Elliptio complanata (Eastern Elliptio) is typically an abundant species in lotic systems throughout the northeastern US; however, as with many other freshwater mussel species, some populations of ...Eastern Elliptio are in decline. Freshwater mussels have complex life cycles, which are important to understand for their conservation and management. The goal of this study was to determine the timing of Eastern Elliptio spawning, brooding, and glochidia release. Throughout the spawning season, we used gonad and gill extracts and drift nets to track the timing of reproduction in Otego Creek, NY, a tributary to the Susquehanna River. Females began brooding fertilized eggs by mid-May, and by early June, all females collected were brooding fertilized eggs or d-shaped glochidia. The temperature was 18 °C when all females contained glochidia. Peak glochidia-drift occurred ∼1 week after we recorded the highest levels of brooding and continued at low levels for several weeks. Phenology modeling helped us to determine that accumulated thermal units was the best predictor of reproductive activity. Our work highlights the environmental cues responsible for spawning, brooding, and glochidia release in a population of Eastern Elliptio. This empirical approach to predicting reproductive activity has great potential as a tool for timing the collection of brood stock for propagation or other important conservation measures.
Ecological intensification of agriculture (EI) aims to conserve and promote biodiversity and the sustainable use of associated ecosystem services to support resourceâefficient production. In many ...cases EI requires fundamental changes in farm and landscape management as well as the organizations and institutions that support agriculture. Ecologists can facilitate EI by engaging with stakeholders and, in the process, by generating âactionable knowledgeâ (that is, knowledge that specifically supports stakeholder decision making and consequent actions). Using three case studies as examples, we propose four principles whereby science can improve the delivery of actionable knowledge for EI: (1) biodiversity conservation helps to ensure the delivery of ecosystem services, (2) management of ecosystem services benefits from a landscapeâscale approach, (3) ecosystem service tradeâoffs and synergies need to be articulated, and (4) EI is associated with complex social dynamics involving farmers, governments, researchers, and related institutions. These principles have the potential to enhance adoption of EI, but institutional and policy challenges remain.
The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg ...(n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.
Molecular assays can provide critical information for malaria diagnosis, speciation, and drug resistance, but their cost and resource requirements limit their application to clinical malaria studies. ...This study describes the application of a resource-conserving testing algorithm employing sample pooling for real-time PCR assays for malaria in a cohort of 182 pregnant women in Kinshasa. A total of 1,268 peripheral blood samples were collected during the study. Using a real-time PCR assay that detects all Plasmodium species, microscopy-positive samples were amplified individually; the microscopy-negative samples were amplified after pooling the genomic DNA (gDNA) of four samples prior to testing. Of 176 microscopy-positive samples, 74 were positive by the real-time PCR assay; the 1,092 microscopy-negative samples were initially amplified in 293 pools, and subsequently, 35 samples were real-time PCR positive (3%). With the real-time PCR result as the referent standard, microscopy was 67.9% sensitive (95% confidence interval CI, 58.3% to 76.5%) and 91.2% specific (95% CI, 89.4% to 92.8%) for malaria. In total, we detected 109 parasitemias by real-time PCR and, by pooling samples, obviated over 50% of reactions and halved the cost of testing. Our study highlights both substantial discordance between malaria diagnostics and the utility and parsimony of employing a sample pooling strategy for molecular diagnostics in clinical and epidemiologic malaria studies.
Sweat glands in rat footpads contain a neuronal differentiation activity that switches the phenotype of sympathetic neurons from noradrenergic to cholinergic during normal development in vivo. ...Extracts of developing and adult sweat glands induce changes in neurotransmitter properties in cultured sympathetic neurons that mimic those observed in vivo. We have characterized further the factors present in the extract and compared their properties to those of known cholinergic factors. When assayed on cultured rat sympathetic neurons, the major activities in footpad extracts from postnatal day 21 rat pups that induce choline acetyltransferase (ChAT) and vasoactive intestinal peptide (VIP) and reduce catecholamines and neuropeptide Y (NPY) are associated with a soluble protein of 22-26 x 10(3) M(r) and a pI of 5.0. These properties are similar to those of ciliary neurotrophic factor (CNTF). Moreover, the purified fraction from footpads has ciliary neurotrophic activity. Antibodies to CNTF that immunoprecipitate all differentiation activity from sciatic nerve extracts, a rich source of CNTF, immunoprecipitate 80% of the cholinergic activity in the footpad extracts, 50% of the VIP and 20% of the NPY activities. Neither CNTF protein nor CNTF mRNA, however, can be detected in immunoblot and northern analysis of footpads even though both CNTF protein and mRNA are evident in sciatic nerve. CNTF-immunoreactivity is associated with a sparse plexus of sensory fibers in the footpad but not with sweat glands or the Schwann cells associated with them. In addition, in situ hybridization studies with oligonucleotide probes failed to reveal CNTF mRNA in sweat glands. Comparison of the sweat gland differentiation activity with the cholinergic differentiation factor from heart cells (CDF; also known as leukemia inhibitory factor or LIF) suggests that most of the cholinergic activity in foot pads is biochemically distinct from CDF/LIF. Further, antibodies that block the activity of CDF/LIF purified from heart-cell-conditioned medium do not block the ChAT-inducing activity present in footpad extracts of postnatal day 8 animals. A differentiation factor isolated from skeletal muscle did not induce cholinergic properties in sympathetic neuron cultures and therefore is unlikely to be the cholinergic differentiation factor produced by sweat glands. Taken together, our data suggest that there are at least two differentiation molecules present in the extracts and that the major cholinergic activity obtained from footpads is related to, but distinct from, CNTF. The second factor remains to be characterized. In addition, CNTF associated with sensory fibers may make a minor contribution to the cholinergic inducing activity present in the extract.
Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a ...hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis.
We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes.
There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (−0.21, −0.45, −0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 76%) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg median, p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups.
Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated.
Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients.
Clinical Trials.gov #NCT02960204.
Display omitted
•Phase III trial comparing emricasan vs. placebo in patients with NASH-related cirrhosis and severe portal hypertension.•Despite evidence of target engagement, emricasan did not reduce portal hypertension in the overall study population.•The portal pressure-reducing effect may be more evident in latter stages of portal hypertension.•Treatment-emergent adverse events were similar between emricasan and placebo.
The demand for orthotopic liver transplantation (OLT) is projected to increase, which indicates a need to expand the liver donor pool. We aimed to investigate the use of hepatitis B virus ...(HBV)-positive grafts and the outcomes of recipients undergoing OLT with HBV-positive grafts. We conducted a retrospective cohort study analyzing all deceased donors and OLT recipients in the Organ Procurement and Transplantation Network database from January 1999 through March 2021. Donor HBV status was positive if hepatitis B surface antigen was positive or HBV nucleic acid testing was detectable. Recipients of HBV-positive allografts were matched 1:5 to recipients of HBV-negative allografts based on recipient and donor age, transplant year, recipient sex, donation after circulatory death, recipient location, and Model for End-Stage Liver Disease score at transplant. Among the 185,212 potential donors, 422 (0.2%) were HBV positive, and 265 (63%) of the HBV-positive grafts were transplanted (14 of 265 5.3% in HBV-positive recipients). The overall discard rate for HBV-positive donors of 37.2% (157/422) remained significantly higher than the discard rate for HBV-negative donors of 26.5% (49,026/185,212) during the study period ( p < 0.001). Recipients of HBV-positive ( n = 209) grafts had similar mortality (log-rank, p = 0.47) and graft loss (log-rank, p = 0.72) rates to the matched recipients of HBV-negative allografts ( n = 1045). The 3-year graft survival rate was 77.9% for the HBV-positive group and 79.7% in the matched HBV-negative group. Based on this analysis, transplant recipients of HBV-positive liver allografts do not experience increased rates of mortality or graft loss. One strategy that may help expand the donor pool and lower the waitlist mortality rate is using HBV-positive allografts.
To examine whether an Internet-based learning module and small-group debriefing can improve medical trainees' attitudes and communication skills toward patients with substance use disorders (SUDs).
...In 2011-2012, 129 internal and family medicine residents and 370 medical students at two medical schools participated in a cluster randomized controlled trial, which assessed the effect of adding a two-part intervention to the SUDs curricula. The intervention included a self-directed, media-rich Internet-based learning module and a small-group, faculty-led debriefing. Primary study outcomes were changes in self-assessed attitudes in the intervention group (I-group) compared with those in the control group (C-group) (i.e., a difference of differences). For residents, the authors used real-time, Web-based interviews of standardized patients to assess changes in communication skills. Statistical analyses, conducted separately for residents and students, included hierarchical linear modeling, adjusted for site, participant type, cluster, and individual scores at baseline.
The authors found no significant differences between the I- and C-groups in attitudes for residents or students at baseline. Compared with those in the C-group, residents, but not students, in the I-group had more positive attitudes toward treatment efficacy and self-efficacy at follow-up (P<.006). Likewise, compared with residents in the C-group, residents in the I-group received higher scores on screening and counseling skills during the standardized patient interview at follow-up (P=.0009).
This intervention produced improved attitudes and communication skills toward patients with SUDs among residents. Enhanced attitudes and skills may result in improved care for these patients.
PDF
