Body

Researchers developed a new risk equation, based on six routinely available patient parameters, that yielded improved performance in estimating the risk of a chronic kidney disease (CKD) patient to progress to end-stage kidney disease (ESKD) requiring kidney replacement therapy (KRT).

A novel risk equation for the timely identification of chronic kidney disease (CKD) patients at risk for progressing to kidney failure requiring kidney replacement therapy was developed in 4,915 patients with CKD stage 1-5 with and without albuminuria, from the German Chronic Kidney Disease (GCKD) Study. It includes six laboratory tests: serum creatinine, albumin, cystatin C, and urea, in addition to hemoglobin and the urine albumin-to-creatinine ratio. The newly derived 6-variable (Z6) risk score achieved high predictive performance and good calibration both in a resampling approach in the GCKD study and in three independent validation cohorts that included a total of 3,063 patients with CKD. Implementation of this risk equation in clinical practice holds promise for enhanced patient care.

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

1. Currently used SARS-CoV-2 vaccines more than 95% effective in preventing confirmed infection
Free full text: https://www.acpjournals.org/doi/10.7326/M21-1577

A large case-control study of participants in the Veterans Administration (VA) health care system, found that currently used SARS-CoV-2 vaccines are more than 95% effective in preventing confirmed infection. Because veterans are at particularly high risk given their older age and greater burden of comorbidities compared with the general population, these findings should be reassuring. The study is published in Annals of Internal Medicine.

Researchers from VA Pittsburgh Healthcare System studied health records from the VA COVID-19 Shared Data Resource who had SARS-CoV-2 testing between December 2020 and March 2021 to evaluate the short-term effectiveness of vaccines in preventing SARS-CoV-2 infection. For each person who tested positive, a propensity score- and demographic/health characteristic-matched control participant who tested negative was identified. Data on vaccine administration date and the type of vaccine used were also retrieved. The researchers found that 18% of the 54,360 matched pairs of veterans who were vaccinated tested positive for SARS-CoV-2 and 32.8% tested negative. The overall vaccine effectiveness was 97.1% 7 or more days after the second dose. Effectiveness was 96.2% for the Pfizer-BioNTech BNT-162b2 vaccine and 98.2% for the Moderna mRNA-1273 vaccine. Vaccine effectiveness was numerically similar (though statistically significantly higher) among persons aged 70 years or older compared with those younger than 70 years. Effectiveness was similar between Blacks and Whites, men and women, and those with and without higher levels of comorbidities.

According to the authors, these findings clearly show the effectiveness of the current vaccines in preventing infection. Their study did not assess vaccine effectiveness in preventing severe disease and death.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The corresponding author, Adeel A. Butt, MBBS, MS, can be reached through Alanna Caffas at Alanna.Caffas@va.gov.

2. Having sickle cell disease quadruples risk for COVID-19-related hospitalization and doubles risk for COVID-19-related death
Free full text: https://www.acpjournals.org/doi/10.7326/M21-1375

A large cohort study found that having sickle cell disease quadrupled a person's risk for COVID-19-related hospitalization and more than doubled the risk for COVID-19-related death. Having sickle cell trait was also associated with increased risks for both outcomes, albeit to a lesser extent. The findings are published in Annals of Internal Medicine.

Researchers from the University of Oxford, Oxford United Kingdom studied a national patient-level database of linked electronic health care records to evaluate the risks for COVID-19-related hospitalization and death in children and adults with sickle cell disorders. The cohort included 5,059 persons with sickle cell disease and 25,682 with sickle cell trait with data observed from January 2020 to September 2020 for hospitalizations and January 2020 to January 2021 for deaths. The researchers found that children with sickle cell disorders had 5 COVID-19-related hospitalizations and no deaths. Adults with sickle cell disease had 40 hospitalizations and 10 deaths. Persons with sickle cell trait had 98 hospitalizations and 50 deaths. The authors note that several aspects of sickle cell phenotypes overlap with the pathophysiology of severe COVID-19, warranting future study.

Given that sickle cell disease affects approximately 15,000 persons in the United Kingdom, 100,000 persons in the United States, and 8 million to 12 million persons globally, the authors suggest that these findings have important implications for informing vaccination strategy and policy decisions.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The corresponding author, Ashley Kieran Clift, MBBS, can be reached at communications@phc.ox.ac.uk.

No benefit of high-flow therapy (HFT) can be derived from the available study data for patients with advanced chronic obstructive pulmonary disease (COPD) or chronic type 1 respiratory failure. It therefore remains unclear whether this form of treatment has advantages over long-term oxygen therapy (LTOT) or non-invasive ventilation (NIV).

This is the conclusion of the benefit assessment that the Institute for Quality and Efficiency in Health Care (IQWiG) has now completed. The Federal Joint Committee (G-BA) had commissioned IQWiG to investigate the advantages and disadvantages of HFT in patients with stable, advanced COPD or chronic respiratory failure with oxygen deficiency (chronic type 1 respiratory failure). Treatment was to be self-administered at home, in inpatient care or rehab, etc.

However, no data were available for the final report that would have been sufficient for a benefit assessment. Since HFT fulfils the legal requirements for the intervention to be classified as having a potential, IQWiG formulated key points for two testing studies: for COPD with type I respiratory failure and for type II.

Different medical indications require different treatment approaches

In HFT, humidified and heated room air with increased flow rates is supplied via a nasal cannula; if necessary, oxygen can also be added. This aims to support breathing problems and secretion clearance and to relieve the respiratory muscle pump. Depending on the type of respiratory failure, the pathophysiology of the disease and thus the modes of action of treatment differ: In chronic type 1 respiratory failure with pulmonary impairment and corresponding respiratory failure (pulmonary failure) in connection with an undersupply of oxygen (hypoxaemia), patients require different treatment than in type 2 respiratory failure, where the respiratory muscle pump is impaired (ventilatory failure) and the disease is associated with carbon dioxide excess in the blood (hypercapnia).

