Search

Abstract Background Benzodiazepines (BZD) are widely prescribed to older adults despite their association with increased fall injury. Our aim is to better characterize risk-elevating factors among those prescribed BZD. Methods A retrospective cohort study using a 20% sample of Medicare beneficiaries with Part D prescription drug coverage. Patients with a BZD prescription (“index”) between 1 April 2016 and 31 December 2017 contributed to incident (n=379,273) and continuing (n=509,634) cohorts based on prescriptions during a 6-month pre-index baseline. Exposures were index BZD average daily dose and days prescribed; baseline BZD medication possession ratio (MPR) (for the continuing cohort); and co-prescribed central nervous system-active medications. Outcome was a treated fall-related injury within 30 days post-index BZD, examined using Cox proportional hazards adjusting for demographic and clinical covariates and the dose prescribed. Results Among incident and continuing cohorts, 0.9% and 0.7% experienced fall injury within 30 days of index. In both cohorts, injury risk was elevated immediately post-index among those prescribed the lowest quantity: e.g., for

Background Long-lasting insecticidal nets (LLINs) are one of the key interventions in the global fight against malaria. Since 2014, mass distribution campaigns of LLINs aim for universal access by all citizens of Burundi. In this context, we assess the impact of LLINs mass distribution campaigns on malaria incidence, focusing on the endemic highland health districts. We also explored the possible correlation between observed trends in malaria incidence with any variations in climate conditions.Methods Malaria cases for 2011—2019 were obtained from the National Health Information System. We developed a generalised additive model based on a time series of routinely collected data with malaria incidence as the response variable and timing of LLIN distribution as an explanatory variable to investigate the duration and magnitude of the LLIN effect on malaria incidence. We added a seasonal and continuous-time component as further explanatory variables, and health district as a random effect to account for random natural variation in malaria cases between districts.Results Malaria transmission in Burundian highlands was clearly seasonal and increased non-linearly over the study period. Further, a fast and steep decline of malaria incidence was noted during the first year after mass LLIN distribution (p

Tuberculosis (TB) remains the second leading cause of death globally from a single infectious agent, and there is a critical need to develop improved imaging biomarkers and aid rapid assessments of responses to therapy. We aimed to utilize radiomics, a rapidly developing image analysis tool, to develop a scoring system for this purpose. A chest X-ray radiomics score (RadScore) was developed by implementing a unique segmentation method, followed by feature extraction and parameter map construction. Signature parameter maps that showed a high correlation to lung pathology were consolidated into four frequency bins to obtain the RadScore. A clinical score (TBscore) and a radiological score (RLscore) were also developed based on existing scoring algorithms. The correlation between the change in the three scores, calculated from serial X-rays taken while patients received TB therapy, was evaluated using Spearman’s correlation. Poor correlations were observed between the changes in the TBscore and the RLscore (0.09 (p-value = 0.36)) and the TBscore and the RadScore (0.02 (p-value = 0.86)). The changes in the RLscore and the RadScore had a much stronger correlation of 0.22, which is statistically significant (p-value = 0.02). This shows that the developed RadScore has the potential to be a quantitative monitoring tool for responses to therapy.

