The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

OBJECTIVES: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

Arabidopsis cyclophilins direct intracellular transport of mobile mRNA via organelle hitchhiking.

Plants convert external cues into mobile mRNAs to synchronize meristematic differentiation with environmental dynamics. These mRNAs are selectively transported to intercellular pores, plasmodesmata (PD), for cell-to-cell movement. However, how plants recognize and deliver mobile mRNAs to PD remains unknown. Here we show that mobile mRNAs hitchhike on organelle trafficking to transport towards PD. Perturbed cytoskeleton organization or organelle trafficking severely disrupts the subcellular distribution of mobile mRNAs. Arabidopsis rotamase cyclophilins (ROCs), which are organelle-localized RNA-binding proteins, specifically bind mobile mRNAs on the surface of organelles to direct intracellular transport. Arabidopsis roc mutants exhibit phenotype alterations and disruptions in the transport of mobile mRNAs. These findings suggest that ROCs play a crucial role in facilitating the systemic delivery of mobile mRNAs. Our results highlight that an RNA-binding protein-mediated hitchhiking system is specifically recruited to orient plant mobile mRNAs for intercellular transport.

Fluid flow-induced modulation of viability and osteodifferentiation of periodontal ligament stem cell spheroids-on-chip.

Developing physiologically relevant in vitro models for studying periodontitis is crucial for understanding its pathogenesis and developing effective therapeutic strategies. In this study, we aimed to integrate the spheroid culture of periodontal ligament stem cells (PDLSCs) within a spheroid-on-chip microfluidic perfusion platform and to investigate the influence of interstitial fluid flow on morphogenesis, cellular viability, and osteogenic differentiation of PDLSC spheroids. PDLSC spheroids were seeded onto the spheroid-on-chip microfluidic device and cultured under static and flow conditions. Computational analysis demonstrated the translation of fluid flow rates of 1.2 µl min-1 (low-flow) and 7.2 µl min-1 (high-flow) to maximum fluid shear stress of 59 µPa and 360 µPa for low and high-flow conditions, respectively. The spheroid-on-chip microfluidic perfusion platform allowed for modulation of flow conditions leading to larger PDLSC spheroids with improved cellular viability under flow compared to static conditions. Modulation of fluid flow enhanced the osteodifferentiation potential of PDLSC spheroids, demonstrated by significantly enhanced alizarin red staining and alkaline phosphatase expression. Additionally, flow conditions, especially high-flow conditions, exhibited extensive calcium staining across both peripheral and central regions of the spheroids, in contrast to the predominantly peripheral staining observed under static conditions. These findings highlight the importance of fluid flow in shaping the morphological and functional properties of PDLSC spheroids. This work paves the way for future investigations exploring the interactions between PDLSC spheroids, microbial pathogens, and biomaterials within a controlled fluidic environment, offering insights for the development of innovative periodontal therapies, tissue engineering strategies, and regenerative approaches.

Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair.

DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20-150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.

Facile and Unplugged Surface Plasmon Resonance Biosensor with NIR-Emitting Perovskite Nanocomposites for Fast Detection of SARS-CoV-2.

The emergence of the coronavirus disease 2019 (COVID-19) pandemic prompted researchers to develop portable biosensing platforms, anticipating to detect the analyte in a label-free, direct, and simple manner, for deploying on site to prevent the spread of the infectious disease. Herein, we developed a facile wavelength-based SPR sensor built with the aid of a 3D printing technology and synthesized air-stable NIR-emitting perovskite nanocomposites as the light source. The simple synthesis processes for the perovskite quantum dots enabled low-cost and large-area production and good emission stability. The integration of the two technologies enabled the proposed SPR sensor to exhibit the characteristics of lightweight, compactness, and being without a plug, just fitting the requirements of on-site detection. Experimentally, the detection limit of the proposed NIR SPR biosensor for refractive index change reached the 10-6 RIU level, comparable with that of state-of-the-art portable SPR sensors. In addition, the bio-applicability of the platform was validated by incorporating a homemade high-affinity polyclonal antibody toward the SARS-CoV-2 spike protein. The results demonstrated that the proposed system was capable of discriminating between clinical swab samples collected from COVID-19 patients and healthy subjects because the used polyclonal antibody exhibited high specificity against SARS-CoV-2. Most importantly, the whole measurement process not only took less than 15 min but also needed no complex procedures or multiple reagents. We believe that the findings disclosed in this work can open an avenue in the field of on-site detection for highly pathogenic viruses.

