Comparative Effectiveness of mRNA-based BNT162b2 Vaccine versus Adenovirus Vector-Based Ad26.COV2.S Vaccine for the Prevention of COVID-19 among Dialysis Patients.

BACKGROUND: Studies have demonstrated that mRNA-based SARS-CoV-2 vaccines are highly effective among patients on dialysis. Because individual vaccines may be differentially available or acceptable to patients, it is important to understand comparative effectiveness relative to other vaccines, such those on the basis of adenovirus technologies. METHODS: In this retrospective study, we compared the clinical effectiveness of adenovirus vector-based Ad26.COV2.S (Janssen/Johnson & Johnson) to mRNA-based BNT162b2 (Pfizer/BioNTech) in a contemporary cohort of patients on dialysis. Patients who received a first BNT162b2 dose were matched 1:1 to Ad26.COV2.S recipients on the basis of date of first vaccine receipt, US state of residence, site of dialysis care (in-center versus home), history of COVID-19, and propensity score. The primary outcome was the comparative rate of COVID-19 diagnoses starting in the 7th week postvaccination. In a subset of consented patients who received Ad26.COV2.S, blood samples were collected ≥28 days after vaccination and anti-SARS-CoV-2 immunoglobulin G antibodies were measured. RESULTS: A total of 2572 matched pairs of patients qualified for analysis. Cumulative incidence rates of COVID-19 did not differ for BNT162b2 versus Ad26.COV2.S. No differences were observed in peri-COVID-19 hospitalizations and deaths among patients receiving BNT162b2 versus Ad26.COV2.S, who were diagnosed with COVID-19 during the at-risk period. Results were similar when excluding patients with a history of COVID-19, in subgroup analyses restricted to patients who completed the two-dose BNT162b2 regimen, and in patients receiving in-center hemodialysis. SARS-CoV-2 antibodies were detected in 59.4% of 244 patients who received Ad26.COV2.S. CONCLUSIONS: In a large real-world cohort of patients on dialysis, no difference was detected in clinical effectiveness of BNT162b2 and Ad26.COV2.S over the first 6 months postvaccination, despite an inconsistent antibody response to the latter.

Prophylactic treatment with CN-105 improves functional outcomes in a murine model of closed head injury.

The treatment of traumatic brain injury (TBI) in military populations is hindered by underreporting and underdiagnosis. Clinical symptoms and outcomes may be mitigated with an effective pre-injury prophylaxis. This study evaluates whether CN-105, a 5-amino acid apolipoprotein E (ApoE) mimetic peptide previously shown to modify the post-traumatic neuroinflammatory response, would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model. CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) and administered to C57-BL/6 mice intravenously (IV) and/or by intraperitoneal (IP) injection at various time points prior to injury while vehicle treated animals received IV and/or IP normal saline. Animals were randomized following injury and behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy), and hippocampal microglial activation was assessed using F4/80 immunohistochemical staining in treated and untreated mice 7 days post-TBI. Separate, in vivo assessments of the pharmacokinetics was performed in healthy CD-1. IV CN-105 administered prior to head injury improved vestibulomotor function compared to vehicle control-treated animals. CN-105 co-administered by IP and IV dosing 6 h prior to injury also improved vestibulomotor function up to 28 days following injury. Microglia counted in CN-105 treated specimens were significantly fewer (P = 0.03) than in vehicle specimens. CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury and could be adapted as a pre-injury prophylaxis for soldiers at high risk for TBI.

Cluster-Randomized Trial of Devices to Prevent Catheter-Related Bloodstream Infection.