Abstract Background Step-recovery responses are critical in preventing falls when balance is lost unexpectedly. We investigated the kinematics and strategies of balance recovery in older adults with a varying history of falls. Methods In a laboratory study, 51 non-fallers (NFs), 20 one-time fallers (OFs), and 12 recurrent-fallers (RFs) were exposed to random right/left unannounced underfoot perturbations in standing of increasing magnitude. The stepping strategies and kinematics across an increasing magnitude of perturbations and the single- and multiple-step threshold trials, i.e., the lowest perturbation magnitude to evoke single step and multiple steps, respectively, were analyzed. Fall efficacy (FES) and self-reported lower-extremity function were also assessed. Results OFs had significantly lower single- and multiple-step threshold levels than NFs; the recovery-step kinematics were similar. Surprisingly, RFs did not differ from NFs in either threshold. The kinematics in the single-step threshold trial in RFs, however, showed a significant delay in step initiation duration, longer step duration, and larger center of mass (CoM) displacement compared with NFs and OFs. In the multiple-step threshold trial, the RFs exhibited larger CoM displacements and longer time to fully recover from balance loss. Interestingly, in the single-stepping trials, 45% of the step-recovery strategies used by RFs were the loaded-leg strategy, about two times more than OFs and NFs (22.5 and 24.2%, respectively). During the multiple-stepping trials, 27.3% of the first-step recovery strategies used by RFs were the loaded-leg strategy about two times more than OFs and NFs (11.9 and 16.4%, respectively), the crossover stepping strategy was the dominated response in all 3 groups (about 50%). In addition, RFs reported a lower low-extremity function compared with NFs, and higher FES in the OFs. Conclusions RFs had impaired kinematics during both single-step and multiple-step recovery responses which was associated with greater leg dysfunction. OFs and NFs had similar recovery-step kinematics, but OFs were more likely to step at lower perturbation magnitudes suggesting a more “responsive” over-reactive step response related from their higher fear of falling and not due to impaired balance abilities. These data provide insight into how a varying history of falls might affect balance recovery to a lateral postural perturbation. Trial registration This study was registered prospectively on November 9th, 2011 at clinicaltrials.gov ( NCT01439451 ).

Abstract Background Ixodes ricinus is a three-host tick, a principal vector of Borrelia burgdorferi (s.l.) and one of the main vectors of tick-borne encephalitis (TBE) virus. Iceland is located in the North Atlantic Ocean with subpolar oceanic climate. During the past 3–4 decades, average temperature has increased, supporting more favourable conditions for ticks. Reports of I. ricinus have increased in recent years. If these ticks were able to establish in a changing climate, Iceland may face new threats posed by tick-borne diseases. Methods Active field surveillance by tick flagging was conducted at 111 sites around Iceland from August 2015 to September 2016. Longworth mammal traps were used to trap Apodemus sylvaticus in southwestern and southern Iceland. Surveillance on tick importation by migratory birds was conducted in southeastern Iceland, using bird nets and a Heligoland trap. Vulpes lagopus carcasses from all regions of the country were inspected for ticks. In addition, existing and new passive surveillance data from two institutes have been merged and are presented. Continental probability of presence models were produced. Boosted Regression Trees spatial modelling methods and its predictions were assessed against reported presence. Results By field sampling 26 questing I. ricinus ticks (7 males, 3 females and 16 nymphs) were collected from vegetation from three locations in southern and southeastern Iceland. Four ticks were found on migratory birds at their arrival in May 2016. A total of 52 A. sylvaticus were live-trapped but no ticks were found nor on 315 V. lagopus carcasses. Passive surveillance data collected since 1976, reports further 214 I. ricinus ticks from 202 records, with an increase of submissions in recent years. The continental probability of presence model correctly predicts approximately 75% of the recorded presences, but fails to predict a fairly specific category of recorded presence in areas where the records are probably opportunistic and not likely to lead to establishment. Conclusions To the best of our knowledge, this study represents the first finding of questing I. ricinus ticks in Iceland. The species could possibly be established locally in Iceland in low abundance, although no questing larvae have yet been detected to confirm established populations. Submitted tick records have increased recently, which may reflect an increase in exposure, or in interest in ticks. Furthermore, the amount of records on dogs, cats and humans indicate that ticks were acquired locally, presenting a local biting risk. Tick findings on migratory birds highlight a possible route of importation. Obtaining questing larvae is now a priority to confirm that I. ricinus populations are established in Iceland. Further surveys on wild mammals (e.g. Rangifer tarandus), livestock and migratory birds are recommended to better understand their role as potential hosts for I. ricinus.