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2.

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

A qualitative study on the influencing factors of parents′ participation in emotional management of adolescents with affective disorder / 中国实用护理杂志

Objective:To understand the barriers and facilitators to parental involvement in emotionally disturbed adolescents′ emotion management and to provide a basis for healthcare professionals to develop interventions for parental involvement in emotionally disturbed adolescents′ emotion management.Methods:Use of purposive sampling method from July to December 2021, 16 face-to-face semi-structured in-depth interviews were conducted with fathers or mothers of adolescents with affective disorders from the Third Hospital of Daqing City, and the data were analyzed using the Colaizzi 7-step analysis method.Results:Refining the theme from two aspects, one was the hindering factors: parents′ own factors including lack of knowledge about the disease, little time for companionship, poor emotional control, inappropriate communication style, and poor couple relationship; the child′s own factors including pathological factors, personality; environmental factors including academic stress, interpersonal relationships; economic factors including high cost of treatment, life stress. The other was the facilitating factors: support from others including family support, professional help; positive coping including finding coping strategies, change of mindset.Conclusions:Healthcare professionals should pay attention to these influencing factors and construct a program for parental involvement in emotionally disturbed adolescents′ emotion management from various aspects, so that parents can actively participate in their children′s emotion management and promote the rehabilitation of emotionally disturbed adolescents.

Boosting the detection performance of severe acute respiratory syndrome coronavirus 2 test through a sensitive optical biosensor with new superior antibody.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in late 2019 leading to the COVID-19 disease pandemic that triggered socioeconomic turmoil worldwide. A precise, prompt, and affordable diagnostic assay is essential for the detection of SARS-CoV-2 as well as its variants. Antibody against SARS-CoV-2 spike (S) protein was reported as a suitable strategy for therapy and diagnosis of COVID-19. We, therefore, developed a quick and precise phase-sensitive surface plasmon resonance (PS-SPR) biosensor integrated with a novel generated anti-S monoclonal antibody (S-mAb). Our results indicated that the newly generated S-mAb could detect the original SARS-CoV-2 strain along with its variants. In addition, a SARS-CoV-2 pseudovirus, which could be processed in BSL-2 facility was generated for evaluation of sensitivity and specificity of the assays including PS-SPR, homemade target-captured ELISA, spike rapid antigen test (SRAT), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Experimentally, PS-SPR exerted high sensitivity to detect SARS-CoV-2 pseudovirus at 589 copies/ml, with 7-fold and 70-fold increase in sensitivity when compared with the two conventional immunoassays, including homemade target-captured ELISA (4 × 103 copies/ml) and SRAT (4 × 104 copies/ml), using the identical antibody. Moreover, the PS-SPR was applied in the measurement of mimic clinical samples containing the SARS-CoV-2 pseudovirus mixed with nasal mucosa. The detection limit of PS-SPR is calculated to be 1725 copies/ml, which has higher accuracy than homemade target-captured ELISA (4 × 104 copies/ml) and SRAT (4 × 105 copies/ml) and is comparable with qRT-PCR (1250 copies/ml). Finally, the ability of PS-SPR to detect SARS-CoV-2 in real clinical specimens was further demonstrated, and the assay time was less than 10 min. Taken together, our results indicate that this novel S-mAb integrated into PS-SPR biosensor demonstrates high sensitivity and is time-saving in SARS-CoV-2 virus detection. This study suggests that incorporation of a high specific recognizer in SPR biosensor is an alternative strategy that could be applied in developing other emerging or re-emerging pathogenic detection platforms.

Constructing internal audit quality evaluation index: evidence from listed companies in Jiangsu province, China.

