[Regulation of Transcription by RNA Polymerase III Promotors in the Norm and Pathology].

RNA polymerase III synthesizes a wide range of noncoding RNAs shorter than 400 nucleotides in length. These RNAs are involved in protein synthesis (tRNA, 5S rRNA, and 7SL RNA), maturation, and splicing of different types of RNA (RPR, MRP RNA, and U6 snRNA), regulation of transcription (7SK RNA), replication (Y RNA), and intracellular transport (vault RNA). BC200 and BC1 RNA genes are transcribed by RNA polymerase III in neurons only where these RNAs regulate protein synthesis. Mutations in the regulatory elements of the genes transcribed by RNA polymerase III as well as in transcription factors of this RNA polymerase are associated with the development of a number of diseases, primarily oncological and neurological. In this regard, the mechanisms of regulation of the expression of the genes containing various RNA polymerase III promoters were actively studied. This review describes the structural and functional classification of polymerase III promoters, as well as the factors involved in the regulation of promoters of different types. A number of examples demonstrate the role of the described factors in the pathogenesis of human diseases.

Childhood growth of singletons conceived following intracytoplasmic sperm injection - irrelevance of gonadotropin stimulation.

Background: In conventional, gonadotropin stimulated, in vitro fertilization or intracytoplasmic sperm injection (c-IVF/ICSI) growth and development of multiple follicles is induced by gonadotropins, combined with gonadotropin-releasing hormone agonist or antagonist. In recent studies, singletons conceived after c-IVF/ICSI cycles had lower birth weight not only than spontaneously conceived children but also children born after unstimulated natural IVF/ICSI cycles (NC-IVF/ICSI). Lower birth weight is associated with a catch-up growth within the first years of life. Following the Barker hypothesis accelerated growth has been associated with a higher risk of cardiovascular diseases later in life. The aim of the study is to assess, if children conceived with NC-IVF/ICSI have a higher birthweight and therefore do not show a catch-up growth within the first two years. Therefore, we assume that children born after NC-IVF/ICSI have a better long-term cardiometabolic risk profile. Whether the weight- and height gain is comparable to spontaneously conceived children is unknown, since to our knowledge we are the first study to investigate the longitudinal growth of children born after unstimulated natural cycle ICSI (NC-ICSI). Material and methods: We conducted a single-center, prospective cohort study (2010-2017) including children (n = 139) born after NC-ICSI or c-ICSI treatment. Growth parameters up to 24 months were collected. Standard deviation scores based on growth references were calculated. Results: The study included 98 children in the NC-ICSI and 41 children in the c-ICSI group. The median birth weight in NC-ICSI children was 3.4 kg [0.1 standard deviation score (SDS)] compared to 3.3 kg (-0.3 SDS) in c-ICSI children (p = 0.61). Median length at birth was 50 cm in both groups (NC-ICSI (-0.5 SDS), c-ICSI children (-0.8 SDS), p = 0.48). At age 24 months, median weight in NC-ICSI children was 12.2 kg (0.3 SDS) versus 12.2 kg (0.2 SDS) in c-ICSI children (p = 0.82) and median length 87.5 cm (0.1 SDS) versus 88.0 cm (0.4 SDS) (p = 0.43). Conclusion: We found no difference in growth between children conceived after stimulated and unstimulated ICSI. Growth parameters of both treatment groups did not differ from Swiss national growth references (N = 8500). One of the main limitations of our study was the small sample size (N = 139) of complete data sets over time and the high drop-out rate of 49% (68/139). Nevertheless, with the increasing number of children born after IVF/ICSI every year it is of immense importance to search for possibilities to reduce their long-term cardiometabolic risk and we want our data to contribute to this discussion.