Background: Atrial fibrillation (AF) is highly common, and is most frequently observed in individuals with hypertension and structural cardiac disease. Sympathetic hyperactivity plays a fundamental role in the progression, maintenance and aggravation of arrhythmia. Endurance exercise training clearly lowers sympathetic activity in sympathoexcitatory disease states, and is well-tolerated by patients with chronic kidney disease (CKD). Methods: We assessed 50 CKD patients with hypertension. Each patient provided a complete medical history and underwent a physical examination. We used an implantable cardiac monitor over a 3-year follow-up period to evaluate the effects of high-intensity interval training (HIIT) and moderate exercise (ModEx) physical activity protocols on AF occurrence, and determined the effectiveness of these protocols in improving renal function. Subjects were followed up every 6 months after the beginning of the intervention. Results: During the 3-year follow-up, AF onset was higher in CKD patients who engaged in HIIT (72%) than in those who engaged in ModEx (24%) (hazard ratio, 3.847; 95% confidence interval, 1.694–8.740, P = 0.0013 by log-rank test). Both groups exhibited significant intra-group changes in the mean systolic 24-hour ambulatory blood pressure measurements (ABPM) between baseline and 12, 24, and 36 months. There were also significant differences in the mean systolic 24-hour ABPM between the groups at the same time points. Conclusion: In CKD patients with hypertension, improvements in AF onset, renal function and some echocardiographic parameters were more evident in subjects who engaged in ModEx than in those who engaged in HIIT during 3 years of follow-up.

Introduction. Tuberculosis is a major cause of morbidity and mortality especially in high HIV burden settings. Active case finding is one strategy to potentially reduce TB disease burden. Xpert MTB/Rif has recently been recommended for diagnosis of TB. Methods. Pragmatic randomized trial to compare diagnosis rate and turnaround time for laboratory testing for Xpert MTB/Rif with TB microscopy and culture in household contacts of patients recently diagnosed with TB. Results. 2464 household contacts enrolled into the study from 768 active TB index cases. 1068 (44%) were unable to give sputum, but 24 of these were already on TB treatment. 863 (53%) participants sputum samples were tested with smear and culture and 2.7% (23/863; CI: 1.62–3.78) were diagnosed with active TB. Xpert MTB/Rif was used in 515 (21%) participants; active TB was diagnosed in 1.6% (8/515; CI: 0.52–2.68). Discussion and Conclusions. Additional 31 cases were diagnosed with contact tracing of household members. When Xpert MTB/Rif is compared with culture, there is no significant difference in diagnostic yield.

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.

[This corrects the article DOI: 10.1038/ncomms15855.].

Background: Leptomeningeal metastases occur across multiple solid and lymphoid cancers, and patients typically undergo cytopathologic assessment of cerebrospinal fluid (CSF) in this setting. For patients diagnosed with metastatic cancer, the detection of actionable somatic mutations in CSF can provide clinically valuable information for treatment without the need for additional tissue collection. Methods: The authors validated a targeted next‐generation sequencing assay for the detection of somatic variants in cancer (OncoPanel) on cell‐free DNA (cfDNA) isolated from archival CSF specimens in a cohort of 25 patients who had undergone molecular testing of a prior tumor specimen. Results: CSF storage time and volume had no impact on cfDNA concentration or mean target coverage of the assay. Previously identified somatic variants in CSF cfDNA were detected in 88%, 50%, and 27% of specimens diagnosed cytologically as positive, suspicious/atypical, and negative for malignancy, respectively. Somatic variants were identified in 81% of CSF specimens from patients who had leptomeningeal enhancement on magnetic resonance imaging compared with 31% from patients without such enhancement. Conclusions: These data highlight the stability of cfDNA in CSF, which allows for cytopathologic evaluation before triage for next‐generation sequencing assays. For a subset of cases in which clinical suspicion is high but cytologic or radiographic studies are inconclusive, the detection of pathogenic somatic variants in CSF cfDNA may aid in the diagnosis of leptomeningeal metastases. This study demonstrates the utility of cell‐free DNA from archival cerebrospinal fluid for the identification of targetable pathogenic tumor variants in patients undergoing cytopathologic assessment for suspected leptomeningeal metastases. The presence of pathogenic tumor variants correlates with cytopathologic and radiographic findings. [ABSTRACT FROM AUTHOR]

