We present a comprehensive simulation of tropospheric chlorine
within the GEOS-Chem global 3-D model of oxidant–aerosol–halogen atmospheric
chemistry. The simulation includes explicit accounting of ...chloride
mobilization from sea salt aerosol by acid displacement of HCl and by other
heterogeneous processes. Additional small sources of tropospheric chlorine
(combustion, organochlorines, transport from stratosphere) are also included.
Reactive gas-phase chlorine Cl*, including Cl, ClO, Cl2, BrCl, ICl,
HOCl, ClNO3, ClNO2, and minor species, is produced by the
HCl+OH reaction and by heterogeneous conversion of sea salt aerosol
chloride to BrCl, ClNO2, Cl2, and ICl. The model
successfully simulates the observed mixing ratios of HCl in marine air
(highest at northern midlatitudes) and the associated HNO3
decrease from acid displacement. It captures the high ClNO2 mixing
ratios observed in continental surface air at night and attributes the
chlorine to HCl volatilized from sea salt aerosol and transported inland
following uptake by fine aerosol. The model successfully simulates the
vertical profiles of HCl measured from aircraft, where enhancements in the
continental boundary layer can again be largely explained by transport inland
of the marine source. It does not reproduce the boundary layer Cl2
mixing ratios measured in the WINTER aircraft campaign (1–5 ppt in the
daytime, low at night); the model is too high at night, which could be due to
uncertainty in the rate of the ClNO2+Cl- reaction, but we have
no explanation for the high observed Cl2 in daytime. The global
mean tropospheric concentration of Cl atoms in the model is 620 cm−3
and contributes 1.0 % of the global oxidation of methane, 20 % of
ethane, 14 % of propane, and 4 % of methanol. Chlorine chemistry
increases global mean tropospheric BrO by 85 %, mainly through the
HOBr+Cl- reaction, and decreases global burdens of tropospheric
ozone by 7 % and OH by 3 % through the associated bromine radical
chemistry. ClNO2 chemistry drives increases in ozone of up to
8 ppb over polluted continents in winter.
The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased
chemical library screen. The activity of APY0201 was confirmed in all 25 ...cell lines tested and in 40% of 100
patient-derived primary samples, with increased activity in primary samples harboring trisomies and lacking t(11;14). The broad anti-multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point half maximal effective concentration (EC
) at nanomolar concentrations in, respectively, 65%, 40%, and 5% of the tested cell lines. Upregulation of genes in the lysosomal pathway and increased cellular vacuolization were observed
following APY0201 treatment, although these cellular effects did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings indicate promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and suggest a strategy to enrich for likely responders.
Good quality cause of death (COD) information is fundamental for formulating and evaluating public health policy; yet most deaths in developing countries, including the Solomon Islands, occur at home ...without medical certification of cause of death (MCCOD). As a result, COD data in such contexts are often of limited use for policy and planning. Verbal autopsies (VAs) are a cost-effective way of generating reliable COD information in populations lacking comprehensive MCCOD coverage, but this method has not previously been applied in the Solomon Islands. This study describes the establishment of a VA system to estimate the cause specific mortality fractions (CSMFs) for community deaths that are not medically certified in the Solomon Islands.
Automated VA methods (SmartVA) were introduced into the Solomon Islands in 2016. Trained data collectors (nurses) conducted VAs on eligible deaths to December 2020 using electronic tablet devices and VA responses were analysed using the Tariff 2.0 automated diagnostic algorithm. CSMFs were generated for both non-inpatient deaths in hospitals (i.e. 'dead on/by arrival') and community deaths.
VA was applied to 914 adolescent-and-adult deaths with a median (IQR) age of 62 (45-75) years, 61% of whom were males. A specific COD could be diagnosed for more than 85% of deaths. The leading causes of death for both sexes combined were: ischemic heart disease (16.3%), stroke (13.5%), diabetes (8.1%), pneumonia (5.7%) and chronic-respiratory disease (4.8%). Stroke was the top-ranked cause for females, and ischaemic heart disease the leading cause for males. The CSMFs from the VAs were similar to Global Burden of Disease (GBD) estimates. Overall, non-communicable diseases (NCDs) accounted for 73% of adult deaths; communicable, maternal and nutritional conditions 15%, and injuries 12%. Six of the ten leading causes reported for facility deaths in the Solomon Islands were also identified as leading causes of community deaths based on the VA diagnoses.