Central venous catheters (CVCs) contribute disproportionately to bloodstream infection (BSI) and, by extension, to infection-related hospitalization, mortality, and health care costs in patients undergoing dialysis. Recent product advancements may reduce BSIs, but a sufficiently powered comparative-effectiveness study is needed to facilitate evidence-based patient care decisions. In a 13-month, prospective, cluster-randomized, open-label trial, we compared BSI rates in facilities using ClearGuard HD antimicrobial barrier caps (ClearGuard group) with those in facilities using Tego hemodialysis connectors plus Curos disinfecting caps (Tego+Curos group). Forty DaVita dialysis facilities in the United States were pair-matched by BSI rate, number of patients using CVCs, and geographic location, and then cluster randomized 1:1. We enrolled all adult patients undergoing dialysis with CVCs at these facilities, except those allergic to heparin or chlorhexidine. Overall, 1671 patients participated in the study, accruing >183,000 CVC-days. The study outcome was positive blood culture (PBC) rate as an indicator of BSI rate. We calculated results at the cluster level and adjusted for the facility cluster effect. During a 3-month run-in period immediately before study interventions, the groups had similar BSI rates (P=0.8). During the 13-month intervention period that immediately followed, the ClearGuard group had a BSI rate significantly lower than that of the Tego+Curos group (0.28 versus 0.75 PBCs per 1000 CVC-days, respectively; P=0.001). No device-related adverse events were reported. In conclusion, compared with Tego connectors plus Curos caps, ClearGuard HD antimicrobial barrier caps significantly lowered the rate of catheter-related BSIs in patients undergoing hemodialysis using CVCs, representing an important advancement in hemodialysis patient care.

The Impact of Midodrine on Outcomes in Patients with Intradialytic Hypotension.

BACKGROUND: Intradialytic hypotension (IDH) is a frequent complication of hemodialysis, and is associated with significant morbidity and mortality. Off-label use of the alpha-1 andrenergic receptor agonist midodrine to reduce the frequency and severity of IDH is common. However, limited data exist to support this practice. This study sought to examine real-world efficacy of midodrine with respect to relevant clinical and hemodynamic outcomes. METHODS: Here, we compared a variety of clinical and hemodynamic outcomes among adult patients who were prescribed midodrine (n = 1,046) and matched controls (n = 2,037), all of whom were receiving in-center hemodialysis treatment at dialysis facilities in the United States (July 2015 - September 2016). Mortality, all-cause hospitalization, cardiovascular hospitalization, and hemodynamic outcomes were considered from the month following the initiation of midodrine (or corresponding month for controls) until censoring for discontinuation of dialysis, transplant, loss to follow-up, or study end (September 30, 2016). Rate outcomes were compared using Poisson models and quantitative outcomes using linear mixed models; all models were adjusted for imbalanced patient characteristics. RESULTS: Compared to non-use, midodrine use was associated with higher rates of death (adjusted incidence rate ratio 1.37, 95% CI 1.15-1.62), all-cause hospitalization (1.31, 1.19-1.43) and cardiovascular hospitalization (1.41, 1.17-1.71). During follow-up, midodrine use tended to be associated with lower pre-dialysis systolic blood pressure (SBP), lower nadir SBP, greater fall in SBP during dialysis, and a greater proportion of treatments affected by IDH. CONCLUSION: Although residual confounding may have influenced the results, the associations observed here are not consistent with a potent beneficial effect of midodrine with respect to either clinical or hemodynamic outcomes.

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

BACKGROUND: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. METHODS: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. RESULTS: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. CONCLUSIONS: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD.

Renal function in patients with non-dialysis chronic kidney disease receiving intravenous ferric carboxymaltose: an analysis of the randomized FIND-CKD trial.

