The RNA exosome is a conserved degradation machinery, which obtains full activity only when associated with cofactors. The most prominent activator of the yeast nuclear exosome is the RNA helicase ...Mtr4p, acting in the context of the Trf4p/Air2p/Mtr4p polyadenylation (TRAMP) complex. The existence of a similar activator(s) in humans remains elusive. By establishing an interaction network of the human nuclear exosome, we identify the trimeric Nuclear Exosome Targeting (NEXT) complex, containing hMTR4, the Zn-knuckle protein ZCCHC8, and the putative RNA binding protein RBM7. ZCCHC8 and RBM7 are excluded from nucleoli, and consistently NEXT is specifically required for the exosomal degradation of promoter upstream transcripts (PROMPTs). We also detect putative homolog TRAMP subunits hTRF4-2 (Trf4p) and ZCCHC7 (Air2p) in hRRP6 and hMTR4 precipitates. However, at least ZCCHC7 function is restricted to nucleoli. Our results suggest that human nuclear exosome degradation pathways comprise modules of spatially organized cofactors that diverge from the yeast model.
Display omitted
► Identification of the human Nuclear Exosome Targeting complex ► NEXT targets promoter upstream transcripts for exosomal degradation ► A putative human TRAMP complex is involved in rRNA degradation in nucleoli ► hMTR4 is a central activator of the human nuclear RNA exosome
The impact of one-way SMS on health outcomes in Africa is unclear. We aimed to conduct a systematic review of one-way SMS randomised trials in Africa and a meta-analysis of their effect on healthcare ...appointments attendance and medicine adherence.
PubMed, Embase, CENTRAL, The Global Health Library, ClinicalTrials.gov, ICTRP, and PACTR were searched for published and unpublished trials in Africa without language restriction (up to April 2018). Trials reporting effect estimates on healthcare appointment attendance and medicine adherence were assessed for risk of bias and included in meta-analyses using random-effects models. Other outcomes were reported descriptively. The protocol is registered in PROSPERO, ID:CRD42018081062.
We included 38 one-way SMS trials conducted in Africa within a broad range of clinical conditions. Eighteen trials were included in the meta-analyses, and four were assessed as overall low risk of bias. One-way SMS improved appointment attendance, OR:2·03; 95% CI:1·40-2·95 (12 trials, 6448 participants), but not medicine adherence, RR:1·10; 95% CI:0·98-1·23 (nine trials, 4213 participants). Subgroup analyses showed that one-way SMS had the highest impact on childhood immunization attendance, OR:3·69; 95% CI:1·67-8·13 (three trials, 1943 participants). There was no clear evidence of one-way SMS improving facility delivery, knowledge level (reproductive/antenatal health, hypertension), diabetes- and hypertension management.
In an African setting, the clinical effect of one-way SMS is uncertain except for appointment attendance where the effect seems to vary depending on which clinical condition it is used in.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Studies have shown that the bulk of eukaryotic genomes is transcribed. Transcriptome maps are frequently updated, but low-abundant transcripts have probably gone unnoticed. To eliminate RNA ...degradation, we depleted the exonucleolytic RNA exosome from human cells and then subjected the RNA to tiling microarray analysis. This revealed a class of short, polyadenylated and highly unstable RNAs. These promoter upstream transcripts (PROMPTs) are produced ~0.5 to 2.5 kilobases upstream of active transcription start sites. PROMPT transcription occurs in both sense and antisense directions with respect to the downstream gene. In addition, it requires the presence of the gene promoter and is positively correlated with gene activity. We propose that PROMPT transcription is a common characteristic of RNA polymerase II (RNAPII) transcribed genes with a possible regulatory potential.
