Food allergy immunotherapy may be heavily influenced by age of initiation.

Investigators from the University of North Carolina School of Medicine 

American Academy of Allergy, Asthma & Immunology (AAAAI) 2021 Virtual Sessions

 last week showing sublingual immunotherapy (SLIT) initiated in children with peanut allergy aged 1-4 years old resulted in significant desensitization to the allergen and sustained unresponsiveness to allergen exposure months after ending once-daily SLIT.

The research, presented by Edwin Kim, MD, MS, builds on previous assessment of SLIT by himself and colleagues which showed the benefit and safety of the 

LEAP Study-informed allergen exposure treatment plan

 in a slightly older pediatric patient population.

With evidence that even younger patients benefit more greatly and for longer, and with the lone regulated peanut immunotherapy 

AR101 (PALFORZIA) being indicated for ages 4-17

, Kim and colleagues are making progress on a promising pathway of research for allergen desensitization.

, Kim discussed the AAAAI 2021 trial results, what may drive earlier immunotherapy response, and what other allergens may be considered for research.

: What were your thoughts on the trial outcomes?

 We're so happy about this, I mean, for multiple reasons. One point I'll make right up front is the ability to go down to this young age, to me, is vitally important. Of course, I think we're trying to promote the LEAP guidelines with early introduction of peanut to try to prevent allergy. And we think that will be successful, but at the same time, we know that there's still going to be kids that are allergic. And I think with the LEAP guidelines, because of that, we're going to start capturing these kids even younger from when they're first diagnosed.

So, to be able to have treatments that we can immediately offer these kids as soon as they are diagnosed, I think is going to be really important for these kids and for their families. Number one, that comes to mind as far as trying to be able to go younger.

Then number two is this kind of hypothesis of the immune systems of these younger kids potentially being more responsive to these treatments is something we've suspected. I feel like our data is small, but seems to support that concept as well. Because our study we published in 2019, that group was on average about age 7. And we saw good effects there. But now that we go down to an average age of 2, those effects are much stronger, where we've got kids routinely eating 4000 milligrams—like 15-16 peanuts without any symptoms at all. And then a bunch of them hanging on to it for at least 3 months without any treatment, which is far stronger than what we saw with the older kids.

I think there's a lot of excitement with our own group that this is real, that this is something that really can become a benefit to these young kids in the future.

What factors do we believe are driving the increased benefit of earlier sublingual immunotherapy initiation in young children? Are there key characteristic differences between the average toddler patient versus a seven-year old?

 It's in hypothesis mode right now as well. But I think a question that I still want to understand, and I think other researchers out there are thinking the same, is trying to separate out whether it's actually chronological age, or is it their IgE level, their peanut-specific testing levels? Because we do know that early on in diagnosis that your IgE level, your skin test levels, are going to likely be on the small side. And then over those first few years of life with the allergy, those numbers, oftentimes will go up until they find their final steady level or whatever you want to call it. That maintenance level.

So, not surprisingly, in our cohort, these young kids, they do have smaller IgE levels. So which one is it? Is it the age? Is it IgE? Is it both? I don't know that we know that answer just yet. But we're hoping to be able to, as we analyze the the lab stuff that we have from this cohort more in-depth, as well as other studies out there looking at the same age group. We're trying to separate that piece out. The idea that those IgE levels and the skin test change a lot in the first year or so goes back to this concept of, is their immune system more moldable? Or is it more willing to change, versus maybe when you're older, your immune system is more set.

I think those are all the thoughts that we have right now. Older kids can respond, there's no doubt about that. I don't want people to get the wrong message that you age out, and you can't get better. But at least our data seems to suggest if you can start earlier, that may give you an a slightly better and a slightly longer-lasting benefit.

What is it particularly about peanut that has made it the most promising prospect for allergen immunotherapy assessment?

 The field sort of just naturally went there, and I think the main reason is that peanut is a very prevalent allergy and the numbers keep going up. But it also tends to be the one that's more severe, it tends to be the one that people don't outgrow. They really hang on to it for life. So, for all those reasons, I think it made sense that peanut is where we started.