Internal audit quality is the foundation for a company's survival and development across the world. As a result, global efforts have been made to develop a scientific and accurate evaluation index for internal audit quality. However, literature shows that existing internal audit quality evaluation indices have many flaws, such as a lack of systematic internal audit evaluation indicators, poor execution, and inability to identify priority areas. To address gaps in the literature, this study intended to construct an internal audit quality evaluation index utilizing the joint approaches of the Balanced Scorecard, Delphi Process, and Analytical Hierarchy Process. A systematic literature review, examination of companies' internal audit guidelines, Balanced Scorecard, and Delphi approaches resulted in a multilevel internal audit quality evaluation index with five dimensions (stakeholder satisfaction, stakeholder contribution, financial results, internal audit process, and learning and growth) and 36 indicators. The Analytical Hierarchy Process revealed that the most prioritized dimension is the internal audit process. The consistency ratio and evaluation feedback from the listed companies' internal auditors, management, and audit committee members revealed that the results are valid and reliable.

Cas12a-assisted RTF-EXPAR for accurate, rapid and simple detection of SARS-CoV-2 RNA.

Developing highly accurate and simple approaches to rapidly identify and isolate SARS-CoV-2 infected patients is important for the control of the COVID-19 pandemic. We, herein, reported the performance of a Cas12a-assisted RTF-EXPAR strategy for the identification of SARS-CoV-2 RNA. This assay combined the advantages of RTF-EXPAR with CRISPR-Cas12a can detect SARS-CoV-2 within 40 min, requiring only isothermal control. Particularly, the simultaneous use of EXPAR amplification and CRISPR improved the detection sensitivity, thereby realizing ultrasensitive SARS-CoV-2 RNA detection with a detection limit of 3.77 aM (∼2 copies/µL) in an end-point fluorescence read-out fashion, and at 4.81 aM (∼3 copies/µL) level via a smartphone-assisted analysis system (RGB analysis). Moreover, Cas12a increases the specificity by intrinsic sequence-specific template recognition. Overall, this method is fast, sensitive, and accurate, needing minimal equipment, which holds great promise to meet the requirements of point-of-care molecular detection of SARS-CoV-2.

Rapid and sensitive detection of Ebola RNA in an unamplified sample based on CRISPR-Cas13a and DNA roller machine.

A fast and simple Cas13a-based assay approach for direct detecting Ebola RNA in unamplified samples is reported. The procedure (named Cas-Roller) is comprised of a 10-min Cas13a-mediated cleavage protocol, followed by a DNA roller running for 30 min. This involves Cas13a collateral cleaving a suitably designed substrate in the presence of Ebola virus RNA sequence, and the cleavage product is used for DNA roller to amplify and generate fluorescent signals. After optimization of the conditions, the assay is able to achieve a limit of detection as low as 291 aM (∼175 copies RNA/µL) along with excellent anti-interfering performance in human serum and blood detection, which is ∼310-fold improved compared with the direct CRISPR assay. The entire workflow can be completed in ∼40 min at 37 °C without any pre-amplification, transcription, or centrifugation steps, thus avoiding the generation of false-negative or positive results. In addition, the downstream roller reaction is independent of the target sequence, this method can be applied to detect any other RNA by merely redesigning the hybridization regions of the crRNA. Overall, this strategy gives a new idea for the construction of simple and accurate Cas13a-based assays for the direct detection of RNA.

The Effectiveness of Mental Health Literacy Curriculum among Undergraduate Public Health Students.

Mental health literacy (MHL) plays an important role in public health. Improving MHL can promote mental health at the individual and public levels. To date, no published studies have assessed the effectiveness of MHL curriculum interventions among undergraduate public health students. The participants in this study were undergraduate public health students (n = 48) who were enrolled in an 18-week MHL curriculum for 100 min per week. MHL was assessed using the Mental Health Literacy Scale for Healthcare Students. A paired sample t-test was performed to examine the immediate and delayed effects of the MHL curriculum. The total MHL score significantly improved, and a moderate effect size was found directly after the intervention and six weeks later. There were significant differences in the recognition of mental illness (p < 0.01), help-seeking efficacy (p < 0.05), and help-seeking attitude (p < 0.05) in the five components of MHL between pre- and post-test. Furthermore, significant improvements were obtained for the maintenance of positive mental health (p < 0.05) and reduction of mental illness stigma (p < 0.001) between the pre-test and follow-up. Our findings provide evidence for the development and implementation of an MHL curriculum for public health education.

Evaluation of tumour surveillance protocols and outcomes in von Hippel-Lindau disease in a national health service.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the "real world" management of VHL disease. METHODS: A national audit of VHL disease in the United Kingdom. RESULTS: VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention. CONCLUSIONS: In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.