The primary treatment goal, regardless of the type of failure, is to avoid acute worsening of chronic dyspnoea (exacerbations). However, the main treatment approaches differ: (long-term) oxygen therapy (LTOT) is recommended for the treatment of (chronic) hypoxaemia in type 1 respiratory failure. Various applications such as breathing masks are available for this purpose. For the treatment of type 2 (hypercapnic) respiratory failure, besides oxygen administration, CO? release must be supported, so invasive (intubation) or non-invasive ventilation therapy (with a breathing mask or helmet) is used.

Key points for testing studies

For the different medical indications, the IQWiG project team identified both completed and ongoing randomized controlled trials (RCTs) on HFT. However, these are insufficient to assess the benefit of HFT in patients with type 1 respiratory failure. For a robust conclusion on the benefit of HFT, further studies are needed to generate more evidence. Based on the identified potential of the intervention, IQWiG proposes two testing studies.

Because of the different treatment mechanisms, it is not meaningful to conjointly consider the studies on HFT versus long-term oxygen therapy (LTOT) or non-invasive ventilation (NIV). IQWiG therefore proposes to test the intervention in two studies: In COPD and chronic type 1 respiratory failure, HFT should be investigated as an add-on to LTOT versus LTOT alone. In COPD and chronic type 2 respiratory failure, HFT can be used instead of NIV.

Procedure of report production

In February 2021, IQWiG published the preliminary results, the preliminary report, for discussion. After completion of the commenting procedure, the project team revised the preliminary report and in May sent the final report to the contracting agency, the G-BA. The final report contains changes resulting from the commenting procedure. The written comments received are published in a separate document at the same time as the final report.

Vaccine hesitancy continues to be a hurdle in the development of widespread immunity within the U.S. population as the COVID-19 pandemic enters its second year.

Researchers at the University of Cincinnati College of Medicine have developed a computerized decision analytic model to compare projected outcomes of three vaccine strategies: a patient opts for a messenger RNA vaccine, a patient decides to get an adenovirus vector vaccine or the patient simply forgoes a vaccine altogether.

Pfizer and Moderna produce mRNA vaccines while Johnson & Johnson manufacture an adenovirus vector vaccine. The decision analytic model uses a metric of quality adjusted life expectancy that accounts for both survival and quality of life as affected by hospitalization, COVID-19 disease and long-term post-infection complications on a patient, also commonly known as long-haul syndrome, explains Mark Eckman, MD, director and professor in the UC Division of General Internal Medicine and lead author of the study.

The model simulated the health outcomes for a 65-year-old and found the patient would gain a net of 7.4 days -- an extra week of life -- if the person received the mRNA vaccine versus opting to not vaccinate at all. Of the two strategies that include receiving a vaccine, both yield virtually equivalent results, with the mRNA vaccine demonstrating a minimal gain of roughly one day of life compared with the J&J vaccine, says Eckman.

The study findings are available online in the scholarly journal Medical Decision Making Policy & Practice. Other co-authors include Richard Lofgren, MD, President and CEO of UC Health, and faculty members in the UC Department of Internal Medicine: Margaret Powers-Fletcher, PhD, assistant professor; Jennifer Forrester, MD, associate professor; Carl Fichtenbaum, MD, professor and George Smulian, MD, professor.

"The important point is that both types of vaccines are better than no vaccine," says Eckman, also a primary care physician at UC Health, the UC affiliated health system that teaches and trains residents, medical students and other students in health care professions. "If we take a public health perspective by multiplying that gain over the vaccine eligible population, it results in a large net benefit for the nation."

Eckman says if the U.S. extends the per person benefit to the remaining unvaccinated and eligible population (individuals 12 years old and up) in the country, the aggregate benefit would be 3.92 million quality-adjusted life years for those receiving an mRNA vaccine. If the aggregate benefit were calculated using the J&J vaccine it would result in a net benefit of 3.38 million quality-adjusted life years.

"Since we did not have time to perform a clinical trial to study this question of vaccination, we developed a computer model to simulate outcomes of the strategies mentioned, using the most up-to-date and best data available," says Eckman. "Our analysis showed that both vaccines yield virtually equivalent results. The take-home message is that receiving either type of the vaccine is better than not getting vaccinated at all."

CAMBRIDGE, MA -- Since the Covid-19 pandemic began last year, face masks and other personal protective equipment have become essential for health care workers. Disposable N95 masks have been in especially high demand to help prevent the spread of SARS-CoV-2, the virus that causes Covid-19.

All of those masks carry both financial and environmental costs. The Covid-19 pandemic is estimated to generate up to 7,200 tons of medical waste every day, much of which is disposable masks. And even as the pandemic slows down in some parts of the world, health care workers are expected to continue wearing masks most of the time.

That toll could be dramatically cut by adopting reusable masks, according to a new study from MIT that has calculated the financial and environmental cost of several different mask usage scenarios. Decontaminating regular N95 masks so that health care workers can wear them for more than one day drops costs and environmental waste by at least 75 percent, compared to using a new mask for every encounter with a patient.

"Perhaps unsurprisingly, the approaches that incorporate reusable aspects stand to have not only the greatest cost savings, but also significant reduction in waste," says Giovanni Traverso, an MIT assistant professor of mechanical engineering, a gastroenterologist at Brigham and Women's Hospital, and the senior author of the study.

The study also found that fully reusable silicone N95 masks could offer an even greater reduction in waste. Traverso and his colleagues are now working on developing such masks, which are not yet commercially available.

Jacqueline Chu, a physician at Massachusetts General Hospital, is the lead author of the study, which appears in the British Medical Journal Open.

Reduce and reuse

In the early stages of the Covid-19 pandemic, N95 masks were in short supply. At many hospitals, health care workers were forced to wear one mask for a full day, instead of switching to a new one for each patient they saw. Later on, some hospitals, including MGH and Brigham and Women's Hospital in Boston, began using decontamination systems that use hydrogen peroxide vapor to sterilize masks. This allows one mask to be worn for a few days.

Last year, Traverso and his colleagues began developing a reusable N95 mask that is made of silicone rubber and contains an N95 filter that can be either discarded or sterilized after use. The masks are designed so they can be sterilized with heat or bleach and reused many times.