But I would guess that more than half of the patients that we see for peanut allergy have other allergies at the same time. And there are plenty of kids out there who are allergic to other things and not peanut. So, this is very much proof that the concept works, that we're not crazy. But I think we very much need to and want to be able to expand this to to the other foods that people can be allergic to—and maybe multiple foods. Not only should we be thinking about can we do SLIT for milk, but we should be thinking can we do SLIT for milk, egg and peanut at the same time.

And there's definitely growing research looking at multiple allergens simultaneously. A lot of work coming out of Stanford is in that area using the the flours in oral immunotherapy. But when thinking about future directions for what we're doing for SLIT, that's very high on the list of how do we get this concept to other foods. I think instinctively, it seems like it should be pretty amenable to multiple foods at the same time. You just mix a bunch of liquids together and go for it. And maybe it's a lot easier than it might be to try to do an adjusted form. So that's very much a direction we want to go.

Articles

Younger patients are faring better, and for longer, with sublingual immunotherapy. A leading investigator discusses what more needs to be learned in the burgeoning field.

Edwin Kim, MD, MS: Uncovering the Factors of Peanut Allergy Immunotherapy

Researchers are pursuing a new way to screen and identify patients who might reject 

A team, led by Rania El Fekih, MD, Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, used urine samples with matched biopsy samples to isolate urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression.

Often the traditional biomarkers used to monitor a kidney allograft for rejection are late markers for injury and lack the needed sensitivity and specificity. However, allograft biopsies are invasive, but costly, showing the need for a noninvasive clinical test that can accurately diagnose kidney allograft rejections to improve allograft outcomes.

In urinary exosome, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Urine is stable enough to make them a useful tool for liquid biopsies and a noninvasive diagnostic biomarker for kidney-transplant rejection.

The investigators used 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy.

To assess the performance of the signatures on multiple data subsets, the investigators used cross-validation.

The investigators found an exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection. This yielded an area under the curve (AUC) of 0.93 (95% CI, 0.87-0.98), which was significantly better than the current standard of care (increase in eGFR AUC, 0.57; 95% CI, 0.49-0.65).

In addition, the exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%.

While using the same approach, the researchers identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76-0.97), with a negative predictive value of 90.6% and positive predictive value of 77.8%.

“Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection,” the authors wrote. “This finding has the potential to assist clinicians in therapeutic decision making.”

Despite effort and acknowledgement, new research shows kidney transplantation has not improved much in the last 2 decades for patients with 

In recent decades researchers have extensively researched and promoted different policies to improve access to kidney transplants for patients with end-stage kidney disease. However, there is still wide variation in transplant referral rates existing between different dialysis facilities.

The study included 1.3 million adult patients in which the cumulative four-year WLT was 29.7%. This was unchanged over the course of 5 eras. The preemptive WLT prior to dialysis increased by era from 5.2% in 1997-2000 to 9.8% in 2013-2016.

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection

Journal of the American Society of Nephrology

Traditional screenings for kidney allograft rejections can be expensive and invasive, highlighting the need for new methods.

Urine Sampling Might Better Forecast Kidney Allograft Rejection

Findings from a new study confirmed the efficacy of terlipressin in adults with cirrhosis and 

Although the vasoconstrictor led to improved renal function, it was nonetheless associated with serious adverse events, including respiratory failure.

The phase 3 CONFIRM trial, led by Florence Wong, MD, Department of Medicine, University of Toronto, evaluated patients with HRS-1, cirrhosis, ascites, and rapidly progressive kidney failure.

The primary outcome sought by the investigators was verified reversal of HRS, which they defined as “2 consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment.”

Wong and colleagues randomized a total of 300 patients 2:1 to receive terlipressin or placebo, with a recommended addition of albumin.

Treatment was administered for up to 14 days, and included intravenous administration of 1 mg of either agent over 2 minutes every 5.5-6.5 hours.

