Author Correction: New infant cranium from the African Miocene sheds light on ape evolution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Biochronology of South African hominin-bearing sites: A reassessment using cercopithecid primates.

Despite recent advances in chronometric techniques (e.g., Uranium-Lead [U-Pb], cosmogenic nuclides, electron spin resonance spectroscopy [ESR]), considerable uncertainty remains regarding the age of many Plio-Pleistocene hominin sites, including several in South Africa. Consequently, biochronology remains important in assessments of Plio-Pleistocene geochronology and provides direct age estimates of the fossils themselves. Historically, cercopithecid monkeys have been among the most useful taxa for biochronology of early hominins because they are widely present and abundant in the African Plio-Pleistocene record. The last major studies using cercopithecids were published over 30 y ago. Since then, new hominin sites have been discovered, radiometric age estimates have been refined, and many changes have occurred in cercopithecid taxonomy and systematics. Thus, a biochronological reassessment using cercopithecids is long overdue. Here, we provide just such a revision based on our recent study of every major cercopithecid collection from African Plio-Pleistocene sites. In addition to correlations based on shared faunal elements, we present an analysis based on the dentition of the abundant cercopithecid Theropithecus oswaldi, which increases in size in a manner that is strongly correlated with geological age (r2 ∼0.83), thereby providing a highly accurate age-estimation tool not previously utilized. In combination with paleomagnetic and U-Pb data, our results provide revised age estimates and suggest that there are no hominin sites in South Africa significantly older than ∼2.8 Ma. Where conflicting age estimates exist, we suggest that additional data are needed and recall that faunal estimates have ultimately proved reliable in the past (e.g., the age of the KBS Tuff).

Cytomegalovirus antiviral resistance among participants in the phase 3 trial of letermovir vs valganciclovir prophylaxis in kidney transplant recipients.

BACKGROUND: In a phase 3 trial, letermovir was non-inferior to valganciclovir for CMV disease prophylaxis in CMV-seronegative (R-) kidney transplant recipients (KTRs) who received a kidney from a CMV-seropositive donor (D+). Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported. METHODS: Plasma samples with detectable CMV DNA were sequenced for presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL56, UL89, UL54, UL97) and prevalence of gB (UL55) genotypes (gB1-gB5). RESULTS: 84 of 292 participants in the letermovir and 93 of 297 in the valganciclovir group had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants in the valganciclovir group had valganciclovir RASs (pUL54, pUL97); and 1 who did not receive letermovir during the trial also had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups. CONCLUSION: Letermovir RASs were not detected in the letermovir group, supporting a low risk for development of resistance with letermovir prophylaxis in CMV D+R- KTRs. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT03443869, EudraCT: 2017-001055-30.

A Multicenter, Single-Arm, Prospective Trial Assessing the Diagnostic Yield of Electromagnetic Bronchoscopic and Transthoracic Navigation for Peripheral Pulmonary Nodules.

Rationale: Strict adherence to procedural protocols and diagnostic definitions is critical to understand the efficacy of new technologies. Electromagnetic navigational bronchoscopy (ENB) for lung nodule biopsy has been used for decades without a solid understanding of its efficacy, but offers the opportunity for simultaneous tissue acquisition via electromagnetic navigational transthoracic biopsy (EMN-TTNA) and staging via endobronchial ultrasound (EBUS). Objective: To evaluate the diagnostic yield of EBUS, ENB, and EMN-TTNA during a single procedure using a strict a priori definition of diagnostic yield with central pathology adjudication. Methods: A prospective, single-arm trial was conducted at eight centers enrolling participants with pulmonary nodules (<3 cm; without computed tomography [CT]- and/or positron emission tomography-positive mediastinal lymph nodes) who underwent a staged procedure with same-day CT, EBUS, ENB, and EMN-TTNA. The procedure was staged such that, when a diagnosis had been achieved via rapid on-site pathologic evaluation, the procedure was ended and subsequent biopsy modalities were not attempted. A study finding was diagnostic if an independent pathology core laboratory confirmed malignancy or a definitive benign finding. The primary endpoint was the diagnostic yield of the combination of CT, EBUS, ENB, and EMN-TTNA. Measurements and Main Results: A total of 160 participants at 8 centers with a mean nodule size of 18 ± 6 mm were enrolled. The diagnostic yield of the combined procedure was 59% (94 of 160; 95% confidence interval [CI], 51-66%). Nodule regression was found on same-day CT in 2.5% of cases (4 of 160; 95% CI, 0.69-6.3%), and EBUS confirmed malignancy in 7.1% of cases (11 of 156; 95% CI, 3.6-12%). The yield of ENB alone was 49% (74 of 150; 95% CI, 41-58%), that of EMN-TTNA alone was 27% (8 of 30; 95% CI, 12-46%), and that of ENB plus EMN-TTNA was 53% (79 of 150; 95% CI, 44-61%). Complications included a pneumothorax rate of 10% and a 2% bleeding rate. When EMN-TTNA was performed, the pneumothorax rate was 30%. Conclusions: The diagnostic yield for ENB is 49%, which increases to 59% with the addition of same-day CT, EBUS, and EMN-TTNA, lower than in prior reports in the literature. The high complication rate and low diagnostic yield of EMN-TTNA does not support its routine use. Clinical trial registered with www.clinicaltrials.gov (NCT03338049).