Measurements of the Branching Fraction, Polarization, and CP Asymmetry for the Decay B

We present a comprehensive study of B^{0}→ωω decays using 772×10^{6} BB[over ¯] pairs collected with the Belle detector at the KEKB e^{+}e^{-} collider. This process is a suppressed charmless decay into two vector mesons and can exhibit interesting polarization and CP violation. The decay is observed for the first time with a significance of 7.9 standard deviations. We measure a branching fraction B=(1.53±0.29±0.17)×10^{-6}, a fraction of longitudinal polarization f_{L}=0.87±0.13±0.13, and a time-integrated CP asymmetry A_{CP}=-0.44±0.43±0.11, where the first uncertainties listed are statistical and the second are systematic. This is the first observation of B^{0}→ωω and the first measurements of f_{L} and A_{CP} for this decay.

Cut from the same cloth: RNAs transcribed from regulatory elements.

A certain degree of chromatin openness is necessary for the activity of transcription-regulating regions within the genome, facilitating accessibility to RNA polymerases and subsequent synthesis of regulatory element RNAs (regRNAs) from these regions. The rapidly increasing number of studies underscores the significance of regRNAs across diverse cellular processes and diseases, challenging the paradigm that these transcripts are non-functional transcriptional noise. This review explores the multifaceted roles of regRNAs in human cells, encompassing rather well-studied entities such as promoter RNAs and enhancer RNAs (eRNAs), while also providing insights into overshadowed silencer RNAs and insulator RNAs. Furthermore, we assess notable examples of shorter regRNAs, like miRNAs, snRNAs, and snoRNAs, playing important roles. Expanding our discourse, we deliberate on the potential usage of regRNAs as biomarkers and novel targets for cancer and other human diseases.

Teaching Frailty to Medical Residents: A Needs Assessment Among Geriatrics Faculty.

BACKGROUND: Knowledge of frailty is essential for meeting the Accreditation Council for Graduate Medical Education core competencies for US trainees. The UK General Medical Council requires that frailty be included in undergraduate and graduate medical education curricula. Trainees are expected to appropriately modify care plans and help make patient-centered decisions, while incorporating diagnostic uncertainty, such as frailty, in older adults. Little is known about current needs for frailty instruction in graduate medical education in the US and beyond. OBJECTIVE: We sought to capture faculty perceptions on how frailty should be defined and identified, and what aspects and level of detail should be taught to residents. DESIGN: The authors developed a 4-item short response questionnaire, and faculty had the option to respond via electronic survey or via semi-structured interviews. SETTING AND SUBJECTS: Respondents included 24 fellowship-trained geriatricians based at 6 different academic medical centers in a single urban metropolitan area. METHODS: An invitation to participate in either an electronic survey or semi-structured virtual interview was e-mailed to 30 geriatricians affiliated with an academic multi-campus Geriatric Medicine fellowship. Responses were transcribed and coded independently by two authors. RESULTS: Responses were received from 24 geriatricians via a combination of digital questionnaires (n=18) and semi-structured online interviews (n=6), for a response rate of 80%. Responses revealed significant diversity of opinion on how to define and identify frailty and how these concepts should be taught. CONCLUSIONS: As frailty is increasingly incorporated into clinical practice, consensus is needed on how to define and teach frailty to residents.

Experiences from the implementation of physical therapy via telehealth for individuals with Parkinson disease during the COVID-19 pandemic.

PURPOSE: To (1) determine the characteristics and participation rate of adults with Parkinson disease (PD) in physical therapy (PT) delivered via telehealth, (2) identify the outcome measures and interventions implemented, (3) determine the safety of and (4) patient and therapist satisfaction with PT via telehealth in a clinic specializing in the care of people with PD during the coronavirus pandemic. MATERIALS & METHODS: A retrospective analysis of PT services via telehealth was conducted. Participating patients completed a satisfaction survey. Physical therapists (PTs) who delivered this care were interviewed. Three coders conducted thematic analysis of interviews. Descriptive statistics described the participation rate, demographics, outcome measures, interventions, and safety. RESULTS: There was a 71.4% participation rate. Participants (n = 55) were white (96%), non-Hispanic (100%), older adult (mean = 69.5 years (8.3)) males (65.5%). Non-participants (n = 22) had similar demographics. Therapists selected patient-reported measures more often than performance-based measures. Therapeutic exercise was the most common intervention. All patients (80% response rate) reported satisfaction with their experience. PTs reported the home enhanced specificity of training but impeded evaluation. Therapists endorsed a hybrid model for future practice. CONCLUSIONS: Patients reported satisfaction with PT via telehealth during the pandemic. A hybrid model may support optimal delivery of PT.IMPLICATIONS FOR REHABILITATIONPhysical therapy via telehealth for patients with Parkinson disease was acceptable to patients and physical therapists in our study.Physical therapy via telehealth was safe for people with Parkinson disease in our study, although availability and benefits may not be reaching all populations equitably.Both physical therapists and patients endorse a hybrid model of care (a combination of in-person and remote assessment and treatment) to profit from the strengths of in-person and virtual formats while minimizing barriers to access.

