linguistic changes happening in individual minds.Cross-Dialectal Novel Word Learning and Borrowing provided the first experimental evidence that monolectals and bi-dialectals adopt different mechanisms and differ in abilities in borrowing words . These experimental findings were discussed with historical linguistic evidence to suggest that bi-dialectism as a demographic feature may shape the route of lexical evolution of co-evolving linguistic varieties.■ (7) 3. While the previous two approaches focus on the role of individuals in language co-evolution, the last study (one article) treats languages as self-organizing systems and investigated the interaction of functional constraints and evolutionary mechanisms in language systems.Structural Variability Shows Power-Law Based Organization of Vowel Systems conducted cross-linguistic typological and phylogenetic analyses on the worldwide phonetic database of vowel systems . The findings illustrated that correlated evolutions of these two mechanisms may proceed in an adaptive process and evolutionarily shaped the vowel systems in the world's languages.■ (8) Taken together, this collection of papers provided multiple views and efforts from various angles to entangle the complexity in the evolution of languages. Although each paper probably has only broken a tip of this mountainous iceberg, we may still revisit the biological metaphor of “co-evolution” introduced at the beginning of this Research Topic: comparing languages to genomes, and linguistic communities to species. While embracing this metaphor, we hope our collection can also bring more attention to the fact that language is still different from genomes as a cultural phenomenon bore in individuals' minds and collective behaviors. The “co-evolution” of languages thus involves unique cognitive mechanisms as compared with the co-evolution of species, which is still calling for further inquiry.JW drafted the original version of this editorial. WW and NS revised the manuscript multiple times. All authors contributed to the article and approved the submitted version.JW's work was supported by the Chinese Fundamental Research Funds for the Central Universities (2017ECNU-YYJ017), by Shanghai Philosophy and Social Sciences Fund (2017BYY001), and by National Social Science Fund Major Projects (18ZDA296).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pediatric splenic torsion is a rare entity, and the most common cause is wandering spleen. This study aimed to summarize our clinical experience in the diagnosis and surgical treatment pediatric patients with splenic torsion, and to use preoperative thrombocytosis as a preoperative predictive factor for splenic infarction.From January 1st, 2016 to December 31st, 2021, 6 children diagnosed as splenic torsion were included. All patients were surgically treated and followed up. The clinical data was collected including clinical presentations, laboratory tests, imaging results, surgical procedures, and prognosis. Clinical experience of diagnosis and surgical treatment were summarized.There were 4 females and 2 males, with median age at surgery 102.6 (range 9.4–170.7) months. Abdominal pain and abdominal mass were the most common presentations. The diagnosis of splenic torsion depended on imaging studies, and adjacent organ involvement (gastric and pancreas torsion) was observed on contrast CT in one patient. Five patients were diagnosed as torsion of wandering spleen, and one was torsion of wandering accessory spleen. Emergent laparoscopic or open splenectomy was performed in all patients. Pathology revealed total splenic infarction in 4 patients, partial infarction in 1 patient, and viable spleen with congestion and hemorrhage in 1 patient. Preoperative platelet counts were elevated in all 4 patients with splenic infarction, but normal in the rest 2 with viable spleen. Postoperative transient portal vein branch thromboembolism occurred in one patient.Imaging modalities are crucial for the diagnosis of pediatric splenic torsion and adjacent organ involvement. Preoperative thrombocytosis may predict splenic infarction. Spleen preserving surgery should be seriously considered over splenectomy in patients with a viable spleen.The online version contains supplementary material available at 10.1186/s12887-022-03484-y. Splenic torsion due to wandering