Implications of outgroup selection in the phylogenetic inference of hominoids and fossil hominins.

Understanding the phylogenetic relationships among hominins and other hominoid species is critical to the study of human origins. However, phylogenetic inferences are dependent on both the character data and taxon sampling used. Previous studies of hominin phylogenetics have used Papio and Colobus as outgroups in their analyses; however, these extant monkeys possess many derived traits that may confound the polarities of morphological changes among living apes and hominins. Here, we consider Victoriapithecus and Ekembo as more suitable outgroups. Both Victoriapithecus and Ekembo are anatomically well known and are widely accepted as morphologically primitive stem cercopithecoid and hominoid taxa, respectively, making them more appropriate for inferring polarity for later-occurring hominoid- and hominin-focused analyses. Craniodental characters for both taxa were scored and then added to a previously published matrix of fossil hominin and extant hominoid taxa, replacing outgroups Papio and Colobus over a series of iterative analyses using both parsimony and Bayesian inference methods. Neither the addition nor replacement of outgroup taxa changed tree topology in any analysis. Importantly, however, bootstrap support values and posterior probabilities for nodes supporting their relationships generally increased compared to previous analyses. These increases were the highest at extant hominoid and basal hominin nodes, recovering the molecular ape phylogeny with considerably higher support and strengthening the inferred relationships among basal hominins. Interestingly, however, the inclusion of both extant and fossil outgroups reduced support for the crown hominid node. Our findings suggest that, in addition to improving character polarity estimation, including fossil outgroups generally strengthens confidence in relationships among extant hominoid and basal hominins.

New infant cranium from the African Miocene sheds light on ape evolution.

The evolutionary history of extant hominoids (humans and apes) remains poorly understood. The African fossil record during the crucial time period, the Miocene epoch, largely comprises isolated jaws and teeth, and little is known about ape cranial evolution. Here we report on the, to our knowledge, most complete fossil ape cranium yet described, recovered from the 13 million-year-old Middle Miocene site of Napudet, Kenya. The infant specimen, KNM-NP 59050, is assigned to a new species of Nyanzapithecus on the basis of its unerupted permanent teeth, visualized by synchrotron imaging. Its ear canal has a fully ossified tubular ectotympanic, a derived feature linking the species with crown catarrhines. Although it resembles some hylobatids in aspects of its morphology and dental development, it possesses no definitive hylobatid synapomorphies. The combined evidence suggests that nyanzapithecines were stem hominoids close to the origin of extant apes, and that hylobatid-like facial features evolved multiple times during catarrhine evolution.

Sleep movements and respiratory coupling as a biobehavioral metric for early Alzheimer's disease in independently dwelling adults.

INTRODUCTION: Sleep disorder is often the first symptom of age-related cognitive decline associated with Alzheimer's disease (AD) observed in primary care. The relationship between sleep and early AD was examined using a patented sleep mattress designed to record respiration and high frequency movement arousals. A machine learning algorithm was developed to classify sleep features associated with early AD. METHOD: Community-dwelling older adults (N = 95; 62-90 years) were recruited in a 3-h catchment area. Study participants were tested on the mattress device in the home bed for 2 days, wore a wrist actigraph for 7 days, and provided sleep diary and sleep disorder self-reports during the 1-week study period. Neurocognitive testing was completed in the home within 30-days of the sleep study. Participant performance on executive and memory tasks, health history and demographics were reviewed by a geriatric clinical team yielding Normal Cognition (n = 45) and amnestic MCI-Consensus (n = 33) groups. A diagnosed MCI group (n = 17) was recruited from a hospital memory clinic following diagnostic series of neuroimaging biomarker assessment and cognitive criteria for AD. RESULTS: In cohort analyses, sleep fragmentation and wake after sleep onset duration predicted poorer executive function, particularly memory performance. Group analyses showed increased sleep fragmentation and total sleep time in the diagnosed MCI group compared to the Normal Cognition group. Machine learning algorithm showed that the time latency between movement arousals and coupled respiratory upregulation could be used as a classifier of diagnosed MCI vs. Normal Cognition cases. ROC diagnostics identified MCI with 87% sensitivity; 89% specificity; and 88% positive predictive value. DISCUSSION: AD sleep phenotype was detected with a novel sleep biometric, time latency, associated with the tight gap between sleep movements and respiratory coupling, which is proposed as a corollary of sleep quality/loss that affects the autonomic regulation of respiration during sleep. Diagnosed MCI was associated with sleep fragmentation and arousal intrusion.

Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial.

Importance: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression. Objective: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. Design, Setting, and Participants: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022). Interventions: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos. Main Outcomes and Measures: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome. Results: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%). Conclusion and Relevance: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

A new species of fossil guenon (Cercopithecini, Cercopithecidae) from the Early Pleistocene Lower Ngaloba Beds, Laetoli, Tanzania.

The living guenons (Cercopithecini, Cercopithecidae) are speciose and widely distributed across sub-Saharan Africa but are poorly represented in the fossil record. In addition, the craniodental and skeletal similarity of the guenons has hampered the identification of fragmentary material, likely obscuring the taxonomic diversity represented in the fossil record. Here, we describe a new fossil guenon specimen (LAET 75-3703) from the Lower Ngaloba Beds, Laetoli in Tanzania, dated to ∼1.7-1.2 Ma and preserving the lower face and mandible. Comparison to 278 extant guenon specimens, representing all six extant genera, identified several informative traits for distinguishing between the morphologically similar Chlorocebus and Cercopithecus, and these support the attribution of LAET 75-3703 to Chlorocebus. A discriminant function analysis of seven craniodental indices on a subsample of Chlorocebus and Cercopithecus was robust with an overall correct classification rate of 80.4%, and it classified LAET 75-3703 as a member of Chlorocebus with a posterior probability of 92.7%. LAET 75-3703 shares with Chlorocebus the presence of small 'thumbprint' depressions on the maxilla; a tall, narrow, and diamond-shaped nasal aperture; a relatively longer and shallower face; relatively buccolingually broader molars; and a shallow mandible that decreases in depth posteriorly. In addition, LAET 75-3703 is distinguished from all extant guenons, including other species of Chlorocebus, in having a very small P3 relative to M1 area. As such, LAET 75-3703 is assigned to a new species, Chlorocebus ngedere sp. nov. This specimen represents the first cercopithecin from Laetoli, as well as the oldest fossil cercopithecin confidently attributed to a modern genus.

Clarification of acid site location in MSE-type zeolites by spectroscopic approaches combined with catalytic activity: comparison between UZM-35 and MCM-68.

MSE-type zeolites synthesized by different organic structure-directing agents (OSDAs), UZM-35 and MCM-68, were prepared. The location of Brønsted acid sites derived from the framework Al atoms and acidic properties were investigated based on 27Al MQMAS NMR and in situ IR techniques combined with the evaluation of the catalytic activity. We have successfully found a significant difference in the location of Brønsted acid sites in the MSE-type framework; 61 and 33% of acid sites were located at the 12-ring channel for MCM-68 and UZM-35, respectively. The differences in the location of the acid sites yielded their unique catalytic activities for the hydrocarbon cracking reactions, indicating that a well-chosen type of OSDAs for the synthesis is one of the possibilities for controlling the distribution of the framework Al atoms in the MSE-type framework.

Utilization of palliative care resource remains low, consuming potentially avoidable hospital admissions in stage IV non-small cell lung cancer: a community-based retrospective review.

PURPOSE: Early referral of patients with stage IV non-small cell lung cancer (NSCLC) to outpatient palliative care has been shown to increase survival and reduce unnecessary healthcare resource utilization. We aimed to determine outpatient palliative care referral rate and subsequent resource utilization in patients with stage IV NSCLC in a multistate, community-based hospital network and identify rates and reasons for admissions within a local healthcare system of Washington State. METHODS: A retrospective chart review of a multistate hospital network and a local healthcare system. Patients were identified using ICD billing codes. In the multistate network, 2844 patients diagnosed with stage IV NSCLC between January 1, 2013, and March 1, 2018, were reviewed. In the state healthcare system, 283 patients between August 2014 and June 2017 were reviewed. RESULTS: Referral for outpatient palliative care was low: 8% (217/2844) in the multistate network and 11% (32/283) in the local healthcare system. Early outpatient palliative care (6%, 10/156) was associated with a lower proportion of patients admitted into the intensive care unit in the last 30 days of life compared to no outpatient palliative care (15%, 399/2627; p = 0.003). Outpatient palliative care referral was associated with improved overall survival in Kaplan Meier survival analysis. Within the local system, 51% (104/204) of admissions could have been managed in outpatient setting, and of the patients admitted in the last 30 days of life, 59% (87/147) experienced in-hospital deaths. CONCLUSION: We identified underutilization of outpatient palliative care services within stage IV NSCLC patients. Many patients with NSCLC experience hospitalization the last month of life and in-hospital death.