Quality of life in endometrial cancer survivors by grade of disease.

BACKGROUND: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with overall incidence increasing, particularly high-grade disease. There is sparse information regarding quality of life (QOL) in EC survivors with a focus on grade of disease. METHODS: A total of 259 women with EC diagnosed between 2016 and 2020 were identified via the Metropolitan Detroit Cancer Surveillance System and consented to enroll in the Detroit Research on Cancer Survivors cohort study (if African American, n = 138) or completed the baseline interview (if non-Hispanic white, n = 121). Each respondent provided information about their health history, educational attainment, health behaviors, and demographics. The Functional Assessment of Cancer Therapy-General (FACT-G) and Endometrial-specific (FACT-En) were used to assess QOL. RESULTS: Women diagnosed with high-grade (n = 112) and low-grade (n = 147) EC participated in this study. EC survivors with high-grade disease reported significantly lower QOL compared to survivors with low-grade disease (85 vs. 91, respectively, p value = 0.025) as assessed by the FACT-G. This difference was driven by lower physical and functional subscales among women with high-grade disease compared to those with low-grade disease (p value = 0.016 and p = 0.028, respectively). Interestingly, EC-specific QOL measures, as assessed by the FACT-En, did not differ by grade. CONCLUSION: Grade of disease impacts QOL in EC survivors, as well as socioeconomic, psychological, and physical factors. Most of these factors are amenable to interventions and should be assessed in patients after an EC diagnosis.

[Full and D-Box-Deficient PTTG1 Isoforms: Effects on Cell Proliferation].

Human securin (PTTG1) is a protooncogene whose expression is elevated in many types of malignant cells. We previously discovered a minor short isoform of securin lacking exons 3 and 4. The missing exons encode the main recognition site (D-box) of the anaphase-promoting complex (APC/C). We show that these two PTTG1 isoforms have different effects on transcription. Here, we have studied the effects of overexpression and selective knockdown of the short and complete securin isoforms on cell proliferation using the xCELLigence system. Notably, selective knockdown of the short isoform mRNA led to a dramatic decrease in cell growth, while overexpression of both isoforms accelerated cell growth. To search for genes with alternative isoforms similar to securin, we analyzed the GENCODE database and found that 54 of 128 genes with a PTTG1-like set of APC/C recognition sites have known isoforms without the D-box. Overall, the data obtained indicate the existence of a new class of alternative isoforms and reinstates the importance of minor isoforms.

Differential associations of conduct disorder, callous-unemotional traits and irritability with outcome expectations and values regarding the consequences of aggression.

BACKGROUND: Previous work has examined the association of aggression levels and callous-unemotional traits with outcome expectations and values regarding the consequences of aggression. Less work has examined the outcome expectations and values regarding the consequences of aggression of adolescents with Conduct Disorder (CD). Also, no studies have examined links between irritability (a second socio-affective trait associated with CD) and these social cognitive processes despite the core function of anger in retaliatory aggression and establishing dominance. METHOD: The current study, investigating these issues, involved 193 adolescents (typically developing [TD; N = 106], 87 cases with CD [N = 87]). Participants completed an adaptation of the Outcomes Expectations and Values Questionnaire and were assessed for CU traits and irritability via the Inventory of Callous-Unemotional traits and the Affective Reactivity Index. RESULTS: While CD was associated with atypical outcome expectations this was not seen within statistical models including CU traits and irritability. CU traits were associated with decreased expectation that aggression would result in feelings of remorse and victim suffering, as well as decreased concern that aggressive acts would result in punishment and victim suffering. Irritability was associated with increased expectations and concern that aggression would result in dominance and forced respect. CONCLUSIONS: The results suggest that CU traits and irritability, often present in youth with CD, are associated with different forms of maladaptive outcome expectations and values regarding the consequences of aggression. This suggests that the atypical social cognitive processes underlying aggressive behavior among youth exhibiting CU traits may differ from those exhibiting problems regulating anger.