NCDs are the leading cause of adult deaths in the Solomon Islands. Automated VA methods are an effective means of generating reliable COD information for community deaths in the Solomon Islands and should be routinely incorporated into the national mortality surveillance system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A growing emphasis on antibiotic stewardship has led to a significant amount of literature regarding antibiotic use in spine surgery for surgical prophylaxis and the treatment of spinal infections. ...Developing effective antibiotic prophylaxis regimens is a key strategy in limiting antibiotic resistance. Evaluating guidelines regarding drug, dose, duration, drug-route, and de-escalation for surgical prophylaxis can reduce the burden of surgical site infections. Appropriate antibiotic therapy for primary spinal infections should be guided by the diagnostic work-up and clinical monitoring of treatment response. The future of antibiotics in spine surgery will be highly influenced by improving surgical technique and evidence regarding the role of bacteria in the pathogenesis of degenerative spinal pathology.
To evaluate the effect of Veterans RAND 12-item health survey mental composite score (VR-12 MCS) on postoperative patient-reported outcome measures (PROMs) after undergoing lateral lumbar interbody ...fusion.
Retrospective data from a single-surgeon database created 2 cohorts: patients with VR-12 MCS ≥ 50 or VR-12 MCS < 50. Preoperative, 6-week, and final follow-up (FF)- PROMs including VR-12 MCS/physical composite score (PCS), 12-item Short Form health survey (SF-12) MCS/PCS, Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), Patient Health Questionnaire-9 (PHQ-9), visual analogue scale (VAS)-back/leg pain (VAS-BP/LP), and Oswestry Disability Index (ODI) were collected. ∆6-week and ∆FF-PROMs were calculated. Minimal clinically important difference (MCID) achievement rates were determined from established cutoffs from the literature. For intercohort comparison, chi-square analysis was used for categorical variables, and Student t-test for continuous variables.
Seventy-nine patients were included; 25 were in VR-12 MCS < 50. Mean postoperative follow-up time was 17.12 ± 8.43 months. The VR-12 MCS < 50 cohort had worse VR-12 PCS, SF-12 MCS, PROMIS-PF, PHQ-9, VAS-BP, and ODI scores preoperatively (p ≤ 0.014, all), worse VR-12 MCS/PCS, SF-12 MCS, PROMIS-PF, PHQ-9, and ODI scores at 6-week postoperatively (p ≤ 0.039, all), and worse VR-12 MCS, SF-12 MCS, PROMIS-PF, PHQ-9, VAS-BP, VAS-LP, and ODI scores at FF (p ≤ 0.046, all). The VR-12 MCS < 50 cohort showed greater improvement in VR-12 MCS and SF-12 MCS scores at 6 weeks and FF (p ≤ 0.005, all). The VR-12 MCS < 50 cohort experienced greater MCID achievement for VR-12 MCS, SF-12 MCS, and PHQ-9 (p ≤ 0.006, all).
VR-12 MCS < 50 yielded worse mental health, physical function, pain and disability postoperatively, yet reported greater improvements in magnitude and MCID achievement for mental health.
To evaluate preoperative disability's influence on patient-reported outcomes (PROs) following surgery for degenerative spondylolisthesis (DS).
DS patients who underwent surgical intervention were ...retrospectively identified from a single-surgeon spine registry. Cohorts based on Oswestry Disability Index (ODI) < 41 (milder disability) and ≥ 41 (severe disability) were created. Demographic differences were accounted for with 1:1 propensity score matching. For the matched sample, perioperative and PRO data were additionally collected. PROs assessed included mental health, physical function, pain, and disability. Pre- and up to 2-year postoperative PROs were utilized. Average time to final follow-up was 15.7 ± 8.8 months. Improvements in PROs and minimal clinically important difference (MCID) rates were calculated. Continuous variables were compared through Student t-test and categorical variables were compared through chi-square tests.
