Retinoschisin Is Required for Pineal Gland Calcification and Cellular Communication in Pinealocytes of Rats and Mice.

Retinoschisin (RS1) is a secretory protein specifically localized to the extracellular domains in both the lateral retina and the pineal gland (PG). However, the functions of RS1 in the pineal body are poorly understood. To address this knowledge gap, in this study, we undertook histochemical, ultrastructural, and Western blotting analyses of the PG in rats and RS1-knock-in transgenic. We found that RS1 plays a key role in pineal gland calcification (PGC) in mice through both extracellular and intracellular pathways. RS1 was clustered around the cell membrane or intracellularly in pinealocytes, actively participating in the exchange of calcium and thereby mediating PGC. Additionally, RS1 deposition is essential for maintaining PGC architecture in the intercellular space of the adult PG. In RS1-knock-in mice with a nonsense mutation (p.Y65X) in the Rs1-domain of RS1, the Rs1-domain is chaotically dispersed in pinealocytes and the intercellular region of the PG. This prevents RS1 from binding calcified spots and forming calcified nodules, ultimately leading to the accumulation of calcareous lamellae in microvesicles. Additionally, RS1 was observed to colocalize with connexin-36, thereby modulating intercellular communication in the PG of both rats and mice. Our study revealed for the first time that RS1 is essential for maintaining PGC architecture and that it colocalizes with connexin 36 to modulate intercellular communication in the PG. These findings provide novel insights into the function of the RS1 gene in the PG.

Best-corrected visual acuity results facilitate molecular diagnosis of infantile nystagmus patients harboring FRMD7 mutations.

The visual function of patients with infantile nystagmus (IN) can be significantly decreased owing to constant eye movement. While, reaching a definitive diagnosis becomes a challenge due to genetic heterozygous of this disease. To address it, we investigated whether best-corrected visual acuity (BCVA) results can facilitate the molecular diagnosis of IN patients harboring FRMD7 mutations. 200 patients with IN from 55 families and 133 sporadic cases were enrolled. Mutations were comprehensively screened by direct sequencing using gene-specific primers for FRMD7. We also retrieved related literature to verify the results based on our data. We found that the BCVA of patients with IN harboring FRMD7 mutations was between 0.5 and 0.7, which was confirmed by data retrieved from the literature. Our results showed that BCVA results facilitate the molecular diagnosis of patients with IN harboring FRMD7 mutations. In addition, we identified 31 FRMD7 mutations from the patients, including six novel mutations, namely, frameshift mutation c.1492_1493insT (p.Y498LfsTer14), splice-site mutation c.353C > G, three missense mutations [c.208C > G (p.P70A), c.234G > A (p.M78I), and c.1109G > A (p.H370R)], and nonsense mutation c.1195G > T (p.E399Ter). This study demonstrates that BCVA results may facilitate the molecular diagnosis of IN patients harboring FRMD7 mutations.

Evidence mapping of clinical practice guidelines recommendations and quality for depression in children and adolescents.

This study systematically reviewed the clinical practice guidelines (CPGs) for depression in children and adolescents and assessed the quality and recommendation consistency of those CPGs. Evidence mapping was presented to illustrate the research trends and identify gaps to guide future research. Literature on CPGs for depression was systematically collected from PubMed, Embase, Web of Science, guideline databases, and psychiatric association/ society websites. The basic information, recommendations, methodological quality, and reporting quality of CPGs were extracted, and the supporting evidence strength for the included CPGs was analyzed in Excel. Four appraisers independently assessed the eligible CPGs using AGREE II instrument and the RIGHT checklist. All recommendations from the CPGs were summarized and analyzed, and the evidence mapping bubble charts were plotted in Excel. After excluding 15,184 records, 12 depression CPGs were eventually proved eligible, six of which were of high quality and six medium quality. A total of 39 major recommendations were summarized, 35 of which were supported by high-quality CPGs. Although direct comparisons are challenging due to differences in grading schemes and research quality, most CPGs share many pivotal recommendations that can help guide clinical practice. However, the evidence for some clinical problems is still lacking. Thus, more research is necessary on the screening and treatment of children and adolescents to put forward more evidence-based and high-quality recommendations.