spleen is rare, and no accurate incidence has been reported . It accoFrom January 1st, 2016 to December 31st, 2021, 6 children diagnosed as splenic torsion due to wandering spleen were admitted into our general surgery department, and all 6 patients were included in this case series. The diagnoses of splenic torsion due to wandering spleen were confirmed by surgery. Clinical experience of diagnosis and surgical treatment were summarized.Inpatient and outpatient medical records were thoroughly reviewed for data collection, including demographic characteristics, clinical presentations, laboratory tests, imaging results, surgical procedures, and prognosis. Follow ups were carried out by outpatient visits and phone interviews. Any recorded surgical complications were analyzed, and any post-splenectomy complications, such as overwhelming post-splenectomy infection, arterial and venous thrombotic events, and pulmonary hypertension, were checked during follow-ups.Due to the limited case numbers, data were displayed by statistical descriptions, tables, and charts. IBM SPSS Statistics 26.0 was used to manage the data.There were 4 females and 2 males, with median age at surgery 102.6 (range 9.4–170.7) months. Detailed clinical information is demonstrated in Table The most common clinical presentations were abdominal pain/irritability (6/6) and abdominal mass (3/6). Other symptoms included fever, nausea, and vomiting. The symptom duration ranged from 5 days to 12 months. The diagnoses were established on imaging results, including ultrasonography, and more importantly, the contrast cross sectional imaging. Imaging results demonstrated no splenic perfusion in 4 patients , partial perfusion in 1 patient (case 5), and reduced perfusion in 1 patient (case 3). The wandering spleen/accessory spleen located in left flank in 3 patients and pelvis in the rest 3 patient.In case 5, the first contrast CT on the day of admission showed a large spleen with reduced enhancement and splenic vein thrombosis. Torsion of the spleen was indicated by the whirl sign of the pedicle, with pancreatic tail involved Fig. A. The spIn case 6, the contrast CT showed a normal located main spleen with an accessory spleen of almost equal size, and both receiving blood supply from splenic artery. The artery of the accessory spleen was interrupted soon after branching Fig. . The maiLaparoscopic or open splenectomy was performed in all patients. There were two conversions during laparoscopic procedures, due to dense adhesions to descending colon in case 2 and pedicle vascular bleeding in case 4. In case 3 the spleen was viable after detorsion but large, causing difficulty to perform splenopexy with retroperitoneal pouch , and was finally resected. In case 5, considering the splenic vein thrombosis, though the spleen was partially viable, laparoscopic splenectomy was performed using Endo-GIA linear stapler , and splenic congestion and hemorrhage corresponded with reduced perfusion in 2 patients .The pre- and postoperative (1st and 5th day) blood routine test results of all patients are showed in Table All patients were advised to accept vaccines against encapsuled bacteria  2 weeks after surgery. The median time of postoperative follow-up was 43.4 (range 9.4–74.1) months. In case 4, two days after laparoscopic splenectomy a thrombus (0.6*0.5*0.5 cm) was detected in the sagittal portion of left portal vein (Rex recessus) by ultrasonography, which didn’t cause any adverse effects or symptoms. Ultrasonography showed that the thrombus resolved spontaneously within 3 days, leaving no trace on contrast CT on the 5th postoperative day. This was considered as a thromboembolism event, that the thrombus had fallen off from the splenic vein stump and stayed in left portal vein transiently. No other postoperative complications or postsplenectomy complications were noticed during follow-ups in all patients.Wandering spleen is a spleen with hypermobility which can migrate to any area of the abdomen or pelvis . It’s geWandering spleen is predisposed to pedicle torsion and subsequent infarction, which is the most frequent complication and main reason of symptoms , 13. AboIn a recent systemic review, Bough et al. reported 82% patients with splenic torsion received splenectomy . Early dImaging study is crucial for early and correct preoperative diagnosis , 19. TheNormally, the spleen sequesters one third of the total body platelets as the splenic platelet pool, which is exchangeable with peripheral circulation, playing a key role in regulating peripheral platelet counts . PostsplIn patients with splenic torsion, the splenic vein is compromised first because of its low pressure, causing splenic blood outflow obstruction while still maintaining splenic artery perfusion, which results in splenic congestion/hemorrhage and enlargement . ProgresThe spleen is a main reticuloendothelial organ providing immune protection and blood filtration function  . PatientAdjacent organs involvement is common, occurring in 28% of all splenic torsions, such as pancreatic tail torsion, gastric volvulus and varices, intestinal obstruction, and urinary tract compression . The faiAll patients had good prognosis and no complications occurred except case 5. In case 5 a transient and asymptomatic thrombus was detected in the sagittal portion of left portal vein, which resolved spontaneously within 3 days. Since this patient had a large splenic vein thrombosis, we consider the thrombus had fallen off from the splenic vein stump causing thromboembolism. Portal vein thrombosis after splenectomy is a known complication, occurring in 0.5%-55% cases depending on different diagnostic standard and method, which generally needs anticoagulation treatment . But it’Due to the rarity of pediatric splenic torsion, this is just a descriptive case series with 6 patients, no statistic comparisons were allowed. Due to the retrospective nature of this study, although all patients were treated with splenectomy under certain circumstances, we cannot stress the importance of spleen preserving surgery depending on splenic viability, including splenopexy and splenic autotransplantation.In conclusion, imaging modalities are crucial to the diagnosis of pediatric splenic torsion and adjacent organ involvement. Preoperative thrombocytosis may predict splenic infarction. Spleen preserving surgery should be seriously considered over splenectomy in patients with a viable spleen.Additional file 1.Additional file 2.


Many community-based interventions have been developed to increase parent/caregiver health literacy, yet no systematic review of their effectiveness has been published. Therefore, the aim of this systematic review was to examine the effectiveness of community-based health literacy interventions in improving the health literacy of parents/caregivers.A systematic review of six databases; MEDLINE, PsycINFO, CINAHL, Cochrane Library, Embase, and Education Source were conducted to identify relevant articles. Risk of bias were assessed using version two of the Cochrane risk of bias tool for randomised controlled trials or the Cochrane Collaboration Risk of Bias in Non-Randomised Studies of Interventions. The study findings were grouped and synthesised following the Synthesis Without Meta-analysis framework.Eleven community-based health literacy interventions for parents/caregivers were identified. Study design included randomised controlled trials (n = 4), non-randomised studies with comparison group (n = 4), and non-randomised studies without a comparison group (n = 3). Interventions were delivered digitally, in person or a combination of the two. The main findings of the studies showed some potential for both in person and digital interventions to increase parental health literacy. The risk of bias was high in over half the studies (n = 7) Studies were heterogeneous preventing a meta-analysis.Although no definitive conclusion of the effectiveness of community-based interventions can be drawn there are suggestions of improvement in many of the studies included in this review. The review has brought into question whether the health literacy measurement tools used met the needs of assessing the interventions outcomes. When comparing the cost and resources needed for digital with in person interventions, the findings of this review have implications for both practise and research.Methodologically stronger primary research, informed by theory, is needed to capture the components of effective health literacy intervention for parents.Researchers in the field of health literacy need to consider the suitability of using screening tools to measure change in health literacy post intervention.