Altogether, 214 patients were included with 77 in the milder disability group. The severe disability group had worse postoperative day (POD) 1 pain scores and longer hospital stays (p ≤ 0.038, both). The severe disability group reported worse outcomes pre- and postoperatively (p < 0.011, all), but had greater average improvement in 12-item Short Form health survey mental composite score (SF-12 MCS), 9-Item Patient Health Questionnaire (PHQ-9), visual analogue scale (VAS)-back, and ODI by 6 weeks (p ≤ 0.037, all) and PHQ-9, VAS-back and ODI by final follow-up (p ≤ 0.015, all). The severe disability cohort was more likely to achieve MCID for SF-12 MCS, PHQ-9, and ODI (p ≤ 0.003, all).
Patients with greater baseline disability report higher POD 1 pain and discharge later than patients with milder disability. While these patients report inferior physical/mental health before and after surgery, they report greater improvements in mental health and disability postoperatively.
Abstract
Though outcomes for pediatric cancer patients have significantly improved over the past several decades, too many children still experience poor outcomes and survivors suffer lifelong, ...debilitating late effects after conventional chemotherapy, radiation, and surgical treatment. Consequently, there has been a renewed focus on developing novel targeted therapies to improve survival outcomes. Cancer vaccines are a promising type of immunotherapy that leverage the immune system to mediate targeted, tumor-specific killing through recognition of tumor antigens, thereby minimizing off-target toxicity. As such, cancer vaccines are orthogonal to conventional cancer treatments and can therefore be used alone or in combination with other therapeutic modalities to maximize efficacy. To date, cancer vaccination has remained largely understudied in the pediatric population. In this review, we discuss the different types of tumor antigens and vaccine technologies (dendritic cells, peptides, nucleic acids, and viral vectors) evaluated in clinical trials, with a focus on those used in children. We conclude with perspectives on how advances in combination therapies, tumor antigen (eg, neoantigen) selection, and vaccine platform optimization can be translated into clinical practice to improve outcomes for children with cancer.
Cause of death data are essential for rational health planning yet are not routinely available in Papua New Guinea (PNG) and Solomon Islands. Indirect estimation of cause of death patterns suggests ...these populations are epidemiologically similar, but such assessments are not based on direct evidence.
Verbal autopsy (VA) interviews were conducted at three sites in PNG and nationwide in Solomon Islands. Training courses were also facilitated to improve data from medical certificates of cause of death (MCCODs) in both countries. Data were categorised into broad groups of endemic and emerging conditions to aid assessment of the epidemiological transition.
Between 2017 and 2020, VAs were collected for 1,814 adult deaths in PNG and 819 adult deaths in Solomon Islands. MCCODs were analysed for 662 deaths in PNG and 1,408 deaths in Solomon Islands. The VA data suggest lower NCD mortality (48.8% versus 70.3%); higher infectious mortality (27.0% versus 18.3%) and higher injury mortality (24.5% versus 11.4%) in PNG compared to Solomon Islands. Higher infectious mortality in PNG was evident for both endemic and emerging infections. Higher NCD mortality in Solomon Islands reflected much higher emerging NCDs (43.6% vs 21.4% in PNG). A similar pattern was evident from the MCCOD data.
The cause of death patterns suggested by VA and MCCOD indicate that PNG is earlier in its epidemiological transition than Solomon Islands, with relatively higher infectious mortality and lower NCD mortality. Injury mortality was also particularly high in PNG.
This study was funded by Bloomberg Philanthropies.
STUDY DESIGN.Retrospective cohort study.
OBJECTIVE.The aim of this study was to compare clinical and radiographic outcomes of patients who underwent stand-alone lateral lumbar interbody fusion (LLIF) ...to those who underwent posterolateral fusion (PLF) for symptomatic adjacent segment disease (ASD).
SUMMARY OF BACKGROUND DATA.Recent studies have suggested that LLIF can successfully treat ASD; however, there are no studies to date that compare LLIF with the traditional open PLF in this cohort.