Transgender identity is often associated with gender dysphoria and minority stress. Gender-affirming hormone treatment (GAHT) includes masculinising or feminising treatment and is expected to be ...lifelong in most cases. Sex and sex hormones have a differential effect on metabolism and CVD in cisgender people, and sex hormone replacement in hypogonadism is associated with higher vascular risk, especially in ageing individuals. Using narrative review methods, we present evidence regarding metabolic and cardiovascular outcomes during GAHT and propose recommendations for follow-up and monitoring of metabolic and cardiovascular risk markers during GAHT. Available data show no increased risk for type 2 diabetes in transgender cohorts, but masculinising GAHT increases lean body mass and feminising GAHT is associated with higher fat mass and insulin resistance. The risk of CVD is increased in transgender cohorts, especially during feminising GAHT. Masculinising GAHT is associated with a more adverse lipid profile, higher haematocrit and increased BP, while feminising GAHT is associated with pro-coagulant changes and lower HDL-cholesterol. Assigned male sex at birth, higher age at initiation of GAHT and use of cyproterone acetate are separate risk factors for adverse CVD markers. Metabolic and CVD outcomes may improve during gender-affirming care due to a reduction in minority stress, improved lifestyle and closer surveillance leading to optimised preventive medication (e.g. statins). GAHT should be individualised according to individual risk factors (i.e. drug, dose and form of administration); furthermore, doctors need to discuss lifestyle and preventive medications in order to modify metabolic and CVD risk during GAHT. Follow-up programmes must address the usual cardiovascular risk markers but should consider that biological age and sex may influence individual risk profiling including mental health, lifestyle and novel cardiovascular risk markers during GAHT.Transgender identity is often associated with gender dysphoria and minority stress. Gender-affirming hormone treatment (GAHT) includes masculinising or feminising treatment and is expected to be lifelong in most cases. Sex and sex hormones have a differential effect on metabolism and CVD in cisgender people, and sex hormone replacement in hypogonadism is associated with higher vascular risk, especially in ageing individuals. Using narrative review methods, we present evidence regarding metabolic and cardiovascular outcomes during GAHT and propose recommendations for follow-up and monitoring of metabolic and cardiovascular risk markers during GAHT. Available data show no increased risk for type 2 diabetes in transgender cohorts, but masculinising GAHT increases lean body mass and feminising GAHT is associated with higher fat mass and insulin resistance. The risk of CVD is increased in transgender cohorts, especially during feminising GAHT. Masculinising GAHT is associated with a more adverse lipid profile, higher haematocrit and increased BP, while feminising GAHT is associated with pro-coagulant changes and lower HDL-cholesterol. Assigned male sex at birth, higher age at initiation of GAHT and use of cyproterone acetate are separate risk factors for adverse CVD markers. Metabolic and CVD outcomes may improve during gender-affirming care due to a reduction in minority stress, improved lifestyle and closer surveillance leading to optimised preventive medication (e.g. statins). GAHT should be individualised according to individual risk factors (i.e. drug, dose and form of administration); furthermore, doctors need to discuss lifestyle and preventive medications in order to modify metabolic and CVD risk during GAHT. Follow-up programmes must address the usual cardiovascular risk markers but should consider that biological age and sex may influence individual risk profiling including mental health, lifestyle and novel cardiovascular risk markers during GAHT.
Polycystic ovary syndrome (PCOS) is associated with insulin resistance. Few randomized controlled trials (RCT) compared myoinositol (MI) with metformin (MET) regarding insulin resistance in PCOS. ...This was an open-label six-month RCT in women with PCOS (n = 45) with interventions MI 4 g/day or MET 2 g/day. Primary outcome was the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were fasting glucose, weight, cycle length, lipids, testosterone, adverse effects, quality of life, and depression scores. Median age was 26 years. Body mass was index was 34.4 kg/m2. HOMA-IR was unchanged during MI (p = 0.31) and MET (p = 0.11) (MI vs. MET, p = 0.09). Median fasting glucose changed +0.2 mmol/L during MI (p < 0.001) and −0.1 mmol/L during MET (p = 0.04) (MI vs. MET p < 0.001). Median weight changed −2.3 kg during MI (p = 0.98) and −6.1 kg during MET (p < 0.001) (MI vs. MET, p = 0.02). Median cycle length decreased nine days during MI (p = 0.03) and 13 days during MET (p = 0.03) (MI vs. MET, p = 0.93). High-density lipoprotein (HDL) changed +0.1 mmol/L during MET (p = 0.04) (MI vs. MET, p = 0.07). All other blood parameters and scores of quality of life and depression remained unchanged during MI and MET (all p > 0.06) (MI vs. MET, all p > 0.27). Adverse effects appeared in four women during MI and 16 women during MET (MI vs. MET, p = 0.001). In conclusion, there was no effect on the metabolic outcomes during MI, but positive effects on fasting blood glucose, weight, and HDL during MET. The effect on cycle length was comparable during MI and MET. Adverse effects were less frequent during MI.