"Our vision was that if we had a reusable system, we could reduce the cost," Traverso says. "The majority of disposable masks also have a significant environmental impact, and they take a very long time to degrade. During a pandemic, there's a priority to protect people from the virus, and certainly that remains a priority, but for the longer term, we have to catch up and do the right thing, and strongly consider and minimize the potential negative impact on the environment."

Throughout the pandemic, hospitals in the United States have been using different mask strategies, based on availability of N95 masks and access to decontamination systems. The MIT team decided to model the impacts of several different scenarios, which encompassed usage patterns before and during the pandemic, including: one N95 mask per patient encounter; one N95 mask per day; reuse of N95 masks using ultraviolet decontamination; reuse of N95 masks using hydrogen peroxide sterilization; and one surgical mask per day.

They also modeled the potential cost and waste generated by the reusable silicone mask that they are now developing, which could be used with either disposable or reusable N95 filters.

According to their analysis, if every health care worker in the United States used a new N95 mask for each patient they encountered during the first six months of the pandemic, the total number of masks required would be about 7.4 billion, at a cost of $6.4 billion. This would lead to 84 million kilograms of waste (the equivalent of 252 Boeing 747 airplanes).

They also found that any of the reusable mask strategies would lead to a significant reduction in cost and in waste generated. If each health care worker were able to reuse N95 masks that were decontaminated with hydrogen peroxide or ultraviolet light, costs would drop to $1.4 billion to $1.7 billion over six months, and 13 million to 18 million kilograms of waste would result (the equivalent of 39 to 56 747s).

Those numbers could potentially be reduced even further with a reusable, silicone N95 mask, especially if the filters were also reusable. The researchers estimated that over six months, this type of mask could reduce costs to $18 million and waste to 1.6 million kilograms (about 2.5 747s).

"Masks are here to stay for the foreseeable future, so it's critical that we incorporate sustainability into their use, as well as the use of other disposable personal protective equipment that contribute to medical waste," Chu says.

Environmental burden

The data the researchers used for this study were gathered during the first six months of the pandemic in the United States (late March 2020 to late September 2020). Their calculations are based on the total number of health care workers in the United States, the number of Covid-19 patients at the time, and the length of hospital stay per patient, among other factors. Their calculations do not include any data on mask usage by the general public.

"Our focus here was on health care workers, so it's likely an underrepresentation of the total cost and environmental burden," Traverso notes.

While vaccination has helped to reduce the spread of Covid-19, Traverso believes health care workers will likely continue to wear masks for the foreseeable future, to protect against not only Covid-19 but also other respiratory diseases such as influenza.

He and others have started a company called Teal Bio that is now working on further refining and testing their reusable silicone mask and developing methods for mass manufacturing it. They plan to seek regulatory approval for the mask later this year. While cost and environmental impact are important factors to consider, the effectiveness of the masks also needs to be a priority, Traverso says.

"Ultimately, we want the systems to protect us, so it's important to appreciate whether the decontamination system is compromising the filtering capacity or not," he says. "Whatever you're using, you want to make sure you're using something that's going to protect you and others."

New research adds to a body of evidence indicating decisions about withdrawing life-sustaining treatment for patients with moderate-to-severe traumatic brain injury (TBI) should not be made in the early days following injury.

In a July 6, 2021, study published in JAMA Neurology, researchers led by UC San Francisco, Medical College of Wisconsin and Spaulding Rehabilitation Hospital followed 484 patients with moderate-to-severe TBI. They found that among the patients in a vegetative state, 1 in 4 "regained orientation" - meaning they knew who they were, their location and the date - within 12 months of their injury.

"Withdrawal of life-sustaining treatment based on early prediction of poor outcome accounts for most deaths in patients hospitalized with severe TBI," said senior author Geoffrey Manley, MD, PhD, professor and vice chair of neurological surgery at UCSF and chief of neurosurgery at Zuckerberg San Francisco General Hospital, noting that 64 of the 92 fatalities in the study occurred within two weeks of injury.

"TBI is a life-changing event that can produce significant, lasting disability, and there are cases when it is very clear early on that a patient will not recover," he said. "But results from this study show a significant proportion of our participants experienced major improvements in life functioning, with many regaining independence between two weeks and 12 months after injury."

The patients in the study were enrolled by the brain injury research initiative TRACK-TBI, of which Manley is the principal investigator. All patients were 17 and older and had presented to hospitals with level 1 trauma centers within 24 hours of injury. Their exams met criteria for either moderate TBI (approximately one third of patients) or severe TBI.

In both groups, the most common causes of injury were falls, assault and primarily car and motorcycle crashes in which the patient had been a driver/passenger, pedestrian or cyclist.

The patients, whose average ages were 35 in the severe TBI group (78 percent males) and 38 in the moderate TBI group (80 percent males), were assessed using the Glasgow Outcomes Scale Extended (GOSE), which ranges from 1 for death to 8 for "upper good recovery" and resumption of normal life. The Disability Rating Scale (DRS) was also used to categorize impairment.

At 12 Months, Small but Significant Minority of Severe TBI Patients Had No Disability

At two weeks post-injury, 93 percent of the severe TBI group and 79 percent of the moderate TBI group had moderate-to-severe disability, according to the DRS, and 80 percent had GOSE scores from 2 to 3, meaning they required assistance in basic everyday functioning.

But by 12 months, half of the severe TBI group and three-quarters of the moderate TBI group had GOSE scores of at least 4, indicating they could function independently at home for at least eight hours per day. Moreover, 19 percent of the severe TBI group had no disability, according to the DRS, and a further 14 percent had only mild injury, the researchers noted.

Most surprising were the findings for the 62 surviving patients who had been in a vegetative state, defined as a chronic state of brain dysfunction in which a person shows no signs of awareness. All patients had recovered consciousness by the 12-month mark and 14 out of the 56 with available data (1 in 4) had regained orientation. All but one survivor in this group recovered at least basic communication ability.

"These patients made the cut for favorable outcome," said co-first author, Joseph Giacino, PhD, of Spaulding Rehabilitation Hospital, Massachusetts General Hospital and Harvard Medical School. "Their GOSE scores were 4 or higher, which meant they could be at home unsupervised for at least eight hours a day, since they were able to take care of basic needs, such as eating and toileting."