[The Minor T Allele of the Single Nucleotide Polymorphism rs 13360222 Decreases the Activity of the HAVCR2 Gene Enhancer in a Cell Model of Human Macrophages].

The TIM-3 receptor, encoded by the Hepatitis A Virus Cellular Receptor 2 (HAVCR2) gene, is an immune checkpoint and plays an important role in preventing the development of autoimmune reactions. This receptor is expressed on the surface of various immunocytes and its functions in myeloid cells remain poorly understood, compared to the role of T cell specific TIM-3 that is actively studied in the context of the search for promising therapeutic targets in cancer immunotherapy. During this study, we performed deletion analysis of the promoter region of the HAVCR2 gene, as well as functional characterization of its enhancer, and studied the effect of a number of single nucleotide polymorphisms (SNPs) on the activity of these regulatory elements in the relevant model of human macrophage-like cells-U937 activated monocytes. We have shown that the SNPs rs10515746(A) and rs4704853(A) located in the HAVCR2 gene promoter and associated with the development of a number of pathologies, do not affect the activity of the promoter in activated monocytes. However, a minor T variant of SNP rs13360222 located in the enhancer in the third intron of the gene, significantly reduces the ability of the enhancer to activate the HAVCR2 promoter, presumably due to weakening of the binding of nuclear receptor ESR2 to the respective region.

Long-term effects of lifestyle and metformin interventions in DPP on bone density.

In the Diabetes Prevention Program Outcome Study (DPPOS), a cohort at high risk of diabetes, randomization to intensive lifestyle intervention or metformin, both associated with weight loss, did not have long-term negative effects on BMD compared with the placebo group. Potential positive effects of metformin on bone warrant further investigation. INTRODUCTION: Randomization to lifestyle intervention (ILS) or metformin in the Diabetes Prevention Program (DPP) resulted in weight loss and reduced progression to diabetes. Weight loss is associated with reduced bone mineral density (BMD), but the long-term effects of these interventions on BMD are unknown. In the DPP Outcome Study (DPPOS), we determined if randomization to ILS or metformin, compared with placebo, was associated with differences in BMD approximately 16 years later. METHODS: Of 3234 DPP participants, 2779 continued in DPPOS and were offered ILS in group format. Those randomized to metformin were offered unmasked metformin. At DPPOS year 12, 1367 participants had dual-energy X-ray absorptiometry scans. BMD in metformin and ILS groups was compared to placebo using sex-specific linear regression models, adjusted for age, race/ethnicity, and weight and weight-bearing activity at DPP baseline. RESULTS: At DPPOS year 12, mean age was 66.5 (±9.5) years. Femoral neck BMD was similar in the ILS and placebo groups in men (difference = -0.021 g/cm2, 95%CI (-0.063, 0.021)) and in women (+0.014 g/cm2, 95%CI (-0.014, 0.042)). Femoral neck BMD was higher in the metformin compared to placebo group although not statistically different in men (+0.017 g/cm2, 95% CI (-0.023, 0.058)) and in women (+0.019 g/cm2, 95% CI (-0.009, 0.047)). Prevalence of osteoporosis was low and similar across treatment groups in men (0.9%; p=0.745) and women (2.4%; p=0.466). CONCLUSION: In a cohort at high risk of diabetes, lifestyle intervention or metformin did not appear to have long-term negative effects on BMD. Potential positive effects of metformin on bone warrant further research.