BACKGROUND: Preclinical studies demonstrate renal proximal tubular injury after administration of some intravenous iron preparations but clinical data on renal effects of intravenous iron are sparse. METHODS: FIND-CKD was a 56-week, randomized, open-label, multicenter study in which patients with non-dialysis dependent chronic kidney disease (ND-CKD), anemia and iron deficiency without erythropoiesis-stimulating agent therapy received intravenous ferric carboxymaltose (FCM), targeting either higher (400-600 µg/L) or lower (100-200 µg/L) ferritin values, or oral iron. RESULTS: Mean (SD) eGFR at baseline was 34.9 (11.3), 32.8 (10.8) and 34.2 (12.3) mL/min/1.73 m2 in the high ferritin FCM (n = 97), low ferritin FCM (n = 89) and oral iron (n = 167) groups, respectively. Corresponding values at month 12 were 35.6 (13.8), 32.1 (12.7) and 33.4 (14.5) mL/min/1.73 m2. The pre-specified endpoint of mean (SE) change in eGFR from baseline to month 12 was +0.7 (0.9) mL/min/1.73 m2 with high ferritin FCM (p = 0.15 versus oral iron), -0.9 (0.9) mL/min/1.73 m2 with low ferritin FCM (p = 0.99 versus oral iron) and -0.9 (0.7) mL/min/1.73 m2 with oral iron. No significant association was detected between quartiles of FCM dose, change in ferritin or change in TSAT versus change in eGFR. Dialysis initiation was similar between groups. Renal adverse events were rare, with no indication of between-group differences. CONCLUSION: Intravenous FCM at doses that maintained ferritin levels of 100-200 µg/L or 400-600 µg/L did not negatively impact renal function (eGFR) in patients with ND-CKD over 12 months versus oral iron, and eGFR remained stable. These findings show no evidence of renal toxicity following intravenous FCM over a 1-year period. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00994318 (first registration 12 October 2009).

The FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale.

BACKGROUND: Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD). METHODS: FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 µg/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 µg/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values <10 g/dL without an increase of ≥ 0.5 g/dL). RESULTS: The background, rationale and study design of the trial are presented here. The study has been completed and results are expected in late 2013. DISCUSSION: FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point.

FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia.

BACKGROUND: The optimal iron therapy regimen in patients with non-dialysis-dependent chronic kidney disease (CKD) is unknown. METHODS: Ferinject® assessment in patients with Iron deficiency anaemia and Non-Dialysis-dependent Chronic Kidney Disease (FIND-CKD) was a 56-week, open-label, multicentre, prospective and randomized study of 626 patients with non-dialysis-dependent CKD, anaemia and iron deficiency not receiving erythropoiesis-stimulating agents (ESAs). Patients were randomized (1:1:2) to intravenous (IV) ferric carboxymaltose (FCM), targeting a higher (400-600 µg/L) or lower (100-200 µg/L) ferritin or oral iron therapy. The primary end point was time to initiation of other anaemia management (ESA, other iron therapy or blood transfusion) or haemoglobin (Hb) trigger of two consecutive values <10 g/dL during Weeks 8-52. RESULTS: The primary end point occurred in 36 patients (23.5%), 49 patients (32.2%) and 98 patients (31.8%) in the high-ferritin FCM, low-ferritin FCM and oral iron groups, respectively [hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.44-0.95; P = 0.026 for high-ferritin FCM versus oral iron]. The increase in Hb was greater with high-ferritin FCM versus oral iron (P = 0.014) and a greater proportion of patients achieved an Hb increase ≥1 g/dL with high-ferritin FCM versus oral iron (HR: 2.04; 95% CI: 1.52-2.72; P < 0.001). Rates of adverse events and serious adverse events were similar in all groups. CONCLUSIONS: Compared with oral iron, IV FCM targeting a ferritin of 400-600 µg/L quickly reached and maintained Hb level, and delayed and/or reduced the need for other anaemia management including ESAs. Within the limitations of this trial, no renal toxicity was observed, with no difference in cardiovascular or infectious events. CLINICALTRIALSGOV NUMBER: NCT00994318.

Knowing what we do and doing what we should: quality assurance in hemodialysis.