The study follows previous research that shows a significant percentage of patients with grave impairments achieve favorable functionality many months or years later. This research, led by Giacino, coincided with the recommendation in 2018 from the American Academy of Neurology that in the first 28 days after injury, clinicians should refrain from telling families that a patient's prognosis is beyond hope.

"While a substantial proportion of patients die or suffer lasting disability, our study adds to growing evidence that severe acute impairment does not portend uniformly poor long-term outcome," said Manley, who is also affiliated with the UCSF Weill Institute for Neurosciences. "Even those patients in a vegetative state - an outcome viewed as dire - may improve, since this is a dynamic condition that evolves over the first year."

By Luciana Constantino | Agência FAPESP – A pregnant woman infected by zika virus does not face a greater risk of giving birth to a baby with microcephaly if she has previously been exposed to dengue virus, according to a Brazilian study that compared data for pregnant women in Rio de Janeiro and Manaus.

A zika epidemic broke out in Brazil in 2015-16 in areas where dengue is endemic. Both viruses are transmitted by the mosquito Aedes aegypti. Some of the states affected by the zika epidemic reported a rise in cases of microcephaly, a rare neurological disorder in which the baby’s brain fails to develop completely. Others saw no such rise.

According to this new study by Brazilian researchers, two factors explain the rise in microcephaly in only some areas: the high zika attack rate, and the mother’s having contracted the virus in the first trimester of pregnancy. The term attack rate in epidemiology refers to the number of cases divided by the total population.

The study was supported by FAPESP via two projects (16/15021-1 and 13/21719-3), and was conducted under the aegis of the Network for Research on Zika Virus in São Paulo (Rede Zika). The results are described in an article in Viruses, a peer-reviewed open-access journal published by the Multidisciplinary Digital Publishing Institute (MDPI). The article appeared in late April in a special issue on zika and pregnancy.

“The discrepancies between regions in terms of the numbers of reported cases of microcephaly during the zika epidemic were puzzling. One of the hypotheses was that prior exposure to dengue might make zika more severe, but in the state of São Paulo there weren’t many adverse effects of zika even though the region is highly endemic for dengue, so we decided to try to find out what could explain the differences,” said virologist Maurício Lacerda Nogueira, a professor at the São José do Rio Preto Medical School (FAMERP) in São Paulo, and co-principal investigator for the study alongside Patrícia Brasil, a researcher at Oswaldo Cruz Foundation (FIOCRUZ) in Rio de Janeiro.

According to Nogueira, their attention was drawn to the attack rate when they analyzed the data for the two state capitals. In Rio de Janeiro, where many cases of microcephaly were reported, the number of people infected by zika virus corresponded to 10 per 10,000 inhabitants, while in Manaus, where relatively few babies were born with microcephaly, the attack rate was 0.6 per 10,000.

“Microcephaly caused by zika is a rare phenomenon, but when there are many cases of zika in an area it becomes more apparent. It had been suggested earlier that contracting zika in the first trimester of pregnancy might be relevant, and now we’ve proved that it was,” Nogueira said.

Methodology

The researchers set out to understand the differences in the adverse outcomes of pregnancy and in the babies of the two populations by studying 114 pregnant women infected by zika virus between September 2015 and June 2016. Infection was confirmed by RT-qPCR testing of blood and/or urine samples. The subjects were recruited at Heitor Vieira Dourado Tropical Medicine Foundation (FMT-HVD), an infectious disease hospital in Manaus, and FIOCRUZ’s acute febrile illness clinic in Rio de Janeiro.

Prior exposure to dengue was assessed by serological tests to detect neutralizing antibodies, among others. The goal was to explore potential associations between pregnancy outcomes and the zika attack rate, defined as the number of cases officially reported during the study period divided by the population of each city.

Overall, 31 women had adverse outcomes (27 in Rio and 4 in Manaus). In this group, four babies died before birth and 27 were born with brain anomalies. “Only zika attack rates and infection in the first trimester of pregnancy were associated with adverse pregnancy and infant outcomes. Pre-existing immunity to dengue was not associated with outcomes (normal or abnormal) in patients with zika during pregnancy,” the authors of the article state in the Abstract.

And they conclude: “The strengths of our study include a careful classification of infant outcomes, made possible through detailed assessments at birth by a multidisciplinary team. [...] In addition, the use of a highly sensitive and specific [plaque reduction neutralizing antibody] assay to characterize pre-existing dengue immunity and the use of sera collected during the acute phase of RT-PCR-confirmed zika infection lend credibility to our results. […] Our main limitations are the modest sample size and convenience sample selection.”

An earlier study led by Nogueira in 2017 showed that patients infected by zika after exposure to dengue did not become more severely ill than other people. It was the first scientific study to show this in humans. Prior research involving cells and rodents had suggested the opposite (more at: revistapesquisa.fapesp.br/en/dengue-may-attenuate-zika).

Background

Microcephaly is a rare neurological condition in which an infant’s head and brain are significantly smaller than normal as a result of alterations in the formation of the nervous system during development in the womb. Children with microcephaly usually suffer from retarded or blocked mental, physical and motor development.

The causes of microcephaly include genetic factors and exposure to chemicals, bacteria and viruses. Scientists have recently shown that zika contracted during pregnancy can impair fetal development.

During the epidemic in Brazil, zika affected people of all ages and was associated with the occurrence of a large number of cases of microcephaly. In November 2015, Brazil declared a public health emergency because of the rising number of cases. The World Health Organization (WHO) then issued an epidemiological alert, stressing the possibility of congenital neurological malformations in babies born to women infected by zika.

In 2015 alone, more than 2,400 cases of microcephaly were reported in Brazil. They occurred in about 540 municipalities in 20 states. In the period 2010-14, the total number of reported cases was 781.

In 2016 there were some 214,000 probable cases of zika. The number fell to 17,000 in 2017 and 8,000 in 2018. In the first three months of this year, it was 448, according to the Ministry of Health’s epidemiological bulletin.