“On day 4, patients with a serum creatinine level that had decreased by less than 30% from the baseline level after a minimum of 10 doses of terlipressin or placebo could receive 2 mg every 6 hours, except in those with coronary artery disease, circulatory overload, pulmonary edema, or bronchospasm,” noted the investigators.

As such, of the entire population, verified HRS reversal was identified in 32% of patients in the terlipressin group and 17% in the placebo group (

“With respect to the prespecified secondary end points," the team wrote, "HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (

Further, 34% in the terlipressin group and 17% in the placebo experienced HRS reversal without renal-replacement therapy by day 30 (

The investigators also noted that 84 patients in the terlipressin group and 48 patients in the placebo group had systemic inflammatory response syndrome. As such, 37% and 6%, respectively, likewise experienced verified HRS reversal without recurrence by day 30 (

Verified reversal of HRS without recurrence by day 30 occurred in 26% of terlipressin patients and 17% in the placebo group (

Liver transplantation occurred in 23% in the terlipressin group and 29% in the placebo group at day 90; however, death occurred in 51% of terlipressin-users and 45% of placebo-users.

Adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, were reported more often with terlipressin than placebo.

And finally, death within 90 days due to respiratory disorders occurred in 11% of terlipressin patients and 2% in placebo patients.

“Overall, the results of the CONFIRM Study are in accordance with the data from previous clinical trials that provided evidence that terlipressin improves kidney function in patients with HRS-1,” indicated Wong and team.

Nonetheless, they cautioned use of the drug in patients who are more advanced in liver disease—citing the increased risk for adverse events and death.

Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome

Use of the vasoconstrictor was associated with increased risk for death due to respiratory disorders.

Study Confirms Efficacy of Terlipressin for Type 1 Hepatorenal Syndrome

 pandemic has impacted exercise in a number of ways.

Gyms closed, sports were cancelled, and stress rose. In absence of routine, many began to get creative in their exercise programs, working out at home.

However, new research shows a decrease in exercise could be leading to a significant increase in depression rates and other mental health disorder.

A team, led by Osea Giuntella, PhD, Department of Economics, University of Pittsburgh, quantified the changes in physical activity, sleep, time use and mental health among a dataset of college students before and during the ongoing pandemic.

Overall, there were 3 cohorts of students from the University of Pittsburgh enrolled in the study—spring 2019, fall 2019, and spring 2020.

The researchers sought a primary measure of mental health of depression, which was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D).

Each individual filled out a baseline survey, received a wearable tracker, and installed a custom-made smartphone application on their phone to track the data.

The researchers used a longitudinal dataset linking biometric and survey data from multiple cohorts of young adults before and during the pandemic. Overall, there were 682 individuals included in the study.

At the beginning of the pandemic, the average steps per day for the sample population declined from an average of 10,000 per day to 4600 steps per day. Sleep also increased between 25-30 minutes per night, while the time spent socializing declined by over half to less than 30 minutes per day.

Finally, screen time, unsurprisingly, doubled to over 5 hours a day.

These figures coincided with a 90% increase in depression risk between March and July 2020 in the same patient population just prior to the pandemic. Overall, the proportion of participants at risk for clinical depression ranged from 46-61%.

The researchers used difference-in-difference and individual fixed-effects regressions to show that changes in physical activity, sleep, social interactions, screen time, and depression are all statistically significant when compared to the changes in previous cohorts (

The largest decline between pre-pandemic and during the pandemic occurred in physical activity, which has been previously linked to worsened overall health outcomes.

“Our analyses suggest that disruption to physical activity is a leading risk factor for depression during the pandemic,” the authors wrote. “However, restoration of those habits through a short-term intervention does not meaningfully improve mental well-being.”

According to the US Centers for Disease Control & Prevention (CDC), approximately 33% of adults in the US were suffering from anxiety of depression as of June 2020. This is nearly 2 times higher for young adults, which is a subgroup that was already seeing rising rates of mental illnesses.

More than 60% of individuals between 18-24 years old are at a risk of depression or anxiety, 25% of which reported considering suicide in the previous month.