An international group of around 50 nephrologists and scientists, including representatives from large dialysis provider organisations, formulated recommendations on how to develop and implement quality assurance measures to improve individual hemodialysis patient care, population health and cost effectiveness. Discussed were methods thought to be of highest priority, those clinical indicators which might be most related to meaningful patient outcomes, tools to control treatment delivery and the role of facilitating computerized expert systems. Emphasis was given to the use of new technologies such as measurement of online dialysance and ways of assessing fluid status. The current evidence linking achievement of quality criteria with patient outcomes was reviewed. This paper summarizes useful processes and quality measures supporting quality assurance that have been agreed across the expert panel. It also notes areas where more understanding is required.

ApoE Mimetic Peptides as Therapy for Traumatic Brain Injury.

The lack of targeted therapies for traumatic brain injury (TBI) remains a compelling clinical unmet need. Although knowledge of the pathophysiologic cascades involved in TBI has expanded rapidly, the development of novel pharmacological therapies has remained largely stagnant. Difficulties in creating animal models that recapitulate the different facets of clinical TBI pathology and flaws in the design of clinical trials have contributed to the ongoing failures in neuroprotective drug development. Furthermore, multiple pathophysiological mechanisms initiated early after TBI that progress in the subacute and chronic setting may limit the potential of traditional approaches that target a specific cellular pathway for acute therapeutic intervention. We describe a reverse translational approach that focuses on translating endogenous mechanisms known to influence outcomes after TBI to develop druggable targets. In particular, numerous clinical observations have demonstrated an association between apolipoprotein E (apoE) polymorphism and functional recovery after brain injury. ApoE has been shown to mitigate the response to acute brain injury by exerting immunomodulatory properties that reduce secondary tissue injury as well as protecting neurons from excitotoxicity. CN-105 represents an apoE mimetic peptide that can effectively penetrate the CNS compartment and retains the neuroprotective properties of the intact protein.

Neuroprotection and Therapeutic Implications of Creatine Supplementation for Brain Injury Complications.

Creatine supplementation has not been researched for Traumatic Brain Injury (TBI) extensively, but studies suggest potential as a neuroprotective agent and potential treatment for brain-injury complications. Patients suffering from TBI experience mitochondrial dysfunction, neuropsychological burden, and deficits in cognitive performance due to malperformance of brain creatine levels, diminished brain Adenosine Triphosphate (ATP) levels, glutamate toxicity, and oxidative stress. In this systemic review, the current available research is reviewed to examine the effects of creatine on common sequalae of TBI within children, adolescents, and mice. Past and present data still lacks the knowledge of creatine supplementation for the adult population and military members during TBI. PubMed was searched for studies which assessed the correlation between creatine supplementation of TBI complications. The search strategy yielded 40 results, of which 15 articles were included in this systemic review. The results of the review supported an apparent understanding creatine does offer an obvious benefit to patients suffering from TBI and post-injury complications under specific guidelines. Time and dose dependent metabolic alterations seem to be only exceptionally prevalent when given as a prophylaxis or if given acutely. Results are only clinically significant after a month of supplementation. Although patients may need many therapeutic treatments to recover from TBI, especially in acute resuscitation, creatine shows superior efficacy as a neuroprotective agent in battling the chronic manifestations which lead to oxidative stress and cognitive function post brain injury.

Urgent-start peritoneal dialysis: Association with outcomes.