The clinical support system Electronic Expert Support (EES) is available at all pharmacies in Sweden to examine electronic prescriptions when dispensing to prevent drug-related problems (DRPs). DRPs are common, and result in patient suffering and substantial costs for society. The aim of this research was to study the use of EES for the pediatric population (ages 0–12 years), by describing what types of alerts are generated for potential DRPs, how they are handled, and how the use of EES has changed over time. Data on the number and categories of EES analyses, alerts, and resolved alerts were provided by the Swedish eHealth Agency. The study shows that the use of EES has increased. The most common type of alert for a potential DRP among pediatric patients was regarding high doses in children . The most common type of alert for a potential DRP that was resolved among pediatrics was therapy duplication . The most common reason for closing an alert was dialogue with patient for verification of the treatment . Knowledge of which type of alerts are the most common may contribute to increased prescriber awareness of important potential DRPs. Drug-related problems (DRPs), such as adverse drug events (ADEs), are common . DRPs rePharmacists working in community pharmacies are often the last health care provider in the chain of care, which makes them valuable for preventing DRPs as well as detecting prescription errors . ModificA CDSS provides knowledge combined with patient specific information presented at appropriate times using knowledge-based rules and algorithms . The useThe CDSS called the Electronic Expert Support (EES) is a government-owned system  availablMedication amongst children is challenging ,18,19. TA pharmacist performing an analysis using EES will receive an alert in cases where the system detects a potential problem . The typThe aim of this study was to examine the use of the decision support system EES at pharmacies in Sweden for the pediatric population (ages 0–12 years), by describing what types of alerts for potential DRPs are generated, how they are handled, and how the use of EES has changed over time. More specifically, we wanted to studyThe number and proportion of children (ages 0–12 years) receiving EES analyses over time;The type of alerts for potential DRPs being generated by EES for pediatric patients;The proportion of EES alerts being resolved for pediatric patients and examine potential differences between the types of alerts;What kinds of actions were taken to resolve the generated alerts for pediatric patients.The study used quantitative data from the Swedish eHealth Agency delivered on an aggregated level and analyzed to answer the research questions in the current study. The data are automatically generated and compiled into Excel files at the Swedish eHealth Agency on a weekly basis.Three different types of data were obtained from week 11 of year 2020 to week 11 of year 2022 for the total population and the pediatric population. The available data determined what types of measurements could be taken, resulting in different results being presented in this study for the total population compared to the pediatric population. Two different types of data were obtained from week 11 of year 2022 for the pediatric population. For details see This study included all pharmacies in Sweden, approximately 1400 pharmacies in total. All individuals that were dispensed a prescription at a pharmacy were included. In this study the term pharmacist refers to the two following categories of licensed pharmacy practitioners in Sweden: a prescriptionist with three years of university education and a pharmacist with five years of university education. Both have similar legal rights and obligations.EES is a rule-based decision support system , which reflects the clinical parameters/conditions for a particular drug ,9. It waThe categories elderly and pediatric have two additional warnings being, respectively, “high dose elderly” and “age warning elderly” and “high dose pediatric” and “age warning pediatric” . The EESWhen the EES system is used, an analysis is made for each prescription from a national medication list based on the rules in EES ,7. The pTo perform an EES analysis an active choice is required . In prevThe use of EES, i.e., the number of EES analyses, is calculated as follows: A customer is counted only once per day and per pharmacy. Thus, performing an EES analysis in the morning and another one in the afternoon with the same customer and at the same pharmacy is calculated only once. If the customer goes to different pharmacies in the morning and in the afternoon where an EES analysis is performed each time it will be calculated as two EES analyses, one at each pharmacy. The statistics in EES analyses are based solely on the use of EES, i.e., it does not matter if the prescription was dispensed or not. The number of resolved alerts, i.e., alerts being closed, describe the alerts that are in the system on Monday morning at 6:00 am. This requires that the alerts are still “active”. At least one prescription needs to be current for an alert to remain in the system.The data on the closed alerts have been assigned specific acronyms. The explanation of the alert categories is as follows: DD1 , DD2 , DD3 , DXI  GSX (drug gender warning), HD2 (high dose—a prescribed dose exceeding the maximum daily dose), HDP (high dose