The symptoms of zika are similar to those of dengue. In most infected people, it causes fever, headache, red eyes, joint pain and rash. On average, the symptoms disappear in ten days.

The researchers are proceeding with their analysis of the interactions between zika and dengue, particularly to see if zika modulates infection by dengue virus. Nogueira also participates in an international group that is working on models to predict epidemics of zika, dengue and yellow fever (more at: agencia.fapesp.br/35240/).

The article “Why did ZIKV perinatal outcomes differ in distinct regions of Brazil? An exploratory study of two cohorts” is at: www.mdpi.com/1999-4915/13/5/736/htm.

Journal

Viruses

DOI

10.3390/v13050736

Routine adolescent preventive visits provide important opportunities for promoting sexual and reproductive health and for preventing unintended pregnancy and sexually transmitted infections.

A new study published in Pediatrics -- led by the University of Minnesota -- found that a majority of adolescents and their parents considered health care provider discussions about puberty, sexually transmitted infections, HIV and birth control important. However, less than one-third of these young people reported discussions about such topics, other than puberty, at their most recent preventive visit.

"Our findings suggest clear gaps between parent and adolescent perceived importance of discussing sexual and reproductive health topics and adolescents' experiences during preventive visits," said Renee Sieving, a professor in the School of Nursing and the study's lead author. "While most parents and many youth that were surveyed noted the importance of providers discussing these topics, it does not routinely occur during preventive visits."

Based on data from a nationally representative survey of U.S. adolescents ages 11-to-17 years old and their parents, the study's key findings were that during recent preventive visits:

14% of younger adolescents (ages 11-14 years old) and 38.7% of older adolescents (ages 15-17 years) reported that providers asked about their sexual activity;

of potential sexual and reproductive health topics, provider-adolescent discussions about puberty were most common;

less than one-third of adolescents reported a provider discussing any other sexual and reproductive health topic; and

conversations about confidentiality and time alone between providers and adolescents were infrequent, with 20% of younger adolescents and 44% of older adolescents reporting time alone with their provider at their most recent check-up.

The researchers noted that their work indicates that primary care providers frequently miss opportunities for critical conversations about sexual and reproductive health, particularly with younger adolescents.

"These findings dispel potential concerns that parents may object to providers having these discussions: both parents and adolescents want discussions on a range of sexual and reproductive health topics to start in early adolescence," said Sieving. "Discussions about sexual and reproductive health and other sensitive topics are most likely to happen as a part of confidential conversations between adolescents and their providers, a practice that was infrequent among adolescents in this study."

Further efforts are needed to identify strategies that enhance providers' capacities to engage adolescents in these discussions. It will also be important for research and interventions to address structural barriers and facilitators to provider-adolescent conversations about sexual and reproductive health within primary care settings.

WASHINGTON (July 20, 2021)--A new study of COVID-19 shutdowns in the United States reveals pronounced disparities in air pollution -- with disenfranchised, minority neighborhoods still experiencing more exposure to a harmful air pollutant compared to wealthier, white communities. This first-of-a-kind study published today by researchers at the George Washington University looks at how air pollution changed after schools and businesses shut down in March 2020 in attempts to curb the spread of COVID-19.

"New York and other major urban areas had cleaner air as many commuters and others stayed off the roads," Gaige Kerr, the lead researcher on the study and a research scientist at the GW Milken Institute School of Public Health, said. "At the same time, our study shows that an air pollutant called nitrogen dioxide was still disproportionately higher in marginalized, mostly Latino and Black neighborhoods."

Nitrogen dioxide is formed when fossil fuels such as coal, oil, gas or diesel are burned at high temperatures. Cars, trucks and buses are the largest source of nitrogen dioxide emissions in urban areas followed by stationary sources, including power plants and factories.

With support from NASA, the researchers used data from a recently launched satellite orbiting the earth called the TROPOspheric Monitoring Instrument, along with ground measurements of pollution, to estimate nitrogen dioxide levels both before and after COVID-19 shutdowns. This method allowed the researchers to zoom in and compare one neighborhood's pollution level to another in urban areas throughout the U.S. They then used demographic data to compare how nitrogen dioxide levels changed for different population sub-groups.

While previous studies have documented the inequity in air pollution exposure using models or spatially limited networks of ground monitors, this study relied on both observational and spatially complete satellite data to reveal how these inequities persisted during the unparalleled changes in human activity during COVID-19, the authors said.

The team found that changes in human activity during the COVID-19 pandemic, largely less passenger vehicle traffic, resulted in lower nitrogen dioxide levels among the vast majority of urban areas.

Yet even that sharp decrease was not large enough to eliminate the racial, ethnic and socioeconomic disparities in exposure to this traffic-related pollutant. Marginalized, minority communities still experienced nitrogen dioxide levels during the shutdowns that, in some cities, were 50% higher than pre-pandemic levels in the nearby highest income and mostly white communities, Kerr said.

The researchers linked the biggest drops in nitrogen dioxide pollution during COVID-19 shutdowns to a community's proximity to highways and interstates. Kerr says that marginalized urban areas are also more likely to be located near interstates, where traffic is responsible for a large portion of urban nitrogen dioxide pollution and other forms of pollution.

For example, in New York, the largest reductions in nitrogen dioxide were found near the convergence of the George Washington Bridge and Major Deegan Expressway, an area that also has a heavy concentration of industries. The largest drops in Atlanta were located in the southwest part of the city near the airport and several major roadways. In Detroit, the biggest reduction in nitrogen dioxide occurred on the west shores of the Detroit River, where several interstates and the Ambassador Bridge, a busy U.S.-Canadian border crossing, come together. While passenger vehicle traffic dropped on these highways, heavy-duty trucking was less affected by the pandemic, and, along with other emission sources, continued contributing to high pollution levels in nearby communities.

Previous research by the senior author of the paper, Susan C. Anenberg, an associate professor of environmental and occupational health at GW, shows that nitrogen dioxide triggers millions of serious asthma attacks worldwide and may cause children to develop asthma for the first time.