Aim
To assess case fatality rate (CFR), infant mortality, and long‐term neurodevelopmental disorders (NDDs) after invasive group B streptococcal (GBS; Streptococcus agalactiae) infection in infants.
...Method
Children born in Norway between 1996 and 2019 were included. Data on pregnancies/deliveries, GBS infection, NDDs, and causes of death were retrieved from five national registries. The exposure was culture‐confirmed invasive GBS infection during infancy. Outcomes were mortality and NDDs, the latter at a mean age of 12 years 10 months.
Results
Among 1 415 625 live‐born children, 866 (87%) of 1007 infants diagnosed with GBS infection (prevalence 0.71 per 1000) were included. The CFR was 5.0% (n = 43). GBS infection was associated with higher infant mortality (relative risk 19.41; 95% confidence interval CI 14.79–25.36) than the general population. Among survivors, 169 (20.7%) children were diagnosed with any NDD (relative risk 3.49; 95% CI 3.05–3.98). In particular, GBS meningitis was associated with high risks of attention‐deficit/hyperactivity disorder, cerebral palsy, epilepsy, hearing impairment, and pervasive and specific developmental disorder.
Interpretation
The burden of invasive GBS infection during infancy is considerable and continues to affect children beyond infancy. These findings emphasize the need for new preventive strategies for disease reduction, and the need for survivors to be directly included into early detection pathways to access early intervention if required.
What this paper adds
The burden of invasive group B streptococcal (GBS) infection in Norway is considerable.
Of GBS infection survivors, 20.7% were diagnosed with neurodevelopmental disorders (NDDs) at mean age 12 years 10 months.
Infants with GBS meningitis were more often diagnosed with NDDs.
Absolute risks associated with GBS infections were highest for pervasive and specific developmental disorder, cerebral palsy, and attention‐deficit/hyperactivity disorder.
What this paper adds
The burden of invasive group B streptococcal (GBS) infection in Norway is considerable.
Of GBS infection survivors, 20.7% were diagnosed with neurodevelopmental disorders (NDDs) at mean age 12 years 10 months.
Infants with GBS meningitis were more often diagnosed with NDDs.
Absolute risks associated with GBS infections were highest for pervasive and specific developmental disorder, cerebral palsy, and attention‐deficit/hyperactivity disorder.
The burden of invasive group B streptococcus infection during infancy is considerable and continues to affect children beyond infancy. Novel preventive strategies for disease reduction, as well as systematic follow‐up of survivors, is therefore needed.
This original article is commented on by Le Doare on pages 11–12 of this issue.
To prevent type 2 diabetes mellitus (T2D) and reduce the risk of complications, early identification of people at risk of developing T2D, preferably through simple diabetes risk scores, is essential. ...The aim of this study was to create a risk score for identifying subjects with undiagnosed prediabetes or T2D among Saharawi refugees in Algeria and compare the performance of this score to the Finnish diabetes risk score (FINDRISC).
A cross-sectional survey was carried out in five Saharawi refugee camps in Algeria in 2014. A total of 180 women and 175 men were included. HbA1c and cut-offs proposed by the American Diabetes Association (ADA) were used to define cases. Variables to include in the risk score were determined by backwards elimination in logistic regression. Simplified scores were created based on beta coefficients from the multivariable model after internal validation with bootstrapping and shrinkage. The empirical cut-off value for the simplified score and FINDRISC was determined by Area Under the Receiver Operating Curve (AUROC) analysis.
Variables included in the final risk score were age, body mass index (BMI), and waist circumference. The area under the curve (AUC) (C.I) was 0.82 (0.76, 0.88). The sensitivity, specificity, and positive and negative predictive values were 89, 65, 28, and 97%, respectively. AUC and sensitivity were slightly higher and specificity somewhat lower than for FINDRISC.