Development of a split fluorescent protein-based RNA live-cell imaging system to visualize mRNA distribution in plants.

BACKGROUND: RNA live-cell imaging systems have been used to visualize subcellular mRNA distribution in living cells. The RNA-binding protein (RBP)-based RNA imaging system exploits specific RBP and the corresponding RNA recognition sequences to indirectly label mRNAs. Co-expression of fluorescent protein-fused RBP and target mRNA conjugated with corresponding RNA recognition sequences allows for visualizing mRNAs by confocal microscopy. To minimize the background fluorescence in the cytosol, the nuclear localization sequence has been used to sequester the RBP not bound to mRNA in the nucleus. However, strong fluorescence in the nucleus may limit the visualization of nucleus-localized RNA and sometimes may interfere in detecting fluorescence signals in the cytosol, especially in cells with low signal-to-noise ratio. RESULTS: We eliminated the background fluorescence in the nucleus by using the split fluorescent protein-based approach. We fused two different RBPs with the N- or C-terminus of split fluorescent proteins (FPs). Co-expression of RBPs with the target mRNA conjugated with the corresponding RNA recognition sequences can bring split FPs together to reconstitute functional FPs for visualizing target mRNAs. We optimized the system with minimal background fluorescence and used the imaging system to visualize mRNAs in living plant cells. CONCLUSIONS: We established a background-free RNA live-cell imaging system that provides a platform to visualize subcellular mRNA distribution in living plant cells.

Clinical characteristics and prognosis of middle-aged and elderly in-patients with acute decompensated and mid-range ejection fraction heart failure in the medical alliance setting / 中华老年医学杂志

Objective:To investigate the clinical characteristics and the risk of major adverse cardiac events within 1 year of middle-aged and elderly in-patients with acute decompensated and mid-range ejection fraction heart failure(HF)in the medical alliance setting.Methods:A retrospective cohort study was conducted among a total of 180 in-patients with acute decompensated heart failure in Cardiovascular Hexi Hospital Consulting Area of Tianjin Chest Hospital.According to ejection fraction measured by echocardiogram, the in-patients were classified into three groups: heart failure with reduced ejection fraction(HFrEF)group(n=70, 38.9%), HFmEF group(n=50, 27.8%), and heart failure with preserved ejection fraction(HFpEF)group(n=60, 33.3%). Clinical feature and 1-year prognosis between different groups were compared.Results:Univariate Cox regression analysis of 1-year all-cause death and cardiovascular death showed that there was no significant difference between HFrEF group and HFmEF group, HFpEF group and HFmEF group(all P>0.05); 1-year readmission analysis of heart failure showed that 47.1%(33 cases)of HFrEF group was higher than 24.0%(12 cases)of HFmEF group, 48.3%(29 cases)of HFpEF group was higher than HFmEF group( HR=2.307, 2.368, 95% CI: 0.187-4.480, 1.207-4.644, respectively, all P<0.05); The major 1-year cardiovascular events were 57.1%(40 cases)higher in the HFrEF group than 34.0%(17 cases)in the HFmEF group( HR=2.053, 95% CI: 0.187-4.408, P< 0.05). Multivariate analysis showed that the 1-year risk of major cardiovascular events was significantly different between HFmEF group and HFpEF group( HR=0.477, 95% CI: 0.241-0.941, P< 0.05). Pulmonary heart disease( P< 0.05), atrial flutter and/or atrial fibrillation( P< 0.01), New York Cardiology class Ⅳ( P< 0.01)were risk factors for death.Hypertension and cor pulmonale were the risk factors for readmission in patients with heart failure(all P< 0.01). Conclusions:The clinical characteristics of inpatients with HFmEF in the medical alliance setting tended to be consistent with those with HFrEF, while the feature of ischemic heart disease was more prominent in HFmEF.The 1-year risk of heart failure readmission in HFmEF group was significantly lower than that in HFpEF and HFrEF group, and the risk of all-cause mortality and cardiovascular mortality at 1 year was not significantly different among the three groups.