Quality and clinical applicability of recommendations for incontinence-associated dermatitis: A systematic review of guidelines and consensus statements.

AIMS AND OBJECTIVES: The aim of this study was to assess methodological quality of all currently available guidelines and consensus statements for IAD using the Appraisal of Guidelines, Research and Evaluation (AGREE) II and the AGREE Recommendation Excellence (AGREE-REX) instruments. BACKGROUND: Globally, incontinence-associated dermatitis (IAD) is a significant health challenge. IAD is a complex healthcare problem that reduces quality of life of patients, increases healthcare costs and prolongs hospital stays. Several guidelines and consensus statements are available for IAD. However, the quality of these guidelines and consensus statements remains unclear. DESIGN: A systematic review of guidelines and consensus statements. METHODS: Our study was undertaken using PRISMA guidelines. We searched seven electronic databases. Guidelines and consensus statements had to be published in English, Chinese or German languages. Five independent reviewers assessed the methodological quality of guidelines and consensus statements using the AGREE II and AGREE-REX instruments. Mean with standard deviation (SD) and median with interquartile range (IQR) were calculated for descriptive analyses. We generated bubble plots to describe the assessment results of each domain of each guideline and consensus statement. RESULTS: We included ten guidelines and consensus statements. The NICE guidelines, obtained the highest scores, fulfilled 86.11%-98.61% of criteria in AGREE II and 76.67%-91.11% for AGREE-REX. In the domains 'Stakeholder Involvement' (4.39 ± 1.64), 'Rigor of Development' (3.38 ± 1.86), 'Applicability' (3.62 ± 1.64), 'Editorial Independence' (3.91 ± 2.56) and 'Values and Preferences' (2.98 ± 1.41), the remaining guidelines and consensus statements showed deficiencies. CONCLUSIONS: Altogether, this study demonstrated that the currently available guidelines and consensus statements for IAD have room for methodological improvement. NICE guidelines on faecal incontinence and urinary incontinence have better quality. Remaining guidelines and consensus statements showed substantial methodological weaknesses, especially the domains of 'Stakeholder Involvement', 'Rigor of Development', 'Applicability', 'Editorial independence' and 'Values and Preferences'. This study was registered on INPLASY. (Registration number: INPLASY202190078). RELEVANCE TO CLINICAL PRACTICE: The currently available guidelines and consensus statements on IAD have room for methodological improvement.

Nervous system diseases are associated with the severity and mortality of patients with COVID-19: a systematic review and meta-analysis.

Coronavirus disease 2019 (COVID-19) has become a global pandemic. Previous studies showed that comorbidities in patients with COVID-19 are risk factors for adverse outcomes. This study aimed to clarify the association between nervous system diseases and severity or mortality in patients with COVID-19. We performed a systematic literature search of four electronic databases and included studies reporting the prevalence of nervous system diseases in COVID-19 patients with severe and non-severe disease or among survivors and non-survivors. The included studies were pooled into a meta-analysis to calculate the odds ratio (OR) with 95% confidence intervals (95%CI). We included 69 studies involving 17 879 patients. The nervous system diseases were associated with COVID-19 severity (OR = 3.19, 95%CI: 2.37 to 4.30, P < 0.001) and mortality (OR = 3.75, 95%CI: 2.68 to 5.25, P < 0.001). Specifically, compared with the patients without cerebrovascular disease, patients with cerebrovascular disease infected with COVID-19 had a higher risk of severity (OR = 3.10, 95%CI: 2.21 to 4.36, P < 0.001) and mortality (OR = 3.45, 95% CI: 2.46 to 4.84, P < 0.001). Stroke was associated with severe COVID-19 disease (OR = 1.95, 95%CI: 1.11 to 3.42, P = 0.020). No significant differences were found for the prevalence of epilepsy (OR = 1.00, 95%CI: 0.42 to 2.35, P = 0.994) and dementia (OR = 2.39, 95%CI: 0.55 to 10.48, P = 0.247) between non-severe and severe COVID-19 patients. There was no significant association between stroke (OR = 1.79, 95%CI: 0.76 to 4.23, P = 0.185), epilepsy (OR = 2.08, 95%CI: 0.08 to 50.91, P = 0.654) and COVID-19 mortality. In conclusion, nervous system diseases and cerebrovascular disease were associated with severity and mortality of patients with COVID-19. There might be confounding factors that influence the relationship between nervous system diseases and COVID-19 severity as well as mortality.