Lifestyle and mental health disruptions during COVID-19

Proceedings of the National Academy of Sciences of the United States of America

Sleep has increased since the beginning of the pandemic in college students, while social activity has decreased. 

Depression Increased as Physical Activity Decreased During COVID-19 Pandemic

The US Food and Drug Administration (FDA) has approved a cell-based quadrivalent 

vaccine (QIVc; FLUCELVAX QUADRIVALENT) for individuals ≥2 years of age.

Granted to Seqirus, the approval expands use from previous indication of ≥4 years of age.

The approval was based on efficacy data that showed the QIVc was effective in producing a sufficient immune response against seasonal influence in pediatric patients ≥2 to <18 of age—as compared with a non-influenza agent.

The response was observed over 3 influenza seasons in the Southern Hemisphere (2017) and Northern Hemisphere (2017/18 and 2018/19).

Even more, the data represents the first absolute study efficacy study of a cell-based influenza vaccine for this population.

"Young children are at a high risk of complications from influenza, which is why annual vaccination is critical," said Gregg Sylvester, MD, Chief Medical Officer, Seqirus, in a 

"The absolute efficacy results for Flucelvax Quadrivalent that served as the basis for this approval indicate that the cell-based vaccine offers an important new option for children as young as two years of age,” he continued.

Flucelvax Quadrivalent will be used as a 0.5 ml intramuscular vaccine per dose just in time for the 2021/22 influenza season in the United States. 

Current US Centers for Disease Control and Prevention (CDC) recommendations encourage all individuals ≥6 months of age and without contradictions annually receive their influenza shot.

Young children are at especially high risk of developing complications related to influenza. In the 2019/2020 US flu season, more than 52,000 hospitalizations occurred in children ≤18 years old—as did 434 influenza-related deaths.

The approval is based on absolute efficacy data from 3 influenza seasons. 

FDA Expands Pediatric Indication for Cell-Based Quadrivalent Flu Vaccine

) infection remained elevated for up to a year after the conclusion of treatment with proton-pump inhibitors (PPIs), according to a 

Investigators from Copenhagen, Denmark used a nationwide cohort of adults with 

 infection in order to compare periods with and without exposure to PPIs. The adults were all treated between February 2010 and December 2013. The nationwide database included health information such as 

 testing, filled prescriptions, and patient characteristics. The investigators also accounted for previous hospitalization in the previous 12 weeks in the patients, in addition to chronic disease, genetics, socioeconomic status, length of hospital stay, and antibiotic and corticosteroid use.

Ultimately, the study authors identified 3583 episodes of community-acquired 

 infection, of which 964 occurred during current use of PPIs. This is an observation in the current literature, but what wasn’t understood was the full extent of the relationship due to missing data from randomized controlled trials, variability between studies, and insufficient adjustment for confounding.

“While a history of prior hospital admission, advanced age, and antibiotic use are well-known risk factors for 

 infection, the role of PPIs has remained controversial,” the study authors wrote.

The investigators defined new PPI use as a new prescription for individuals who had not used PPI in the prior 365 days. They split up the periods of 0-6 months and 6-12 months because in the first period, cessation was considered indeterminate use because of the possibility for intermittent use or drug exposure continuing beyond the use period. Exposure during the 6-12 month period was “unlikely.”

Of the infections that occurred with use of PPIs, 324 occurred within 0-6 months after treatment conclusion. Additionally, 123 cases occurred between 6 and 12 months after treatment cessation.

 infection cases occurred during time periods without use of PPIs, the investigators said.

Comparing use of PPIs with nonuse, the study authors found that the adjusted estimate incidence rate ratio (IRR) was 2.03, they said. But the risk remained elevated in later time periods too: 1.54 for 0-6 months, and 1.24 for 6-12 months.

“In conclusion, in this nationwide study in Denmark, we showed that exposure to PPIs was associated with a moderate increase in the risk of community-acquired 

 infection,” the study authors said, , while noting that the mechanism by which PPIs may increase the 

 infection risk remains unclear. “The increased risk was most prominent during current PPI use but also persisted after treatment discontinuation.”