The majority of end-stage kidney disease (ESKD) patients start dialysis without adequate pre-dialysis planning. Of these patients, the vast majority initiate in-centre haemodialysis using a central venous catheter (ICHD-CVC). A minority utilise urgent-start peritoneal dialysis (USPD), whereby a peritoneal dialysis catheter is placed and used for dialysis without the usual 2-4-week waiting period. In this multicentre, retrospective study of adult patients initiating dialysis during 2018, we compared outcomes among patients utilising these two dialysis initiation routes. Patients who initiated dialysis via ICHD-CVC were matched 1:1 to patients who utilised USPD on the basis of aetiology of ESKD, race, diabetes status and insurance type. Hospitalisation and mortality were evaluated from dialysis initiation through the first of death, transplant, loss to follow-up or study end (30 June 2019). Outcomes were compared using models adjusted for age and sex. A total of 717 USPD patients were matched to ICHD-CVC patients. During follow-up, USPD patients were hospitalised at a rate of 1.21 admissions/patient-year (pt-yr) versus 1.51 admissions/pt-yr for ICHD-CVC. This corresponded to a 24% lower rate of hospitalisation among USPD patients (adjusted incidence rate ratio 0.76, 95% confidence interval [CI] 0.65-0.88). Mortality rates were 0.08 and 0.11 deaths/pt-yr among USPD patients and ICHD-CVC patients, respectively (adjusted hazard ratio 0.84, 95% CI 0.62, 1.15). These findings suggest that more widespread adoption of USPD may be beneficial among patients with limited pre-dialysis planning.

23.4% Hypertonic Saline: A Tactical Option for the Management of Severe Traumatic Brain Injury With Impending or Ongoing Herniation.

There are limited options available to the combat medic for management of traumatic brain injury (TBI) with impending or ongoing herniation. Current pararescue and Tactical Combat Casualty Care (TCCC) guidelines prescribe a bolus of 3% or 5% hypertonic saline. However, this fluid bears a tactical burden of weight (~570g) and pack volume (~500cm3). Thus, 23.4% hypertonic saline is an attractive option, because it has a lighter weight (80g) and pack volume (55cm3), and it provides a similar osmotic load per dose. Current literature supports the use of 23.4% hypertonic saline in the management of acute TBI, and evidence indicates that it is safe to administer via peripheral and intraosseous cannulas. Current combat medic TBI treatment algorithms should be updated to include the use of 23.4% hypertonic saline as an alternative to 3% and 5% solutions, given its effectiveness and tactical advantages.

Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis.

BACKGROUND: Patients with chronic kidney disease (stage 5) who undergo hemodialysis treatment have similarities to heart failure patients in that both populations retain fluid frequently and have excessively high mortality. Volume overload in heart failure is associated with worse outcomes. We hypothesized that in hemodialysis patients, greater interdialytic fluid gain is associated with poor all-cause and cardiovascular survival. METHODS AND RESULTS: We examined 2-year (July 2001 to June 2003) mortality in 34,107 hemodialysis patients across the United States who had an average weight gain of at least 0.5 kg above their end-dialysis dry weight by the time the subsequent hemodialysis treatment started. The 3-month averaged interdialytic weight gain was divided into 8 categories of 0.5-kg increments (up to > or =4.0 kg). Eighty-six percent of patients gained >1.5 kg between 2 dialysis sessions. In unadjusted analyses, higher weight gain was associated with better nutritional status (higher protein intake, serum albumin, and body mass index) and tended to be linked to greater survival. However, after multivariate adjustment for demographics (case mix) and surrogates of malnutrition-inflammation complex, higher weight-gain increments were associated with increased risk of all-cause and cardiovascular death. The hazard ratios (95% confidence intervals) of cardiovascular death for weight gain <1.0 kg and > or =4.0 kg (compared with 1.5 to 2.0 kg as the reference) were 0.67 (0.58 to 0.76) and 1.25 (1.12 to 1.39), respectively. CONCLUSIONS: In hemodialysis patients, greater fluid retention between 2 subsequent hemodialysis treatment sessions is associated with higher risk of all-cause and cardiovascular death. The mechanisms by which fluid retention influences cardiovascular survival in hemodialysis may be similar to those in patients with heart failure and warrant further research.

Analytical and biological variation in measures of anemia and iron status in patients treated with maintenance hemodialysis.