[Analysis of traditional Chinese medicine from patent information sharing platform of coronavirus disease 2019 (COVID-19)].

Coronavirus disease 2019(COVID-19) is a newly emerged and highly contagious respiratory disease. Traditional Chinese medicine(TCM) has both systematism theory knowledge and clinical practical value in the prevention and treatment of COVID-19. Therefore, it was particularly important to examine the effect of TCM in the prevention and treatment of COVID-19. The patents of TCM might reflect the latest progression of scientific research. We aimed to provide reference for the prevention and treatment of COVID-19 by extracting and analyzing the TCM patents from the Patent Information Sharing Platform of COVID-19. The antiviral TCM patents were screened and exported from the Patent Information Sharing Platform. VOSviewer 1.6.14 was used to visualize and analyze the network of TCM in these patents. There were total 292 TCM patents, including 52 patents for etiological treatment and 240 patents for symptomatic treatment. Thirty-two provinces and 1 076 inventors were involved, mainly from Beijing, Guangdong and Jiangsu. Overall, there were 356 TCMs, 71 single prescriptions, and 221 compound prescriptions. The patents for treatment of coronavirus mainly focused on the treatment of coronavirus, while the patents for symptomatic treatment mainly focuses on the improvement of respiratory symptoms, such as fever and cough. There were 14 highly frequently used TCMs, including Glycyrrhizae Radix et Rhizoma, Scutellariae Radix, Lonicerae Japonicae Flos, Forsythiae Fructus, Isatidis Radix, Astragali Radix, Menthae Haplocalycis Herba, Gypsum Fibrosum, Houttuyniae Herba, Isatidis Folium, Rhei Radix et Rhizoma, Gardeniae Fructus, Platycodonis Radix, Armeniacae Semen Amarum. The analyzed results of the TCM patents from the patent information sharing platform of COVID-19 were consistent with the Guideline of Diagnosis and Treatment of COVID-19(7th edition), and the combination of TCM in each cluster may also provide future directions for drug compatibility.

Structure-Based Optimization of One Neutralizing Antibody against SARS-CoV-2 Variants Bearing the L452R Mutation.

Neutralizing antibodies (nAbs) play an important role against SARS-CoV-2 infections. Previously, we have reported one potent receptor binding domain (RBD)-binding nAb Ab08 against the SARS-CoV-2 prototype and a panel of variants, but Ab08 showed much less efficacy against the variants harboring the L452R mutation. To overcome the antibody escape caused by the L452R mutation, we generated several structure-based Ab08 derivatives. One derivative, Ab08-K99E, displayed the mostly enhanced neutralizing potency against the Delta pseudovirus bearing the L452R mutation compared to the Ab08 and other derivatives. Ab08-K99E also showed improved neutralizing effects against the prototype, Omicron BA.1, and Omicron BA.4/5 pseudoviruses. In addition, compared to the original Ab08, Ab08-K99E exhibited high binding properties and affinities to the RBDs of the prototype, Delta, and Omicron BA.4/5 variants. Altogether, our findings report an optimized nAb, Ab08-K99E, against SARS-CoV-2 variants and demonstrate structure-based optimization as an effective way for antibody development against pathogens.

Establishing a nutrition calculation model for catering food according to the influencing factors of energy and nutrient content in food processing.