METHODS.A total of 47 consecutive patients who underwent LLIF or PLF for symptomatic ASD between January 2007 and August 2016 after failure of conservative management were reviewed for this study. Patient-reported outcomes (PROs) were collected on all patients at preoperative, postoperative, and most recent post-operative visit using the Oswestry Disability Index, Visual Analog Scale (VAS)–Back, and VAS–Leg surveys. Preoperative, immediate postoperative, and most recent postoperative radiographs were assessed for pelvic incidence, fusion, intervertebral disc height, segmental and overall lumbar lordosis (LL). Symptomatic ASD was diagnosed if back pain, neurogenic claudication, or lower extremity radiculopathy presented following a previous lumbar fusion. Preoperative plain radiographs were evaluated for evidence of adjacent segment degeneration.
RESULTS.A total of 47 patients (23 LLIF, 24 PLF) met inclusion criteria. Operative times (P < 0.001) and intraoperative blood loss (P < 0.001) were significantly higher in the PLF group. Patients who underwent PLF were discharged approximately 3 days after the LLIF patients (P < 0.001). PROs in the PLF and LLIF cohorts showed significant and equivalent improvement, with equivalent radiographic fusion rates. LLIF significantly improve segmental lordosis (P < 0.001), total LL (P = 0.003), and disc height (P < 0.001) from preoperative to immediate postoperative and final follow-up (P = 0.004, P = 0.019, P ≤ 0.001, respectively).
CONCLUSION.Although LLIF may provide less perioperative morbidity and shorter length of hospitalization, both techniques are safe and effective approaches to restore radiographic alignment and provide successful clinical outcomes in patients with adjacent segment degeneration following previous lumbar fusion surgery.Level of Evidence3
•A total of 7 studies evaluated outcomes of Impella versus IABP in patients with cardiogenic shock on venoarterial extracorporeal membrane oxygenation.•The use of Impella and IABP in patients on ...venoarterial extracorporeal membrane oxygenation has comparable effects on short-term mortality.•However, Impella use was associated with a significantly higher risk of major bleeding and hemolysis.•No significant differences were observed in left ventricular assist devices transition, continuous renal replacement therapy initiation, or stroke.•In patients with cardiogenic shock, IABP may be as effective as Impella in LV unloading.
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use for circulatory support in cardiogenic shock results in increased left ventricular (LV) afterload. The use of concomitant Impella or intra-aortic balloon pump (IABP) have been proposed as adjunct devices for LV unloading. The authors sought to compare head-to-head efficacy and safety outcomes between the 2 LV unloading strategies. We conducted a search of Medline, EMBASE, and Cochrane databases to identify studies comparing the use of Impella to IABP in patients on VA-ECMO. The primary outcome of interest was in-hospital mortality. The secondary outcomes included transition to durable LV assist devices/cardiac transplantation, stroke, limb ischemia, need for continuous renal replacement therapy, major bleeding, and hemolysis. Pooled risk ratios (RRs) with 95% confidence interval and heterogeneity statistic I2 were calculated using a random-effects model. A total of 7 observational studies with 698 patients were included. Patients on VA-ECMO unloaded with Impella vs IABP had similar risk of short-term all-cause mortality, defined as either 30-day or in-hospital mortality- 60.8% vs 64.9% (RR 0.93 0.71 to 1.21, I2 = 71%). No significant difference was observed in transition to durable LV assist devices/cardiac transplantation, continuous renal replacement therapy initiation, stroke, or limb ischemia between the 2 strategies. However, the use of VA-ECMO with Impella was associated with increased risk of major bleeding (57.2% vs 39.7%) (RR 1.66 1.12 to 2.44, I2 = 82%) and hemolysis (31% vs 7%) (RR 4.61 1.24 to 17.17, I2 = 66%) compared with VA-ECMO, along with IABP. In conclusion, in patients requiring VA-ECMO for circulatory support, the concomitant use of Impella or IABP had comparable short-term mortality. However, Impella use was associated with increased risk of major bleeding and hemolysis.
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