Other evidence indicates that exposure to air pollution, including nitrogen dioxide, may increase the likelihood of people getting very sick or dying from COVID-19. Researchers also know that COVID-19 disproportionately strikes minority communities.

"With new satellite data, we can actually observe how pollution levels differ between neighborhoods within cities and track changes over time," Anenberg said. "Our research shows how individual behavior change won't solve environmental injustice. We need long-term policy solutions to reduce emissions and help keep people healthy, especially those living in disadvantaged neighborhoods."

Policies aimed at reducing traffic related emissions -- such as public transportation and widespread use of electric cars -- may not be enough to reduce the nitrogen dioxide pollution in disenfranchised, minority neighborhoods, the authors note. Policymakers who want to reduce the disparities in air pollution across demographic subgroups should also target other sources of pollution that are found in disadvantaged neighborhoods, such as heavy-duty trucking.

"This study shows that an unparalleled pandemic and an unprecedented drop in emissions were not large enough to clean the air for poor, minority neighborhoods," Kerr said. "Urgent action is need to reduce or eliminate these disparities, protect public health, and advance environmental justice."

LA JOLLA--Fighting a tumor is a marathon, not a sprint. For cancer-fighting T cells, the race is sometimes just too long, and the T cells quit fighting. Researchers even have a name for this phenomenon: T cell exhaustion.

In a new Nature Immunology study, researchers at La Jolla Institute for Immunology (LJI) report that T cells can be engineered to clear tumors without succumbing to T cell exhaustion.

"The idea is to give the cells a little bit of armor against the exhaustion program," says LJI Professor Patrick Hogan, Ph.D. "The cells can go into the tumor to do their job, and then they can stick around as memory cells."

This research builds on a decades-long collaboration between Hogan and LJI Professor Anjana Rao, Ph.D. Their work has shown the key role of proteins called transcription factors in the cellular pathway that triggers T cell exhaustion.

This work is important because T cell exhaustion continues to plague even the most cutting-edge cancer immunotherapies.

With CAR T therapies, for example, researchers take T cells from a cancer patient and "arm" them by altering the expression of genes that aid in the cancer fight. Researchers make more of these special T cells, which then go back into the patient. CAR T therapies are different from immunotherapies, which aim to activate the patient's existing T cell population.

With both approaches, T cell exhaustion rears its ugly head. "Many people have tried to use CAR T therapies to kill solid tumors, but it's been impossible because the T cells become exhausted," says study co-first author Hyungseok Seo, Ph.D., a former postdoctoral fellow in the Rao Lab who is currently working at Novartis.

The new study addresses this problem by giving T cells the ability to fight exhaustion itself.

To accomplish this, the researchers screened T cells to uncover which transcription factors could boost a T cell's "effector" program, an important step in readying T cells to kill cancer cells.

This screening process led the researchers to BATF, a transcription factor that they found cooperates with another transcription factor called IRF4 to counter the T cell exhaustion program.

In mouse melanoma and colorectal carcinoma tumor models, altering CAR T cells to also overexpress BATF led to tumor clearance without prompting T cell exhaustion. The CAR T therapy worked against solid tumors.

"BATF and IRF4 are cooperating to make T cells better," says Seo.

Further testing showed that while IRF4 is important, it shouldn't be overexpressed to the same degree as BATF. For maximum effect, BATF was overexpressed around 20 times more than in normal cells.

Encouragingly, some altered T cells also stuck around and became memory T cells. This is important because T cell exhaustion often prevents T cells from mounting a strong memory response to recurrent cancers.

"We didn't just increase the ability of T cells to fight exhaustion--we increased the ability of cells to fight tumors," says study co-first author Edahí González-Avalos, a graduate student in the Rao Lab who led the bioinformatic analysis for the project.

Hogan thinks overexpressing BATF could be a promising approach for improving CAR T therapies and for tackling some hard-to-treat cancer types, such as pancreatic ductal carcinoma. These types of cancers are known as "immunologically cold" because they don't spark a strong anti-cancer response from the immune system. T cells don't fight them in force.

Other laboratories have been exploring ways to make these cold tumors "hot," so they will attract T cells. The LJI team thinks a promising strategy would combine those approaches with targeting transcription factors to render T cells exhaustion-proof.

"We wouldn't necessarily need a transgenic approach to do this," says Hogan. "Maybe even an oral drug molecule could do it, if you knew what transcriptional pathways you wanted to go after."

The researchers emphasize that BATF is just one of many transcription factors that may prove important to manipulate when countering T cell exhaustion.

"We're going to keep looking for answers," adds González-Avalos.

BOSTON - Lymph nodes are critical to the body's immune response against tumors but paradoxically, cancer cells that spread, or metastasize, to lymph nodes can often avoid being eliminated by immune cells. Recent experiments by investigators at Massachusetts General Hospital (MGH) and Boston University School of Medicine provide insights on the details behind this immune evasion, which could help scientists develop strategies to overcome it. The findings are published in Nature Biomedical Engineering.

"We know that lymph nodes are often the first place cancer spreads as it progresses. We also know that our immune system can attack and kill cancer cells," explains senior and co-corresponding author Timothy P. Padera, PhD, an investigator in Radiation Oncology at MGH and a 2021-2026 MGH Research Scholar. "One of the perplexing questions that has been at the core of the recent work in my lab is how can organs that generate our immune responses--lymph nodes--permit cancer cells to survive and take them over instead of attacking them? This was the driving motivation behind this study."

By analyzing patient tissue from breast, colon, and head and neck cancers, combined with animal models of breast cancer lymph node metastases, Padera and his colleagues showed that immune cells called T cells are abundant in metastatic lymph nodes but fail to penetrate tumors that have spread to such nodes. The team measured increased physical forces, known as solid stress, in lymph nodes with metastatic cancer. "We hypothesized that solid stress in lymph node tumors can impair both blood flow and the T cell trafficking capacity of blood vessels in lymph nodes," says lead and co-corresponding author Dennis Jones, PhD, an assistant professor of Pathology & Laboratory Medicine at the Boston University School of Medicine.