Objective: This study aimed to establish an accurate and efficient scientific calculation model for the nutritional composition of catering food to estimate energy and nutrient content of catering food. Methods: We constructed a scientific raw material classification database based on the Chinese food composition table by calculating the representative values of each food raw material type. Using China's common cooking methods, we cooked 150 dishes including grains, meat, poultry, fish, eggs, and vegetables and established a database showing the raw and cooked ratios of various food materials by calculating the ratio of raw to cooked and the China Total Diet Research database. The effects of various cooking methods on the nutritional composition of catering food were analyzed to determine correction factors for such methods on the nutritional components. Finally, we linked the raw material classification, raw and cooked ratio, and nutritional component correction factor databases to establish a model for calculating the nutritional components of catering food. The model was verified with nine representative Chinese dishes. Results: We have completed the construction of an accurate and efficient scientific calculation model for the nutritional composition of catering food, which improves the accuracy of nutrition composition calculation. Conclusion: The model constructed in this study was scientific, accurate, and efficient, thereby promising in facilitating the accurate calculation and correct labeling of nutritional components in catering food.

Risk factors and consequences of mental health problems in nurses: A scoping review of cohort studies.

Mental health problems in nurses are prevalent and impairing. To date, no literature has comprehensively synthesised cohort evidence on mental health among nurses. This scoping review aimed to synthesise the existing literature on the risk factors and consequences of mental health problems in nurses. A systematic search was conducted on PubMed, EMBASE, Epistemonikos database, Web of Science, CINAHL, and PsycINFO from inception to March 2023. We identified 171 cohort studies from 16 countries, mostly (95.3%) from high-income economies. This review indicated that nurses worldwide encountered significant mental health challenges, including depression, cognitive impairment, anxiety, trauma/post-traumatic stress disorder, burnout, sleep disorder, and other negative mental health problems. These problems were closely related to various modifiable risk factors such as nurses' behaviours and lifestyles, social support, workplace bullying and violence, shift work, job demands, and job resources. Moreover, nurses' mental health problems have negative effects on their physical health, behaviour and lifestyle, occupation and organisation, and intrapersonal factors. These findings provided an enhanced understanding of mental health complexities among nurses, and shed light on policy enactment to alleviate the negative impact of mental health problems on nurses. Addressing mental health among nurses should be a top priority.

A blueprint for tumor-infiltrating B cells across human cancers.

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.

Mirk/Dyrk1B mediates G0/G1 to S phase cell cycle progression and cell survival involving MAPK/ERK signaling in human cancer cells.

BACKGROUND: Mirk/Dyrk1B contributes to G0 arrest by destabilization of cyclin D1 and stabilization of p27kip1 to maintain the viability of quiescent human cancer cells, and it could be negatively regulated by mitogenic-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling. This study was performed to investigate the effect of Mirk/Dyrk1B on cell cycle and survival of human cancer cells involving MAPK/ERK signaling. METHODS: The correlations between Mirk/Dyrk1B expression and active ERK1/2 detected by western blot in both ovarian cancer and non-small cell lung cancer (NSCLC) cells were analyzed by simple regression. Mirk/Dyrk1B unique phosphopeptides with sites associated with Mirk/Dyrk1B protein were isolated and quantitated by liquid chromatography coupled to tandem mass/mass spectrometry (LC-MS/MS) proteomics analysis. The human cancer cells were treated with small interfering RNAs (siRNAs) and/or U0126, an inhibitor of MEK for indicated duration, followed by investigating the alterations of cell cycle and apoptosis as well as related proteins examined by flow cytometry and Western blot, respectively. RESULTS: Our study demonstrated the widely expressed Mirk/Dyrk1B proteins in the human cancer cells were positively correlated with the levels of activated ERK1/2. Moreover, Mirk/Dyrk1B protein expressions consistent with the tyrosine autophosphorylated levels in the human cancer cells were increased by U0126 or growth factor-depleted culture. Conversely, knockdown of Mirk/Dyrk1B by siRNA led to up-regulated activation of c-Raf-MEK-ERK1/2 pathway and subsequent changes in cell cycle proteins (cyclin D1, p27kip1), accompanied by increased growth rate and cells from G0/G1 into S of cell cycle which could be blocked by U0126 in a dose-dependent manner, indicating Mirk/Dyrk1B may sequester MAPK/ERK pathway, and vice versa. Whereas, combined Mirk siRNA and U0126 induced cell apoptosis in the human cancer cells. CONCLUSIONS: These data together show that Mirk/Dyrk1B mediates cell cycle and survival via interacting with MAPK/ERK signals and simultaneous inhibition of both pathways may be a novel therapeutic target for human cancer.