Effect of testosterone treatment on the trabecular bone score in older men with low serum testosterone.

The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. Our objective was to examine the effect of testosterone treatment on TBS. One hundred and ninety-seven hypogonadal men were randomized to testosterone or placebo. After 12 months, there was no difference in the changes in TBS by randomized group. INTRODUCTION: In the Bone Trial of the Testosterone Trials, testosterone treatment increased trabecular volumetric bone mineral density (vBMD) and increased estimated bone strength as determined by finite element analysis. The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. TBS predicts fracture independent of lumbar spine areal (a) BMD. The objective of this study was to examine the effect of testosterone treatment on TBS compared to its effects on vBMD and aBMD. METHODS: Two hundred and eleven men were enrolled in the Bone Trial of the Testosterone Trials. Of these, 197 men had 2 repeat TBS and vBMD measurements; 105 men were allocated to receive testosterone, and 92 men to placebo for 1 year. TBS, aBMD, and vBMD were assessed at baseline and month 12. RESULTS: There was no difference in the percent change in TBS by randomized group: 1.6% (95% confidence intervals (CI) 0.2-3.9) in the testosterone group and 1.4% (95% CI -0.2, 3.1) in the placebo group. In contrast, vBMD increased by 6% (95% CI 4.5-7.5) in the testosterone group compared to 0.4% (95% CI -1.65-0.88) in the placebo groups. CONCLUSIONS: TBS is not clinically useful in monitoring the 1-year effect of testosterone treatment on bone structure in older hypogonadal men.

[Telemedicine in stroke-pertinent to stroke care in Germany]. / Telemedizin in der Schlaganfallversorgung ­ versorgungsrelevant für Deutschland.

BACKGROUND AND OBJECTIVE: Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution. METHODS: The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks. RESULTS: Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1-3) as well as 225 cooperating hospitals (per network: median 9, IQR 4-17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319-2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6-14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5-8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states. CONCLUSION: Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future.

Autochthonous Thelazia callipaeda Infection in Dog, New York, USA, 2020.

We report a case of autochthonous infection of the eye worm Thelazia callipaeda in a dog in the northeastern United States. Integrated morphologic identification and molecular diagnosis confirmed the species. Phylogenetic analysis suggested introduction from Europe. The zoonotic potential of this parasite warrants broader surveillance and increased awareness among physicians and veterinarians.

Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vaginal swabs of women with acute SARS-CoV-2 infection: a prospective study.

OBJECTIVE: To determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is present in the vaginal secretions of both reproductive-aged and postmenopausal women during acute SARS-CoV-2 infection. DESIGN: Prospective study. SETTING: A single tertiary, university-affiliated medical centre in Israel. Time period, 1 June 2020 through to 31 July 2020. POPULATION: Women who were hospitalised in a single tertiary medical centre, who were diagnosed with acute SARS-CoV-2 infection by a nasopharyngeal RT-PCR test. METHODS: Women were diagnosed with acute SARS-CoV-2 infection by a nasopharyngeal RT-PCR test. Vaginal RT-PCR swabs were obtained from all study participants after a proper cleansing of the perineum. MAIN OUTCOME MEASURES: Detection of SARS-CoV-2 in vaginal RT-PCR swabs. RESULTS: Vaginal and nasopharyngeal swabs were obtained from 35 women, aged 21-93 years. Twenty-one women (60%) were in their reproductive years, of whom, five were in their third trimester of pregnancy. Most of the participants (57%) were healthy without any underlying medical conditions. Of the 35 patients sampled, 2 (5.7%) had a positive vaginal RT-PCR for SARS-CoV-2, one was premenopausal and the other was a postmenopausal woman. Both women had mild disease. CONCLUSION: Our findings contradict most previous reports, which did not detect the presence of viral colonisation in the vagina. Although passage through the birth canal exposes neonates to the vaginal polymicrobial flora, an acquisition of pathogens does not necessarily mandate neonatal infection or clinical disease. Nevertheless, when delivering the infant of a woman with acute SARS-CoV-2 infection, a clinician should consider the possibility of vaginal colonisation, even if it is uncommon. TWEETABLE ABSTRACT: When delivering the infant of a woman with acute SARS-CoV-2 infection, a clinician should consider the possibility of vaginal colonisation.