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder in which blood glucose level remains persistently higher than the physiologically normal range. Two important genes, namely fat mass and obesity-related gene (FTO) and Leptin (LEP), are involved with obesity and progression to diabetes. The aim of this study is to identify the underlying genetic make-up that predisposes individuals to T2DM, namely, rs9939609 and rs7799039 variants of FTO and LEP genes, respectively, were analyzed in a subset of the Bangladeshi population. DNA samples were collected from Blood samples, and the genetic polymorphisms were identified using allele-specific polymerase chain reactions (AS-PCR). The data collected by a standard questionnaire were then analyzed by SPSS for Windows. A total of 257 Bangladeshi individuals were included in the study, among whom 158 were T2DM patients, and 99 were non-diabetic healthy controls. Logistic regression analysis showed that the homozygous FTO rs9939609 variant genotype is significantly associated with type 2 diabetes (P=0.006) in the Bangladeshi population. Meanwhile, the Leptin rs7799039 variant is significantly associated with T2DM in males (P=0.006) but not in females. No association was observed for these variants with body mass index (BMI) and hypertension. The inheritance model analyses showed that the FTO co-dominant, dominant and recessive models are associated with T2D. The study revealed that the FTO rs9939609 variants have a significant role, and Leptin rs7799039 variants have a male-specific effect on T2D of Bangladeshi subjects. [ABSTRACT FROM AUTHOR]

Aims: The invasive pattern in HPV‐associated endocervical adenocarcinoma (HPVA) has prognostic value. Non‐destructive (pattern A) HPVA has excellent prognosis mirroring adenocarcinoma in‐situ (AIS). However, the rare occurrence of ovarian spread in these tumours suggests aggressiveness in a subset of patients with these otherwise indolent lesions. We hypothesise that AIS/pattern A HPVA with ovarian metastases are biologically different than metastatic destructively invasive HPVA. Methods and results: Samples from patients with HPVA and synchronous or metachronous metastases were retrieved and reviewed to confirm diagnosis and determine the Silva pattern in the primary lesion. For each case, normal tissue, cervical tumour and at least one metastasis underwent comprehensive sequencing using a 447‐gene panel. Pathogenic single‐nucleotide variants and segmental copy‐number alterations (CNA), tumour mutational burden and molecular signatures were evaluated and compared between primary and metastases and among invasive pattern categories. We identified 13 patients: four had AIS/pattern A primaries, while nine had pattern B/C tumours. All AIS/pattern A lesions had metastasis only to ovary; 50% of patients with ovarian involvement, regardless of invasive pattern, also had involvement of the endometrium and/or fallopian tube mucosa by HPVA. In the ovary, AIS/pattern A HPVA showed deceptive well‐differentiated glands, often with adenofibroma‐like appearance. Conversely, pattern C HPVAs consistently showed overt infiltrative features in the ovary. Sequencing confirmed the genetic relationship between primary and metastatic tumours in each case. PIK3CA alterations were identified in three of four AIS/pattern A HPVAs and three of eight pattern B/C tumours with sequenced metastases. Pattern C tumours showed a notably higher number of CNA in primary tumours compared to pattern A/B tumours. Only one metastatic AIS/pattern A HPVA had a novel pathogenic variant compared to the primary. Conversely, five of eight pattern B/C tumours with sequenced metastases developed novel pathogenic variants in the metastasis not seen in the primary. All four AIS/pattern A patients were alive and free of disease at 31, 47, 58 and 212 months after initial diagnosis. Conversely, cancer‐related death was documented in five of nine pattern B/C patients with follow‐up at 7, 20, 20, 43 and 87 months. Conclusion: Morphologically and genomically, AIS/pattern A HPVA with secondary ovarian involvement appears distinct from destructively invasive tumours. In at least a subset of these cases, ovarian spread appears to occur via trans‐Mullerian superficial extension, different from the stromal and lymphatic vascular spread typical of more aggressive tumours (pattern C). These differences may explain the indolent outcome observed in the rare subset of patients with AIS/pattern A HPVA and ovarian metastasis. Our data underscore the potential for conservative surgical management approaches to pattern A HPVA. [ABSTRACT FROM AUTHOR]