One limitation the study authors provided for was that initial symptoms of 

 infection could have been misinterpreted and patients prescribed PPIs could not be excluded. But, they also admitted, “it is unlikely that this would lead to biased results because the symptoms of 

 infection (diarrhea) are distinct from the upper gastrointestinal symptoms that represent the most common indication for PPIs.”

Exposure to PPIs was associated with a moderate increase in the risk of community-acquired C diff infection, even after treatment discontinuation. 

Elevated Risk for C diff with Proton-Pump Inhibitor Use

Tocilizumab (Actemra) has been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary function in patients with 

systemic sclerosis-associated interstitial lung disease (SSc-ILD).

The FDA approval, granted to Genentech’s subcutanenous injection, indicates tocilizumab as the first biologic therapy regulated to treat the rare pulmonary disease.

Systemic sclerosis currently affects about 75,000 Americans—approximately 80% of whom may be burdened with ILD, a progressive condition associated with worsened long function and risk of death.

Since 2010, tocilizumab has been granted 6 FDA indications, including for rheumatoid arthritis and giant cell arteritis.

In phase 3 randomized, double-blind, placebo-controlled clinical trial data supporting Genentech’s application to the FDA, investigators observed significantly reduced declines in percent predicted forced vital capacity (FVC) among patients treated with the interleukin 6 (IL-6) receptor antagonist.

Though this trial, dubbed focuSSed, failed to meet its primary endpoint of change from baseline to week 48 in modified Rodnan Skin Score (mRSS)—a common metric for skin fibrosis change in patients with SSc—outcomes for percent predicted and overall FVC were bettered among tocilizumab-treated patients.

Patients with SSc-ILD reported a lesser decline in mean percent predicted FVC than patients treated with placebo at 48 weeks: 0.07% versus -6.4%, for a mean difference of 6.47%. FVC decline was also smaller for patients treated with SSc-ILD versus placebo in the same observed period: -14 mL versus -255 mL.

At 48 weeks, tocilizumab’s safety profile was comparable for both SSc-ILD and lone SSc patients, and consistent with the known profile of the therapy in previous assessments. Infections were the most common adverse event among treated patients.

 at the American Thoracic Society (ATS) 2019 International Meeting, Kristin B. Highland, MD, director of the Rheumatic Lung Disease Program at the Cleveland Clinic, explained the value of lessened FVC decline in patients being treated for SSc-ILD.

“Forced vital capacity is really our best surrogate for overall lung function and it does track with what we see on chest CT; it does track with survival,” Highland explained. “This is an orphan disease—it would be a little difficult to power design the study to be a mortality study. So forced vital capacity, at this point in time, is probably our best surrogate in in all comers with interstitial lung disease.”

Regarding this new approval, Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, highlighted the privilege of reaching a landmark indication for the burdensome rare disease.

“We are honored to offer the very first FDA-approved biologic treatment option to people living with systemic sclerosis-associated interstitial lung disease,” Garraway said in a 

. “We worked closely with the FDA to evaluate Actemra’s impact on lung function in this setting. This milestone approval provides a much-needed new treatment option for people living with this rare, debilitating disease.”

The indication makes the IL-6 inhibitor the first biologic approved for treating pulmonary function in patients with the rare disease.

FDA Approves Tocilizumab for SSc Interstitial Lung Disease

A study found that ibuprofen use was associated with an increased risk of hospital-acquired 

Led by Licong Su, MD, National Clinical Research Center for Kidney Disease, Nanfang Hospital, China, the investigative team evaluated a total of 50,420 hospitalized children.

“Although ibuprofen is the most commonly prescribed nonsteroidal anti-inflammatory drugs (NSAID) in the world, few large studies have specifically studied the association between ibuprofen and hospital-acquired AKI in children,” wrote the investigators.

“Furthermore,” they continued, “these studies were generally limited by a small sample size and reported inconsistent findings.”