The impact of whole brain radiation therapy on overall survival in patients with extensive stage small cell lung cancer with brain metastases / 中华放射肿瘤学杂志

Objective:To evaluate whether whole brain radiation therapy(WBRT) could benefit small cell lung cancer (SCLC) patients with brain metastases.Methods:Clinical data of 245 patients who were diagnosed with extensive stage SCLC with brain metastases admitted to our hospital from 2010 to 2020 were retrospectively analyzed. Among them, 168 patients received WRBT (WBRT group, radiation dose: 30Gy in 10 fractions), and 77 patients did not receive WBRT (non-WBRT group). All patients received 4-6 cycles of chemotherapy, and the chemotherapy regimen included cisplatin (or carboplatin) plus etoposide. One hundred and fifteen patients received thoracic radiotherapy. The endpoint was overall survival after brain metastases(BM-OS). Chi-square test was used to compare categorical data, and stabilized inverse probability of treatment weighting(sIPTW) was used to match the factors between WBRT and no-WBRT groups. Survival analysis was estimated by Kaplan-Meier method, and the log-rank test was used to compare survival curves between two groups. Results:The median BM-OS for the whole group of patients was 9.1 months, and 10.6 months and 6.7 months in the WBRT and non-WBRT groups, respectively( P=0.003). After balanced influencing factors with stabilized sIPTW, significant difference still existed in BM-OS between two groups( P=0.02). In 118 patients with synchronous brain metastases, the median BM-OS in two groups were 13.0 months and 9.6 months( P=0.007); and in 127 patients with metachronous brain metastases, the median BM-OS were 8.0 months and 4.1 months( P=0.003). In 50 patients without extracranial metastases, the median BM-OS were 13.3 months and 10.9 months( P=0.259)in two groups; while in 195 patients with extracranial metastases, the median BM-OS were 9.5 months and 5.9 months( P=0.009)in two groups. Conclusions:WBRT could prolong the OS in extensive stage SCLC patients with brain metastases.

A Simple Phase-Sensitive Surface Plasmon Resonance Sensor Based on Simultaneous Polarization Measurement Strategy.

The SPR phenomenon results in an abrupt change in the optical phase such that one can measure the phase shift of the reflected light as a sensing parameter. Moreover, many studies have demonstrated that the phase changes more acutely than the intensity, leading to a higher sensitivity to the refractive index change. However, currently, the optical phase cannot be measured directly because of its high frequency; therefore, investigators usually have to use complicated techniques for the extraction of phase information. In this study, we propose a simple and effective strategy for measuring the SPR phase shift based on phase-shift interferometry. In this system, the polarization-dependent interference signals are recorded simultaneously by a pixelated polarization camera in a single snapshot. Subsequently, the phase information can be effortlessly acquired by a phase extraction algorithm. Experimentally, the proposed phase-sensitive SPR sensor was successfully applied for the detection of small molecules of glyphosate, which is the most frequently used herbicide worldwide. Additionally, the sensor exhibited a detection limit of 15 ng/mL (0.015 ppm). Regarding its simplicity and effectiveness, we believe that our phase-sensitive SPR system presents a prospective method for acquiring phase signals.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Effects of Acupuncture on Postoperative Pain After Total Knee Replacement: Systematic Literature Review and Meta-Analysis.

OBJECTIVE: To identify the analgesic effectiveness of acupuncture after total knee replacement by systematic review. METHODS: A search of randomized controlled trials was conducted in five English medical electronic databases and five Chinese databases. Two reviewers independently searched in five English medical electronic databases and five Chinese databases. Two reviewers independently retrieved related studies, assessed the methodological quality, and extracted data with a standardized data form. Meta-analyses were performed with all-time-points meta-analysis. RESULTS: A total of seven studies with 891 participants were included. The meta-analysis results indicated that acupuncture had a statistically significant influence on pain relief (standardized mean difference = -0.705, 95% CI -1.027 to -0.382, P = 0.000). The subgroup analysis results showed that acupuncture's effects on analgesia had a statistically significant influence (standardized mean difference= -0.567, 95% CI -0.865 to -0.269, P = 0.000). The main acupuncture points that produced an analgesic effect when they were used after total knee replacement included the Xuehai, Liangqiu, Dubi, Neixiyan, Yanglingquan, and Zusanli points. Electroacupuncture frequency ranged between 2 and 100 Hz. CONCLUSIONS: As an adjunct modality, the use of acupuncture is associated with reduced pain and use of analgesic medications in postoperative patients. In particular, ear acupuncture 1 day before surgery could reduce analgesia .