[Relationship between single nucleotide polymorphism in repair gene XPD751 and prognosis in colorectal carcinoma patients].

OBJECTIVE: To investigate whether single nucleotide polymorphism (SNP) in DNA repair gene XPD751 is associated with sensitivity and time to progression (TTP) for platinum-containing combination chemotherapy in advanced colorectal carcinoma. METHODS: A total of 98 patients pathologically diagnosed as advanced colorectal cancer were treated with FOLFOX chemotherapy. TheDNA of peripheral blood-leukocytes was obtained before treatment, and XPD genetype was detected by PCR-RFLP analysis. RESULTS: The frequency of XPD751 Lys/lys was 76 cases (77.6%), lys/Gln 17 cases (17.4%), and Gln/Gln genetype 5 cases (5.1%). The effective rate of FOLFOX chemotherapy among patients with XPD751 Lys/lys was 50.0%, lys/Gln 29.4%, and Gln/Gln genetypes 20.0%. The difference between Lys/lys and lys/Gln was statistically significant, χ(2) = 4.04, P < 0.05. The results indicated that the failure of chemotherapy in patients with Lys/Lys genetype was 3.8-fold to those with Lys/Gln, by adjusting of gender, age, and tumor metastasis (OR = 3.800). The MTTP of the 98 patients was 10.1 months. The MTTP was 11.3 months for patients with Lys/Lys genotypes of XPD751 gene and 2.9 months for patients with Lys/Gln and Gln/Gln genotypes of XPD751 gene, the difference between Lys/Lys and at least one Gln was significant (P < 0.05). CONCLUSIONS: Single nucleotide polymorphism of XPD751 correlates with the clinical response to FOLFOX chemotherapy. XPD751 genetic polymorphisms may be associated with TTP of advanced colorectal carcinoma patients treated with oxaliplatin as the first line chemotherapy. XPD751 genotype detected by the PCR-RFLP method may be a predictor of prognosis for FOLFOX chemotherapy.

Can SpRY recognize any PAM in human cells?

The application of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) can be limited due to a lack of compatible protospacer adjacent motif (PAM) sequences in the DNA regions of interest. Recently, SpRY, a variant of Streptococcus pyogenes Cas9 (SpCas9), was reported, which nearly completely fulfils the PAM requirement. Meanwhile, PAMs for SpRY have not been well addressed. In our previous study, we developed the PAM Definition by Observable Sequence Excision (PAM-DOSE) and green fluorescent protein (GFP)|-reporter systems to study PAMs in human cells. Herein, we endeavored to identify the PAMs of SpRY with these two methods. The results indicated that 5'-NRN-3', 5'-NTA-3', and 5'-NCK-3' could be considered as canonical PAMs. 5'-NCA-3' and 5'-NTK-3' may serve as non-priority PAMs. At the same time, PAM of 5'-NYC-3' is not recommended for human cells. These findings provide further insights into the application of SpRY for human genome editing.

Establishing a core outcome set for neurogenic bladder trials: study protocol for a scoping review and Delphi surveys.

BACKGROUND: Neurogenic bladder (NGB) is a chronic and disabling condition with a high prevalence rate, which can cause economic burden on patients and their families and reduce the quality of life of patients. Researchers have carried out a large number of clinical trials on the effectiveness and safety of different interventions for the treatment of NGB. The published clinical trials of NGB generally suffered from inconsistent and irregular reporting of outcome indicators. To facilitate future research studies of NGB, a core outcome set (COS) is required, which helps translate the results into high-quality evidence. METHODS AND ANALYSIS: This mixed-method project has four phases instrument: in phase 1, a scoping review of the literature to identify outcomes that have been reported in clinical trials and systematic reviews of clinical trials of interventions for NGB; in phase 2, a qualitative component using interviews to obtain the views of NGB patients, families, and their caregivers; in phase 3, Delphi survey among stakeholders to prioritize the core outcomes; and in phase 4, a face-to-face consensus meeting to discuss and agree on the final NBG COS. CONCLUSIONS: We will develop a COS that should be reported in future clinical trials of NGB. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) Initiative database registration: http://www.comet-initiative.org/studies/details/1985 . Registered on 02 January 2022. INPLASY  INPLASY202210007.