Caregiving burden among informal caregivers of African American cancer survivors.

PURPOSE: Relatively little is known about caregivers of African American cancer survivors. Our goal was to identify the extent of burden among this group of caregivers. METHODS: Responses from 560 informal caregivers of African American participants of the Research on Cancer Survivors (ROCS) study in Detroit, MI, were analyzed including demographics, assistance provided including activities of daily living (ADLs) and instrumental activities of daily living (IADLs), time spent in caregiving, and caregiver burden (CGB). We assessed relationships between CGB and demographic variables, ADLs/IADLs, and level of care. Multivariable logistic regression determined which ADLs and IADLs were associated with high CGB. RESULTS: Over 75% of caregivers were female and 97% identified as African American. Mean age was 52.6 years. Fifty-six percent were employed outside the home, and 90% were related to the survivor. Caregivers averaged 35.7 h/week providing care, assisting with on average 2.8 ADLs and 5.0 IADLs. Despite the many hours and activities reported, no caregivers rated CGB as severe; only 4% rated it moderate to severe. ADLs associated with the top quartile of CGB were feeding and toileting; IADLs were finances, telephoning, housework, and medications. CONCLUSIONS: Caregivers for African American cancer survivors provide many hours of care, yet most describe their CGB as low. Although ADL assistance is often available through the healthcare system, assistance with IADLs presents an opportunity to lessen the burden for these caregivers and their care recipients. IMPLICATIONS FOR CANCER SURVIVORS: African American cancer survivors receive much care from informal family caregivers, who assist with multiple ADLs and IADLs. Formal IADL assistance programs, similar to those available for ADLs, would benefit both survivors and caregivers.

[Functional Characteristics of Long Noncoding RNAs Containing Sequences of Mobile Genetic Elements].

Long nonconding RNAs (lncRNAs) perform a variety of functions: they are involved in chromatin organization, regulation of gene expression at the transcriptional and post-transcriptional levels, and regulation of activity and stability of some proteins. The majority of known lncRNAs contain sequences of mobile genetic elements (MGEs) in a sense or antisense orientation. According to several studies, MGE may serve as functional modules responsible for interactions between the lncRNA and certain proteins, DNA regions, or other RNAs. The available data make it possible to describe groups of lncRNAs that possess common structural features and contain certain MGEs and to predict the characteristics of new lncRNAs. The review summarizes the data on the role that MGE sequences play in lncRNA functions.

Short-term application of ibuprofen before ovulation.

AIM OF THE STUDY: The aim was to analyse if ibuprofen, as a non-selective cyclooxygenase (COX) inhibitor, has any negative effect on oocyte competence and embryo quality. COX- inhibitors are popular over-the-counter analgesics. Whereas selective COX inhibitors have been shown to impair female fertility, data on non-selective COX inhibitors are poor. Hence, they have not been recommended for women trying to conceive. METHODS: This is an observational study comparing ibuprofen exposed and unexposed women from 18 to 42 years of age, using the model of natural cycle in vitro fertilisation (IVF) to determine oocyte and embryo quality. Follicular growth was monitored and if the follicle was mature (≥ 15mm size and estimated oestradiol level of ≥ 800pmol/l), ovulation was triggered. Women with luteinising hormone (LH) surge received 400mg ibuprofen every 8 hours to postpone ovulation, whereas women without LH surge received none (controls). Oocyte retrieval rate, oocyte maturity, fertilization rate, embryo development and embryo quality as well as implantation rate were analysed. RESULTS: Of the 111 women included, 63 received ibuprofen, and 48 did not. Rates of mature oocytes and implantation rate did not differ. Logistic regression showed no significant association of ibuprofen intake, LH- level or reason for infertility on embryo quality. CONCLUSION: Based on our results, we suggest that, particularly within natural cycle IVF, ibuprofen does no harm around ovulation as analgesic treatment.