BACKGROUND: To make informed decisions in dosing erythropoiesis-stimulating agents and intravenous iron therapy, clinicians must determine whether differences between current and previous test results for anemia and iron status markers reflect expected variation, a significant change, or an actual trend. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 30 patients undergoing thrice-weekly in-center hemodialysis. PREDICTOR: Within-patient biological variations in hemoglobin (Hb) level, hematocrit (Hct), reticulocyte Hb content, transferrin saturation (TSAT), and ferritin level were determined over 12 consecutive treatment days. OUTCOMES & MEASUREMENTS: We separately measured same-sample analytical variation and within-patient biological variation (coefficient of variation), then calculated the number of sampling days needed to determine the true or homeostatic value for each analyte with 95% probability. We also evaluated whether results differed among the first, second, and third dialysis days of the week. RESULTS: Biological variation differed by analyte. Hb level (4.0%), Hct (4.0%), and reticulocyte Hb content (4.8%) showed much lower variation than TSAT (38.2%) or ferritin level (15.1%). Analytical variation ranged from 2.0%-6.9% for all analytes. We found that one sample day would be sufficient to establish the true mean Hb level or Hct within a level of closeness+/-20% and 95% probability. For the same levels of closeness and probability, one sample day would be needed for reticulocyte Hb content, 15 for TSAT, and 3 for ferritin level. No pairwise comparison for any of the 5 analytes yielded a significant difference between results obtained on the first, second, or third dialysis day of the week. LIMITATIONS: These findings may not apply to other patient populations. CONCLUSIONS: Low biological variation renders Hb level, Hct, and reticulocyte Hb content, but not TSAT and ferritin level, suitable for trend analysis using results from 2 successive samples. TSAT and ferritin test results, unlike reticulocyte Hb content, have limited value in evaluating changes in iron status within individual hemodialysis patients.

Association of hemodialysis treatment time and dose with mortality and the role of race and sex.

BACKGROUND: The association of survival with characteristics of thrice-weekly hemodialysis (HD) treatment, including dose or duration of treatment, has not been completely elucidated, especially in different race and sex categories. STUDY DESIGN: We examined associations of time-averaged and quarterly varying (time-dependent) delivered HD dose and treatment time and 5-year (July 2001-June 2006) survival. SETTING & PARTICIPANTS: 88,153 thrice-weekly-treated HD patients from DaVita dialysis clinics. PREDICTORS: HD treatment dose (single-pool Kt/V) and treatment time. OUTCOMES & OTHER MEASUREMENTS: 5-Year mortality. RESULTS: Thrice-weekly treatment time < 3 hours (but > or = 2.5 hours) per HD session compared with > or = 3.5 hours (but < 5 hours) was associated with increased death risk independent of Kt/V dose. The greatest survival gain of higher HD dose was associated with a Kt/V approaching the 1.6-1.8 range, beyond which survival gain was minimal, nonexistent, or even tended to reverse in African American men and those with 4-5 hours of HD treatment. In non-Hispanic white women, Kt/V > 1.8 continued to show survival advantage trends, especially in time-dependent models. LIMITATIONS: Our results may incorporate uncontrolled confounding. Achieved Kt/V may have different associations than targeted Kt/V. CONCLUSIONS: HD treatment dose and time appear to have different associations with survival in different sex or race groups. Randomized controlled trials may be warranted to examine these associations across different racial and demographic groups.

Beyond the burn: Studies on the physiological effects of flamethrowers during World War II.

Flamethrowers are widely considered one of warfare's most controversial weapons and are capable of inflicting gruesome physical injuries and intense psychological trauma. Despite being the last of the major combatants in World War II (WWII) to develop them, the United States military quickly became the most frequent and adept operator of portable flamethrowers. This gave the U.S. military ample opportunity to observe the effects of flamethrowers on enemy soldiers. However, while most people in modern times would consider immolation by flamethrower to be an unnecessarily painful and inhumane way to inflict casualties, immolation was, at one point during World War II (WWII), referred to as "mercy killing" by the U.S. Chemical Warfare Service (CWS). This mischaracterization arose from a series of first-hand accounts describing what were believed to be quick, painless, and unmarred deaths, as well as from a poor and incomplete understanding of flamethrower lethality. As a result, indirect mechanisms such as hypoxia and carbon monoxide poisoning were generally absent from accounts of the flamethrower's fatal effects. It was not until several years after flamethrowers were introduced to the frontlines that the CWS and National Defense Research Committee (NDRC) conducted a series of tests to better understand the physiological and toxicological effects of flamethrowers. This article examines how the initial absence of scientific data on the physiologic effects of flamethrowers led to an inaccurate understanding of their lethality, and bizarre claims that one of history's most horrific instruments of war was considered one of the more "humane" weapons on the battlefield.