The standards of obstetrics and gynecology core outcome sets: A scoping review.

BACKGROUND: Core outcome sets (COSs) are the minimum outcomes which should be measured and reported by researchers investigating a specific condition. The definition of standards of COSs vary across different health-related areas. This investigated the characteristics of COSs regarding obstetrics and gynecology (OG) and examined the reports and designs of standards of OG COSs. METHODS: A comprehensive search was conduced on the COMET database on December 20, 2019 to identify systematic reviews on COSs. Two reviewers independently evaluated whether the reported OG COS met the reporting requirements as stipulated in the Core Outcome Set-STAndards for Reporting (COS-STAR) statement checklist and the minimum design recommendations as outlined in the Core Outcome Set-STAndards for Development (COS-STAD) checklist. RESULTS: Forty-four OG COSs related to 26 topics were identified. None of them met all the 25 standards of COS-STAR statement which representing 18 items considered essential for transparent and complete reporting list for all COS studies (range: 6.0-24.0, median: 14.0). The compliance rates to 16 standards of methods and result sections ranged from 27.3%-68.2%. Total COS-STAR compliance items for OG COSs with the prior protocol was significantly higher than without prior protocol (MD = 3.846, 95% CI: 0.835-6.858, P = 0.012). None of the OG COSs met all the 12 criteria in the COS-STAD minimum standards (range: 3.0-11.0, median: 5.0). The compliance rates for all three standards of stakeholders involved and all four standards of the consensus process were lower than 60%. CONCLUSIONS: Methodological and reporting standards of OG COSs should be improved.

Effect of light-emitting diodes with different color rendering indexes on the ocular tissues of rat.

AIM: To compare the damage of light-emitting diodes (LEDs) with different color rendering indexes (CRIs) to the ocular surface and retina of rats. METHODS: Totally 20 Sprague-Dawley (SD) rats were randomly divided into four groups: the first group was normal control group without any intervention, other three groups were exposed by LEDs with low (LED-L), medium (LED-M), and high (LED-H) CRI respectively for 12h a day, continuously for 4wk. The changes in tear secretion (Schirmer I test, SIt), tear film break-up time (BUT), and corneal fluorescein sodium staining (CFS) scores were compared at different times (1d before experiment, 2 and 4wk after the experiment). The histopathological changes of rat lacrimal gland and retina were observed at 4wk, and the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lacrimal gland were detected by immunofluorescence method. RESULTS: With the increase of light exposed time, the CFS value of each light exposed group continued to increase, and the BUT and SIt scores continued to decrease, which were different from the control group, and the differences between the light exposed groups were statistically significant. Hematoxylin-eosin (HE) results showed that the lacrimal glands of each exposed group were seen varying degrees of acinar atrophy, vacuole distribution, increasing of eosinophil granules, etc.; the retina showed obvious reduction of photoreceptor cell layer and changes in retinal thickness; LED-L group has the most significant change in all tests. Immunofluorescence suggested that the positive expressions of TNF-α and IL-6 in the lacrimal glands of each exposed group were higher than those of the control group. CONCLUSION: LED exposure for 4wk can cause the pathological changes of lacrimal gland and retina of rats, and increase the expression of TNF-α and IL-6 in lacrimal gland, the degree of damage is negatively correlated with the CRI.

A multi-center effectiveness comparison study of fruquintinib with constructed external control cohort of other targeted kinase inhibitors using real-world data in third-line treatment of metastatic colorectal cancer.