pediatric—a prescribed dose exceeding the maximum daily dose for pediatric), PAP (age warning pediatric), and TD1 (therapy duplication—dispensing of two or more drugs within the same therapeutic class), and TR1 (not a specific category). TR1 is not a specific category but is called “Supplementary review” and has been created to distinguish certain alerts from their respective categories.For parts of the analysis, five reference weeks were chosen during the period for which data were collected: it was week 11 of year 2020, week 36 of year 2020, week 11 of year 2021, week 36 of year 2021, week 11 of year 2022. The reference weeks were chosen to be as representative as possible, i.e., no holidays or events. Data on the use of EES from previous studies show for example a decrease in the use during June to August .Pharmacists handle and make decisions based on the generated alerts and have the option to close alerts after being handled . ClosingYear 2018 (week 15), focused on the elderly (aged 75 years or older);Year 2019 (week 15) focused on the elderly (aged 75 years or older);Year 2020 (week 43) focused on the pediatric population (aged 0–12 years);Year 2021 (week 16) focused on therapy duplication;Year 2022 (week 14) focused on DDIs.National interventions called “focus weeks” are initiated by the Swedish Pharmacy Association, and have been conducted each year starting in 2018 with a chosen focus each time ,30. The Data were analyzed using Excel. In total, the data included 106 weeks. Major events that may have affected the use of EES, i.e., the number of EES analyses, were highlighted . These major events were when the new law on a national medication list came into force, the need for patients’ consent to perform an EES analysis was removed, and when the focus weeks took place (one focus week each year).The statistics on the number of prescriptions dispensed and the number of EES analyses is displayed for the total population and for the pediatric population. The pediatric population cover however slightly different age groups. The number of prescriptions dispensed cover ages below 13 years, i.e., all children who have not reached the age of 13 are included. The number of EES analyses cover ages 0–12 years, i.e., until the day the child turns twelve. The calculation was made on the date of birth, resulting in a difference of approximately one year.The data obtained from the Swedish eHealth Agency were extracted, delivered, and handled in an aggregated form with no data on the individual level. The study did not include any intervention or changes to the ordinary work at pharmacies. The researchers did not affect the use of the EES system, and only analyzed data generated. Thus, ethical approval was not necessary.The use of EES, i.e., the number of EES analyses, has increased markedly during the period March 2020–March 2022, both for the total population and the pediatric population. Events that may have affected the use of EES, i.e., the number of EES analyses, were marked in figures following weeks . The neeThere are large variations in the use of EES during the period analyzed . The levThe focus week during week 43 of year 2020 focused on pediatrics. This coincides with the clear increased EES use in children during this week. The number of analyses per week was 12,802 in week 42 of 2020 and 21,527 in week 43 of 2020, resulting in an almost twofold increase . See SupThe amount of dispensing maintains a relatively even level, in comparison with the increased level of EES use as seen by the change of the black line . The amoWhen comparing the number of EES analyses and the proportion of individuals receiving an EES analysis during each of the five reference weeks there is a clear increase between each week for both the total population and the pediatric population . For patThe same week, alerts that were closed in the system of patients aged 0–12 years represented almost 2.8% of the alerts. Each time the pharmacists use EES, one or more alerts can be generated. The number of EES alerts for patients aged 0–12 years was 30,870 during week 11 of year 2022, which gives an average number of alerts per EES analysis of 1.1. The numbers and proportions of EES analyses varied during the five weeks of measurements, but similarity in the changes of numbers of patients receiving an EES analysis are observed when comparing patients of all ages and patients aged 0–12 years. See The most common type of alert for a potential DRP that was resolved, i.e., alerts being closed, among pediatric patients aged 0–12 years during week 11 of 2022 was therapy duplication, for which 4.6% of alerts were resolved . The mosThe most common type of generated alert for a potential DRP among pediatric patients aged 0–12 years during week 11 of 2022 was high dose pediatric  . Other cTo our knowledge, this nationwide study is the first analyzing the type of alerts generated by the EES system for the pediatric population with a focus on how these were resolved, i.e., the reason for closing the alert. This study shows that the number of EES analyses increased for both the total population and the pediatric population (ages 0–12 years). The number of closed alerts increased as well, although the proportion of alerts being closed was still as low as 2.5% of all alerts in 2022. The most common type of generated alert for a potential DRP among pediatric patients was high dose pediatric . The most common type of alert for a potential DRP that was resolved among pediatrics was therapy duplication . The most common reason for closing an alert was dialogue with patient for verification of the treatment .Despite the large variations in the use of EES during the period analyzed, the statistics showed an increase during each focus week. Results from a previous study in 2020  showed aThe proportion of the pediatric population receiving an EES analysis in week 11 of year 2022 seems to be quite similar to the proportion for the total population . CompariIt is not feasible to analyze any effect of the removal of the need for patients’ consent to perform an EES analysis due to the timeline of the obtained data. Data begin from week 11 of year 2020 and the consent was removed week 23 of year 2020. However, in previous studies , this waOn 1 May 2021, a new law on a national medication list (NLL) came into force in Sweden, providing a nationwide source of information about a patient’s prescribed and dispensed medications . The proOne of the main challenges with implementing a CDSS is the risk of non-relevant alerts taking up time and attention, and EES is not an exception. One reason for some alerts not being relevant is that analyses are based on a list of prescriptions that contains many errors and non-current medications. One recent study showed that one third of patients had at least one discrepancy in their list of prescriptions, which is the same list used to generate EES alerts . A shareIn other settings it has previously been shown that CDSS can decrease prescribing errors and wrong doses in children ,28. LittA previous study , which fChildren are a distinct and heterogeneous group of patients that differ from adults regarding pharmacokinetics, pharmacodynamics, and medicine-related toxicity . “High dThe most common DRPs in prescribing among pediatric outpatients aged 0 to 16 years in Vietnam is “dose selection” and “dose timing relative to meals”, according to a study from 2021 . In lineThe proportion of alerts being closed for the pediatric population is about 2.8% , which is quite similar to the findings for the total population in a previous study , 2.1% , and with the first Swedish case being confirmed 31 January 2020, data after this date have only been analyzed. Future studies may fill in this knowledge gap. Furthermore, insufficient data has been obtained to study any effect of the latest focus week . Thus, there is room for further research that may provide valuable knowledge about the use of EES.No analyses have been carried out on the pharmacists’ reasoning to the kinds of actions that were taken to resolve the generated alerts. Analyses of which the most common type of combined drugs that generated the signal “interactions” was not possible either. Future studies should investigate this, and the clinical relevance of the generated alerts. Pediatrics are a very vulnerable group, and so a great deal of focus should be put on understanding the potential DRPs that are generated using the CDSS EES.The use of EES, i.e., the number of EES analyses, has increased for both the total population and the pediatric population. The most common type of generated alert for a potential DRP among children aged 0–12 years was high dose warning for pediatric patients. The results regarding which types of alert are the most common may contribute to an increased prescriber awareness of important potential DRPs. The most common type of alert for a potential DRP that was resolved was therapy duplication . The two most common reasons for closing an alert are dialogue with patient for verification of the treatment and pharmaceutical assessment. The clinical effect from using this system is however unclear, and the clinical relevance of the generated alerts for pediatric patients cannot be assessed. The lack of patient-specific information contributes to the difficulty of drawing any conclusions. Despite the number of closed alerts also having increased, it is still very low.


Sir,There is increasing interest in the use of vitamins and minerals for preeclampsia prophylaxis. On current evidence, however, the systematic review by Christiansen et al.Nevertheless, we believe the existing literature indicates that multivitamins may reduce the risk of preeclampsia. To start with, considering the limited evidence base identified by Christiansen et al.,Accordingly, we performed a random effects meta‐analysis including the aforementioned randomized controlled trials (RCTs).I2 = 39%, P = 0.13). Meanwhile, subgroup analyses found a reduced risk of preeclampsia with multivitamin use in women with a body mass index (BMI) ≥25 but not in women with BMI <25.Turning to the non‐significant meta‐analysis of adjusted observational data by Christiansen et al.,In conclusion, there is evidence of moderate certainty that multivitamin use may be beneficial for women at increased risk of preeclampsia (including having low antioxidant levels), with downgrading of evidence due to differences in population and intervention. However, the certainty of evidence for multivitamin use in healthy women is low, being based largely on observational data. Nevertheless, it is unclear whether the decreased risk is driven by certain multivitamin components (eg calciumACQL and CCWL conceived the study, and wrote and reviewed the manuscript. ACQL performed the statistical analyses.