All children were drawn from a cohort of the Epidemiology of AKI in Chinese Hospitalized Patients (EACH) study, a multicenter retrospective study of 3, 044, 023 patients.

Patients were admitted to third-tier medical centers in China between January 1, 2013 — December 31, 2015.

Using electronic health records of the participating centers, the investigators obtained relevant patient data.

“Hospitalized children aged 1 month to 18 years who had prescriptions and a certain number of serum creatinine (SCr) tests were included,” they noted.

“Children with end-stage renal disease, community-acquired AKI, low baseline SCr level (<10 μmol/L), high standardized baseline SCr level (>4 times the sex- and age-specific reference value), or missing diagnosis code were excluded.”

They defined acute kidney injury (AKI) as an increase in SCr level of 26.5 μmol/L or higher within 48 hours or by 50% or more over the baseline value. Their definition was in accordance with the Kidney Disease: Improving Global Outcomes guidelines.

Thus, the mean age of the population was 5.0 years, and the majority (60.8%) was male.

Furthermore, of the population, 11.0% used ibuprofen and 6.9% developed hospital-acquired AKI during hospitalization.

Following adjustment for confounders, the investigators found that ibuprofen use was associated with a statistically significant increased risk of hospital-acquired AKI (hazard ratio [HR], 1.23; 95% CI, 1.14-1.34).

Additionally, ibuprofen use was associated with a greater hazard in children with chronic kidney disease (HR, 2.31; 95% CI, 1.73-3.10) compared to those without it (HR, 1.19; 95% CI, 1.09-1.29).

Increased hazard linked to ibuprofen was also noted for children who required intensive care (HR, 1.47; 95% CI, 1.24-1.75) versus those who did not (1.18; 95% CI, 1.07-1.29).

Children who were >10 years old had an HR of 1.64 (95% CI, 1.32-2.05]), children who were >1 year – 10 years had an HR of 1.36 (95% CI, 1.23-1.52), and children who were 1 month – 1 year had an HR of 0.99 (95% CI, 0.86-1.13).

And finally, the team noted that the association of ibuprofen with risk of hospital-acquired AKI was dose-dependent—according to their dose-response analysis.

The investigators cautioned for physicians to be judicious in prescribing ibuprofen among this population. They also encouraged close monitoring of kidney function in such patients.

“The exact mechanisms for these interactions were not clear,” they noted.

“Children with chronic kidney disease may have an elevated in vivo drug concentration, and children with more risk factors for developing AKI may be more susceptible to the potential nephrotoxic effect of ibuprofen."

They acknowledged that their study was limited by the lack of long-term data in the population as well as ethnic diversity.

“As in all other association studies, this study may still have unknown confounders, and causal inference is not possible,” they concluded.

Association of Ibuprofen Prescription with Acute Kidney Injury Among Hospitalized Children in China,

Risk was greater in children requiring intensive care, those with chronic kidney disease, and older patients.

Ibuprofen Use in Children Linked to Hospital-Acquired Kidney Injury

This article was originally published in NeurologyLive.

A recent study failed to show tumor necrosis factor receptor 1 (TNF-TNFR1) signaling inhibition can prevent or delay the risk or age at onset of Parkinson disease (PD).

Lead author Xioying Kang, MPH, BSc, department of medical epidemiology and biostatistics, Karolinka Institut, and colleagues found that TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating C-reactive protein [CRP], 0.99; 95% CI, 0.91–1.08) or age at onset (0.13 years later onset; 95% CI, –0.66 to 0.92).

To the authors’ knowledge, this was the first Mendelian randomization (MR) study to address whether exposure to TNF inhibitors affect PD.

"Human genetics provides valuable guidance for therapeutic programs because the chances of successful drug development are substantially improved when genetic evidence links a drug’s target to an indication for therapeutic use,” Kang et al wrote. “Hence, our findings should be considered as part of discourse on the repurposing potential of TNF inhibitors for PD prevention and treatment, particularly if/when selective inhibitors of TNF-TNFR1 signaling become available.”