Objective: The objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs. Materials and methods: The arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan-Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively. Results: Overall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95%CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042). Conclusion: With the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as third-line mCRC treatment.

Comparative efficacy and acceptability of cognitive behavioral therapy delivery formats for insomnia in adults: A systematic review and network meta-analysis.

This review compared the efficacy and acceptability of different delivery formats for cognitive behavioral therapy for insomnia (CBT-I) in insomnia. We searched five databases for randomized clinical trials that compared one CBT-I delivery format against another format or control conditions for insomnia in adults. We used pairwise meta-analyses and frequentist network meta-analyses with the random-effects model to synthesize data. A total of 61 unique trials including 11,571 participants compared six CBT-I delivery formats with four control conditions. At post-intervention, with low to high certainty evidence, individual, group, guided self-help, digital assisted, and unguided self-help CBT-I could significantly increase sleep efficiency and total sleep time (TST) and reduce sleep onset latency (SOL), wake after sleep onset (WASO), and insomnia severity compared with treatment as usual (MD range for sleep efficiency: 7.81%-12.45%; MD range for TST: 16.14-33.96 min; MD range for SOL: -22.42 to -13.81 min; MD range for WASO: -40.84 to -19.48 min; MD range for insomnia severity: -6.40 to -3.93) and waitlist (MD range for sleep efficiency: 7.68%-12.32%; MD range for TST: 12.67-30.49 min; MD range for SOL: -19.07 to -10.46 min; MD range for WASO: -47.10 to -19.15 min; MD range for insomnia severity: -7.59 to -5.07). The effects of different CBT-I formats persisted at short-term follow-up (4 wk-6 mo). Individual, group, and digital assisted CBT-I delivery formats would be the more appropriate choices for insomnia in adults, based on post-intervention and short-term effects. Further trials are needed to investigate the long-term effects of different CBT-I formats.

Cognitive behavior therapy for insomnia in cancer patients: a systematic review and network meta-analysis.

OBJECTIVE: The aim of this study was to examine the most effective delivery format of cognitive behavioral therapy for insomnia (CBT-I) on insomnia in cancer patients. METHODS: We searched five databases up to February 2021 for randomized clinical trials that compared CBT-I with inactive or active controls for insomnia in cancer patients. Outcomes were insomnia severity, sleep efficiency, sleep onset latency (SOL), wake after sleep onset (WASO), and total sleep time (TST). Pairwise meta-analyses and frequentist network meta-analyses with the random-effects model were applied for data analyses. RESULTS: Sixteen unique trials including 1523 participants met inclusion criteria. Compared with inactive control, CBT-I could significantly reduce insomnia severity (mean differences [MD] = -4.98 points, 95% confidence interval [CI]: -5.82 to -4.14), SOL (MD = -12.29 min, 95%CI: -16.48 to -8.09), and WASO (MD = -16.58 min, 95%CI: -22.00 to -11.15), while increasing sleep efficiency (MD = 7.62%, 95%CI: 5.82% to 9.41%) at postintervention. Compared with active control, CBT-I could significantly reduce insomnia severity (MD = -2.75 points, 95%CI: -4.28 to -1.21), SOL (MD = -13.56 min, 95%CI: -18.93 to -8.18), and WASO (MD = -6.99 min, 95%CI: -11.65 to -2.32) at postintervention. These effects diminished in short-term follow-up and almost disappeared in long-term follow-up. Most of the results were rated as "moderate" to "low" certainty of evidence. Network meta-analysis showed that group CBT-I had an increase in sleep efficiency of 10.61%, an increase in TST of 21.98 min, a reduction in SOL of 14.65 min, and a reduction in WASO of 24.30 min, compared with inactive control at postintervention, with effects sustained at short-term follow-up. CONCLUSIONS: CBT-I is effective for the management of insomnia in cancer patients postintervention, with diminished effects in short-term follow-up. Group CBT-I is the preferred choice based on postintervention and short-term effects. The low quality of evidence and limited sample size demonstrate the need for robust evidence from high-quality, large-scale trials providing long-term follow-up data.