Impact of Rescheduling a Missed Hemodialysis Treatment on Clinical Outcomes.

RATIONALE & OBJECTIVE: Among patients treated with in-center hemodialysis (HD), missed treatments are associated with higher subsequent rates of hospitalization and other adverse outcomes compared with attending treatment. The objective of this study was to determine whether and to what degree attending a rescheduled treatment on the day following a missed treatment ameliorates these risks. STUDY DESIGN: Retrospective, observational. SETTING & PARTICIPANTS: Included patients were those who were, as of any of 12 index dates during 2014, adult Medicare beneficiaries treated with in-center HD (vintage ≥ 90 days) on a Monday/Wednesday/Friday schedule. EXPOSURE: Treatment attendance on the index date and the subsequent day. OUTCOMES: Hospital admissions, emergency department visits, mortality, blood pressure, and anemia measures, considered during the 7- and 30-day periods following exposure. ANALYTICAL APPROACH: In parallel analyses, patients who missed or rescheduled treatment were each matched (1:5) to patients who attended treatment on the index date on the basis of index day of week and propensity score. Within the matched cohorts, outcomes were compared across exposures using repeated-measures generalized linear models. RESULTS: Compared with attending treatment (N = 19,260), a missed treatment (N = 3,852) was associated with a 2.09-fold higher rate of hospitalization in the subsequent 7 days; a rescheduled treatment (N = 2,128) was associated with a 1.68-fold higher rate of hospitalization than attending (N = 10,640). Compared with attending treatment, hospitalization rates were 1.39- and 1.28-fold higher among patients who missed and rescheduled treatment, respectively, during the 30-day outcome period. Emergency department visits followed a similar pattern of associations as hospitalization. No statistically significant associations were observed with respect to mortality for either missed or rescheduled treatments compared with attending treatment. LIMITATIONS: Possible influence of unmeasured confounding; unknown generalizability to patients with non-Medicare insurance. CONCLUSIONS: Attending a rescheduled in-center HD treatment attenuates but does not fully mitigate the adverse effects of a missed treatment.

The Prehospital Evaluation and Care of Moderate/Severe TBI in the Austere Environment.

Increased resource constraints secondary to a smaller medical footprint, prolonged evacuation times, or overwhelming casualty volumes all increase the challenges of effective management of traumatic brain injury (TBI) in the austere environment. Prehospital providers are responsible for the battlefield recognition and initial management of TBI. As such, targeted education is critical to efficient injury recognition, promoting both provider readiness and improved patient outcomes. When austere conditions limit or prevent definitive treatment, a comprehensive understanding of TBI pathophysiology can help inform acute care and enhance prevention of secondary brain injury. Field deployable, noninvasive TBI assessment and monitoring devices are urgently needed and are currently undergoing clinical evaluation. Evidence shows that the assessment, monitoring, and treatment in the first few hours and days after injury should focus on the preservation of cerebral perfusion and oxygenation. For cases where medical management is inadequate (eg, evidence of an enlarging intracranial hematoma), guidelines have been developed for the performance of cranial surgery by nonneurosurgeons. TBI management in the austere environment will continue to be a challenge, but research focused on improving evidence-based monitoring and therapeutic interventions can help to mitigate some of these challenges and improve patient outcomes.