Morphological analysis of new Dryas Monkey specimens from the Central Congo Basin: Taxonomic considerations and an emended diagnosis.

OBJECTIVES: The little known guenon Cercopithecus dryas has a controversial taxonomic history with some recognizing two taxa (C. dryas and C. salongo) instead of one. New adult specimens from the TL2 region of the central Congo Basin allow further assessment of C. dryas morphology and, along with CT scans of the juvenile holotype, provide ontogenetically stable comparisons across all C. dryas and "C. salongo" specimens for the first time. MATERIALS AND METHODS: The skins and skulls of two newly acquired C. dryas specimens, male YPM MAM 16890 and female YPM MAM 17066, were compared to previously described C. dryas and "C. salongo" specimens, along with a broader guenon comparative sample (cranial sample n = 146, dental sample n = 102). Qualitative and quantitative assessments were made on the basis of commonly noted pelage features as well as craniodental characters in the form of shape ratios and multivariate discriminant analyses. RESULTS: All C. dryas specimens, including the TL2 adults, are comparatively small in overall cranial size, have relatively small I1 s, and display tall molar cusps; these osteological characters, along with pelage features, are shared with known "C. salongo" specimens. Discriminant analyses of dental features separate C. dryas/salongo specimens from all other guenons. DISCUSSION: In addition to pelage-based evidence, direct osteological evidence suggests "C. salongo" is a junior synonym of C. dryas. Combined with molecular analyses suggesting C. dryas is most closely related to Chlorocebus spp., we emend the species diagnosis and support its transfer to Chlorocebus or possibly a new genus to reflect its distinctiveness.

Cumulative radiation dose incurred during the management of complex pleural space infection.

BACKGROUND: Complex pleural space infections are commonly managed with antibiotics, pleural drainage, intrapleural fibrinolytic therapy, and surgery. These strategies often utilize radiographic imaging during management, however little data is available on cumulative radiation exposure received during inpatient management. We aimed to identify the type and quantity of radiographic studies along with the resultant radiation exposure during the management of complex pleural space infections. METHODS: Retrospective review of community network healthcare system from January 2015 to July 2018. Patients were identified through billing databases as receiving intrapleural fibrinolytic therapy and/or surgical intervention. Patient demographics, clinical outcomes, and inpatient radiographic imaging was collected to calculate cumulative effective dose. RESULTS: A total of 566 patients were identified with 7275 total radiographic studies performed and a median cumulative effective dose of 16.9 (IQR 9.9-26.3) mSv. Multivariable linear regression analysis revealed computed tomography use was associated with increased cumulative dose, whereas increased age was associated with lower cumulative dose. Over 74% of patients received more than 10 mSv, with 7.4% receiving more than 40 mSv. CONCLUSIONS: The number of radiographic studies and overall cumulative effective dose in patients hospitalized for complex pleural space infection was high with the median cumulative effective dose > 5 times normal yearly exposure. Ionizing radiation and modern radiology techniques have revolutionized medical care, but are likely not without risk. Additional study is warranted to identify the frequency and imaging type needed during complex pleural space infection management, attempting to keep ionizing radiation exposure as low as reasonably possible.

Quantification of the Mean and Distribution of Hemoglobin Content in Normal Human Blood Using Cell Tracking Velocimetry.

The current clinical method for detecting anemia focuses on measuring the concentration of hemoglobin (Hb) in blood. However, recent developments in particle tracking algorithms and the understanding of the relationship between Hb and magnetism has enabled the quantitative measurement of the Hb content in a single red blood cell, RBC, based on magnetophoretic mobility. To further explore this relationship, 22 human blood samples obtained from 17 healthy volunteers were analyzed by the cell tracking velocimetry system, and the calculated Hb concentration from these measurements was compared to the values measured by UV-visible spectrophotometry, the standard method for measuring Hb in clinical laboratories. The results show close correlations between the mean of the spectrophotometric and magnetophoretic methods; however, single cell analysis with the magnetophoretic mobility method allows further elucidation of the distribution of Hb concentration within RBCs from a donor sample to be determined. Histograms of these magnetophoretic mobility distributions indicate that the fraction of RBCs that are below the bulk Hb concentration that defines anemia varies not only from donor to donor but also in the same donor over time. Consistent with a variable fraction below the anemic Hb concentration, the distribution around the mean has a large range. Previous studies have indicated that RBCs lose Hb during ex vivo storage; however, it is not known if this variability in the distribution of Hb content is a function of the age of the RBCs in a donor, suggesting a variable rate in RBC production between donors, or variability in available iron at the time of RBC formation. We suggest our cell tracking velocimetry system can reveal more information regarding this matter.