A total of 23 single nucleotide polymorphisms (SNPs) in the vicinity of the gene 

which encodes TNFR1, the principal effector of pro-inflammatory signaling following TNF agonism were present in the CRP data (genome-wide association studies [GWAS], n = 204,402).

The effects of TNF-TNFR1 inhibition were estimated for PD risk (Ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson’s Disease Genomics Consortium and 23andMe, Inc.

Researchers found, however, that genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn’s disease (OR, 0.75; 95% CI, 0.65–0.86) and ulcerative colitis (OR, 0.84; 95% CI, 0.74–0.97), and increased the risk of multiple sclerosis (MS; OR, 1.57; 95% CI, 1.36–1.81), as the authors noted was expected.

In secondary analyses, the more liberal linkage disequilibrium (LD) clumping yielded 4 correlated SNPs associated with CRP at false discovery rate-corrected (

<.05), 1 of which was not associated with either white blood cell count (WBC; 

The other 3 variants were associated with all 3 inflammatory markers for secondary MR models.

Using adapted inverse variance weighting (IVW) methodology to account for correlations between the variants, MR estimates based on the 3 SNPs remained consistent with the main results that neither PD risk nor age at onset were predicted to be affected by TNF-TNFR1 blockade.

Kang and colleagues also found that there were no associations of the genotypes of implicated functional variant (rs1800693) with PD risk (OR, 1.00 per TNF-inhibiting allele; 95% CI, 0.98–1.02) or age at onset (0.05 years of increase per TNF-inhibiting allele; 95% CI, –0.13 to 0.24), despite strong associations of this SNP with other inflammatory traits.

Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study

Genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn’s disease and ulcerative colitis, and increased the risk of multiple sclerosis.

TNF Treatment Fails to Prevent or Delay Parkinson Disease in Clinical Trial

While previous studies show albumin provides anti-inflammatory properties of 

 patients, there is a scarcity of larger clinical trials.

Whether targeting a serum albumin level of 30 g per liter or greater in this patient population with repeated daily infusions of 20% human albumin solution, compared to standard care, could reduce the incidences of infection, kidney dysfunction, and death is largely unknown.

A team, led by Louise China, PhD, Institute for Liver and Digestive Health, examined whether albumin is beneficial for hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment.

In the randomized, multicenter, open-label, parallel-group trial, the investigators randomly assigned 777 patients to receive either targeted 20% human albumin solution for up to 14 days or until discharge or standard care.

Treatment commended within 3 days following admission.

Infection and increased systemic inflammation can cause organ dysfunction and death for patients with decompensated cirrhosis.

The investigators sought a composite primary endpoint of new infections, kidney dysfunction, or deaths between days 3-15 following treatment initiation.

The majority of patients in the study reported alcohol as the cause for cirrhosis.

A median total infusion of albumin of 200 g (interquartile range, 140-280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared to a median of 20 g (interquartile range, 0-120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% CI, 127-158.2).

Overall, the proportion of patients who met the primary endpoint did not significantly differ between the 2 groups.

In the targeted albumin group, 113 patients (29.7%) met the primary endpoint, while 120 individuals (30.2%) in the standard care group met the primary endpoint (aOR, 0.98; 95% CI, 0.71-1.33; 

In a time-to-event analysis where the researchers censored data at the time of discharge or at day 15, they found now significant between-group differences (HR, 1.04; 95% CI, 0.81-1.35).

In addition, more severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group.

“In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom,” the authors wrote.

 might be especially beneficial for cirrhosis patients, reducing the risk of death.

The study, which was presented at Digestive Disease Week 2019 in San Diego, CA, found that physical activity was associated with a 73% lower risk of dying from liver disease after studying more than 117,000 people over a 26-year period.

While past studies and research have been limited, usually only assessing physical activity at one point or have had short follow-up periods. This study represented the first prospective study in a large US population to included updated measurements of physical activity over such a prolonged period. The longer study period allowed investigators to more accurately estimate the relationship between physical activity.

A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis

Albumin infusions did not result in statistically significant differences in predefined study endpoints.

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