The scientists then developed a device to compress lymph nodes in order to simulate the gradual growth of lymph node metastases. When they applied compressive force to lymph nodes, there was a clear link between physical force and disruption of T cell entry into lymph nodes. "Our findings indicate that as cancer cells grow in the lymph node, they reorganize and alter the lymph node, disabling critical functional responses of the immune system," says Padera. "By understanding how cancer cells are disabling lymph node function, we hope to fight back to help the lymph nodes generate anti-cancer immune responses, which will help fight cancer cells everywhere in the body."

Alleviating solid stress with the blood pressure drug losartan boosted the numbers of blood vessels and T cells in lymph node metastases, suggesting that alleviating solid stress is a potential strategy to improve T cell entry into tumors.

"Our work now leads to many important additional questions," says Jones. "Does losartan treatment combined with immunotherapy cause the eradication of metastatic cancer cells in lymph nodes by T cell killing? And further, does this lead to a strong systemic anti-cancer immune response that helps clear the cancer from the entire body?" Jones notes that finding the answers to these questions could lead to new treatment strategies for patients with metastatic cancer.

WHAT:

A new study published in JAMA Neurology suggests that certain features that appear on CT scans help predict outcomes following mild traumatic brain injury (TBI). Patterns detected on the scans may help guide follow up treatment as well as improve recruitment and research study design for head injury clinical trials.

Researchers led by Geoffrey Manley, M.D., Ph.D., professor of neurological surgery at the University of California San Francisco, conducted CT scans in 1,935 subjects with mild TBI and followed their outcomes up to 12 months after injury.

This research was part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, a large research effort funded by the National Institutes of Health to improve understanding of the short- and long-term effects of head injury and to identify potential treatments.

The researchers identified three distinct sets of patterns on the CT scans, indicating different types of damage after head injury which were associated with various outcomes. The results suggest that contusion (bleeding into brain tissue), subarachnoid hemorrhage (bleeding into the cerebrospinal fluid over the brain), subdural hematoma (bleeding between the brain and the thick covering over the brain), and intraventricular hemorrhage (bleeding into the fluid filled spaces in the center of the brain) were associated with worse outcomes 12 months after injury. Epidural hematoma, which describes bleeding between the skull and outer brain covering known as the dura, was associated with incomplete recovery at two weeks and three months, but was not linked to negative longer-term outcomes.

The TRACK-TBI study was designed and executed in collaboration with the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study of 2594 TBI subjects. Both sets of results showed similar patterns on CT scans and similar associations between CT abnormalities with clinical outcomes.

More research is needed to understand the effects of head injury on brain structure and function, and how different types of injury can lead to various short- and long-term outcomes.

New Curtin University-led research has called into question existing health advice that mothers wait a minimum of two years after giving birth to become pregnant again, in order to reduce the risk of adverse pregnancy outcomes, such as preterm and small-for-gestational age births.

The research found that a World Health Organization (WHO) recommendation to wait at least 24 months to conceive after a previous birth may be unnecessarily long for mothers in high-income countries such as Australia, Finland, Norway and the United States.

Lead researcher Dr Gizachew Tessema from the Curtin School of Population Health said because the WHO advice was based on limited evidence from resource-limited countries, it was necessary to investigate whether the 15-year-old recommendation was relevant for higher-income settings.

"We compared approximately 3 million births from 1.2 million women with at least three children and discovered the risk of adverse birth outcomes after an interpregnancy interval of less than six months was no greater than for those born after an 18-23 month interval," Dr Tessema said.

"Given that the current recommendations on birth spacing is for a waiting time of at least 18 months to two years after livebirths, our findings are reassuring for families who conceive sooner than this.

"However, we found siblings born after a greater than 60-month interval had an increased risk of adverse birth outcomes."

Dr Tessema said just as the current WHO recommendations are not age specific, the study's results were not necessarily equally applicable to parents of all ages.

"Our next step with this research is to identify whether intervals between pregnancies affect the risk of adverse birth outcomes among women of different ages," Dr Tessema said.

Philadelphia, July 19, 2021--Researchers at Children's Hospital of Philadelphia (CHOP) have developed a novel method for producing new antibiotics to combat resistant bacteria. Through an approach that would target bacteria with an antibiotic that is masked by a prodrug, which the bacteria would themselves remove, the researchers identified a method that would allow for development of new, effective antibiotics that could overcome issues of resistance. The findings were published today in eLife.

"We've created a sort of 'Trojan Horse' that would allow antibiotics to reach desired tissues undisturbed, until the bacteria itself activates the drug, effectively releasing an 'army' of antibiotics," said senior author Audrey R. Odom John, MD, PhD, Chief of the Division of Pediatric Infectious Diseases at CHOP. "Using structure-guided design, we have developed a new way to design better antibiotics. Given the growing concern over antimicrobial resistance, we think this is an important step forward."

Antimicrobial resistance poses a serious threat to public health, with some estimates suggesting that antimicrobial-resistant infections will cause as many as 10 million deaths per year by 2050. To combat this public health threat, scientists will need to develop new, chemically distinct antibiotics that can circumvent antimicrobial resistance, but most attempts to do so have either failed in animal or human models or have been unable to get sufficient levels of treatment to the desired tissues.

To tackle this problem, the researchers took a new approach that relied on exploiting bacterial metabolism, processes that are essential for bacteria to thrive. Drugs that inhibit these processes could eradicate the bacteria, but the chemical group that would inhibit those enzymes has a negative charge, which prevents the drugs from entering cells, creating a challenge.

One way to overcome that challenge is to chemically mask the undesirable negative charge with another chemical group. This strategy, known as prodrugging, adds a sort of shield - the "Trojan Horse" - that masks the negative charge, allows the drug to enter the cell, and then is removed during absorption to allow the original antibiotic to be taken up. However, the prodrug must also be resistant to host enzymes; otherwise, the prodrug mask will be removed too early, and the drug will never reach the desired tissue.