The risk score developed is a helpful tool to decide who should be screened for prediabetes or T2D by blood sample analysis. The performance of the risk score was adequate based on internal validation with bootstrap analyses, but should be confirmed in external validation studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF‐I) patterns as well as clinical features but whether this also pertains to ...controlled disease is unclear.
Design
In a cross‐sectional, multi‐centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined.
Methods
Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF‐I and completion of two HR‐Qol questionnaires (acromegaly quality of life questionnaire AcroQol and Patient‐assessed Acromegaly Symptom Questionnaire PASQ).
Results
The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF‐I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF‐I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04).
Conclusion
In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF‐I levels, which also translated into impaired metabolic health and well‐being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease‐specific sex differences prevail after treatment.
Introduction
Low socioeconomic status (SES) may be associated with increased risk of polycystic ovary syndrome (PCOS) and vice versa. Possible associations between SES, obesity and ethnicity in PCOS ...are undetermined.
Material and methods
National register‐based study including women with PCOS aged 25 years or above (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital OUH) and one control population. PCOS Denmark (n = 13 891) included women with PCOS in the Danish National Patient Register. Women in PCOS OUH underwent clinical examination (n = 814). Three age‐matched controls were included per patient (n = 41 584). The main outcome measure was SES (personal income, occupational status and education).
Results
The median (Q1; Q3) age of women in PCOS Denmark and controls was 33 (29; 39) years. Women with personal income in the lower tertile had a higher probability of a PCOS diagnosis than women in the high‐income tertile (adjusted odds ratio aOR 1.5, 95% confidence interval CI 1.4‐1.6). Women who were unemployed or on welfare payment (aOR 1.5, 95% CI 1.4‐1.6), or who retired early (OR 1.8, 95% CI 1.7‐2.0) had a higher probability of a PCOS diagnosis than women affiliated to the labor market. Women originating from the Middle East more often had PCOS (aOR 3.2, 95% CI 2.8‐3.7) compared with women originating from Europe. In PCOS OUH, SES was lower in obese than in normal weight women.
Conclusions
A diagnosis of PCOS was associated with lower SES. In PCOS, women of foreign origin and women with obesity more often had low SES.
Rapid human papillomavirus (HPV) DNA testing is an emerging cervical cancer screening strategy in resource-limited countries, yet it requires follow-up of women who test HPV positive.
This study ...aimed to determine if one-way text messages improved attendance to a 14-month follow-up cervical cancer screening among HPV-positive women.
This multicenter, parallel-group randomized controlled trial was conducted at 3 hospitals in Tanzania. Eligible participants were aged between 25 and 60 years, had tested positive to a rapid HPV test during a patient-initiated screening, had been informed of their HPV result, and had a private mobile phone with a valid number. Participants were randomly assigned in a 1:1 ratio to the intervention or control group through an incorporated algorithm in the text message system. The intervention group received one-way text messages, and the control group received no text messages. The primary outcome was attendance at a 14-month health provider-initiated follow-up screening. Participants were not blinded, but outcome assessors were. The analysis was based on intention to treat.
Between August 2015 and July 2017, 4080 women were screened for cervical cancer, of which 705 were included in this trial-358 women were allocated to the intervention group, and 347 women were allocated to the control group. Moreover, 16 women were excluded before the analysis because they developed cervical cancer or died (8 from each group). In the intervention group, 24.0% (84/350) women attended their follow-up screening, and in the control group, 23.8% (80/335) women attended their follow-up screening (risk ratio 1.02, 95% CI 0.79-1.33).
Attendance to a health provider-initiated follow-up cervical cancer screening among HPV-positive women was strikingly low, and one-way text messages did not improve the attendance rate. Implementation of rapid HPV testing as a primary screening method at the clinic level entails the challenge of ensuring a proper follow-up of women.
ClinicalTrials.gov NCT02509702; https://clinicaltrials.gov/ct2/show/NCT02509702.
RR2-10.2196/10.2196/15863.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