New Middle Miocene Ape (Primates: Hylobatidae) from Ramnagar, India fills major gaps in the hominoid fossil record.

The fossil record of 'lesser apes' (i.e. hylobatids = gibbons and siamangs) is virtually non-existent before the latest Miocene of East Asia. However, molecular data strongly and consistently suggest that hylobatids should be present by approximately 20 Ma; thus, there are large temporal, geographical, and morphological gaps between early fossil apes in Africa and the earliest fossil hylobatids in China. Here, we describe a new approximately 12.5-13.8 Ma fossil ape from the Lower Siwaliks of Ramnagar, India, that fills in these long-standing gaps with implications for hylobatid origins. This ape represents the first new hominoid species discovered at Ramnagar in nearly a century, the first new Siwalik ape taxon in more than 30 years, and likely extends the hylobatid fossil record by approximately 5 Myr, providing a minimum age for hylobatid dispersal coeval to that of great apes. The presence of crown hylobatid molar features in the new species indicates an adaptive shift to a more frugivorous diet during the Middle Miocene, consistent with other proposed adaptations to frugivory (e.g. uricase gene silencing) during this time period as well.

Skeletal morphology of the lesula (Cercopithecus lomamiensis) and the evolution of guenon locomotor behavior.

OBJECTIVES: The guenons (tribe Cercopithecini) are a diverse and primarily arboreal radiation of Old World monkeys from Africa. However, preliminary behavioral observations of the lesula (Cercopithecus lomamiensis), a little-known guenon species described in 2012, report it spending substantial amounts of time on the ground. New specimens allow us to present the first description of lesula postcranial morphology and apply a comparative functional morphology approach to supplement our knowledge of its locomotor behavior. MATERIALS AND METHODS: To infer the substrate use preferences of the lesula, 22 postcranial variables correlated with locomotion were assessed in a sample of 151 adult guenon specimens, including two C. lomamiensis. Using multivariate statistical analyses, we predict the amount of time the lesula spends on the ground relative to the comparative sample. RESULTS: Results suggest that the lesula spends nearly half its time on the ground, and the two available individuals were classified as semiterrestrial and terrestrial with strong support. Comparisons with two outgroup cercopithecid taxa (Colobus guereza and Macaca mulatta) demonstrate that, as a group, guenons retain signals of a generalized, semiterrestrially adapted postcranium compared to specialized arboreal cercopithecids. DISCUSSION: These results corroborate preliminary behavioral observations of the lesula as a semiterrestrial to terrestrial primate and imply multiple evolutionary transitions in substrate use among the guenon radiation. A broader view of cercopithecoid evolution suggests that a semiterrestrial ancestor for extant guenons is more parsimonious than an arboreal one, indicating that the arboreal members of the group are probably recently derived from a more semiterrestrial ancestor.

Epitranscriptomics in the Heart: a Focus on m6A.

PURPOSE OF REVIEW: Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (m6A), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of m6A's involvement in cardiac pathologies and processes. RECENT FINDINGS: Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the m6A modification. Results have revealed a multifaceted role for m6A in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of m6A in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by m6A is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.

Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial.

Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).

Particle size, distribution, and behavior of talc preparations: within the United States and beyond.

PURPOSE OF REVIEW: Talc remains a common sclerosant utilized for pleurodesis. However, the use of talc has documented complications and debate has persisted regarding the safety of talc as well as the differences in talc preparations available throughout the world. We sought to describe an up-to-date review of talc preparations available and the impact these preparations may have on the safety profile of talc. RECENT FINDINGS: Within laboratory-based examinations, talc particle size available within the United States appears to be more consistent with prior reported 'safe' particle sizes. The presence of talc within protein-based solutions appears to modify the overall milieu of the solution and likely results in particle aggregation. SUMMARY: The use of talc remains well accepted for pleurodesis as evidenced by inclusion by multiple guidelines. The medical fields' current understanding of talc and its basic interactions within the pleural space remain limited. Multiple questions related to the pleural space and pleurodesis remain unanswered.