Focusing on Staphylococcus aureus, since methicillin-resistant S. aureus (MRSA) has been labeled a "serious threat" by the Centers for Disease Control and Prevention, the researchers looked for bacterial enzymes that interacted with specific targets that would not interact with host enzymes. Doing so, they were able to characterize two enzymes - GloB and FrmB - that each have defined substrate specificities - that is, highly specific molecules with which they will interact - and, importantly, those specificities are different than those of human enzymes. Thus, these enzymes could remove prodrug additions, activating the antibiotic, without the prodrugs first being degraded by the host.

Having determined GloB and FrmB were suitable bacterial enzyme targets, the researchers characterized the three-dimensional structures of GloB and FrmB, which confirmed their active sites and will enable ongoing structure-guided design of FrmB- and GloB-targeted prodrugs.

"This work paves the way for structure-guided development of S. aureus-specific prodrugs and establishes a pipeline for the identification of additional microbial prodrug activating enzymes," John said. "We anticipate that these approaches will both guide the development of novel antimicrobials and lead to a more robust arsenal of anti-infective compounds with targeted specificity for the microbe over the human host."

The second dose of a COVID-19 vaccine induces a powerful boost to a part of the immune system that provides broad antiviral protection, according to a study led by investigators at the Stanford University School of Medicine.

The finding strongly supports the view that the second shot should not be skipped.

"Despite their outstanding efficacy, little is known about how exactly RNA vaccines work," said Bali Pulendran, PhD, professor of pathology and of microbiology and immunology. "So we probed the immune response induced by one of them in exquisite detail."

The study, published July 12 in Nature, was designed to find out exactly what effects the vaccine, marketed by Pfizer Inc., has on the numerous components of the immune response.

The researchers analyzed blood samples from individuals inoculated with the vaccine. They counted antibodies, measured levels of immune-signaling proteins and characterized the expression of every single gene in the genome of 242,479 separate immune cells' type and status.

"The world's attention has recently been fixed on COVID-19 vaccines, particularly on the new RNA vaccines," said Pulendran, the Violetta L. Horton Professor II.

He shares senior authorship of the study with Kari Nadeau, MD, PhD, the Naddisy Foundation Professor of Pediatric Food, Allergy, Immunology, and Asthma and professor of pediatrics, and Purvesh Khatri, PhD, associate professor of biomedical informatics and of biomedical data science. The study's lead authors are Prabhu Arunachalam, PhD, a senior research scientist in Pulendran's lab; medical student Madeleine Scott, PhD, a former graduate student in Khatri's lab; and Thomas Hagan, PhD, a former postdoctoral scholar in Pulendran's Stanford lab and now an assistant professor at the Yerkes National Primate Research Center in Atlanta.

Uncharted territory

"This is the first time RNA vaccines have ever been given to humans, and we have no clue as to how they do what they do: offer 95% protection against COVID-19," said Pulendran.

Traditionally, the chief immunological basis for approval of new vaccines has been their ability to induce neutralizing antibodies: individualized proteins, created by immune cells called B cells, that can tack themselves to a virus and block it from infecting cells.

"Antibodies are easy to measure," Pulendran said. "But the immune system is much more complicated than that. Antibodies alone don't come close to fully reflecting its complexity and potential range of protection."

Pulendran and his colleagues assessed goings-on among all the immune cell types influenced by the vaccine: their numbers, their activation levels, the genes they express and the proteins and metabolites they manufacture and secrete upon inoculation.

One key immune-system component examined by Pulendran and his colleagues was T cells: search-and-destroy immune cells that don't attach themselves to viral particles as antibodies do but rather probe the body's tissues for cells bearing telltale signs of viral infections. On finding them, they tear those cells up.

In addition, the innate immune system, an assortment of first-responder cells, is now understood to be of immense importance. It's the body's sixth sense, Pulendran said, whose constituent cells are the first to become aware of a pathogen's presence. Although they're not good at distinguishing among separate pathogens, they secrete "starting gun" signaling proteins that launch the response of the adaptive immune system -- the B and T cells that attack specific viral or bacterial species or strains. During the week or so it takes for the adaptive immune system to rev up, innate immune cells perform the mission-critical task of holding incipient infections at bay by gobbling up -- or firing noxious substances, albeit somewhat indiscriminately, at -- whatever looks like a pathogen to them.

A different type of vaccine

The Pfizer vaccine, like the one made by Moderna Inc., works quite differently from the classic vaccines composed of live or dead pathogens, individual proteins or carbohydrates that train the immune system to zero in on a particular microbe and wipe it out. The Pfizer and Moderna vaccines instead contain genetic recipes for manufacturing the spike protein that SARS-CoV-2, the virus that causes COVID-19, uses to latch on to cells it infects.

In December 2020, Stanford Medicine began inoculating people with the Pfizer vaccine. This spurred Pulendran's desire to assemble a complete report card on the immune response to it.

The team selected 56 healthy volunteers and drew blood samples from them at multiple time points preceding and following the first and second shots. The researchers found that the first shot increases SARS-CoV-2-specific antibody levels, as expected, but not nearly as much as the second shot does. The second shot also does things the first shot doesn't do, or barely does.

"The second shot has powerful beneficial effects that far exceed those of the first shot," Pulendran said. "It stimulated a manifold increase in antibody levels, a terrific T-cell response that was absent after the first shot alone, and a strikingly enhanced innate immune response."

Unexpectedly, Pulendran said, the vaccine -- particularly the second dose -- caused the massive mobilization of a newly discovered group of first-responder cells that are normally scarce and quiescent.

First identified in a recent vaccine study led by Pulendran, these cells -- a small subset of generally abundant cells called monocytes that express high levels of antiviral genes -- barely budge in response to an actual COVID-19 infection. But the Pfizer vaccine induced them.

This special group of monocytes, which are part of the innate museum, constituted only 0.01% of all circulating blood cells prior to vaccination. But after the second Pfizer-vaccine shot, their numbers expanded 100-fold to account for a full 1% of all blood cells. In addition, their disposition became less inflammatory but more intensely antiviral. They seem uniquely capable of providing broad protection against diverse viral infections, Pulendran said.

"The extraordinary increase in the frequency of these cells, just a day following booster immunization, is surprising," Pulendran said. "It's possible that these cells may be able to mount a holding action against not only SARS-CoV-2 but against other viruses as well."