Body

Patients with end-stage renal disease (ESRD) experience extremely high morbidity and mortality, and there are virtually no therapeutic interventions besides dialysis treatment which are proven, in properly designed randomized controlled trials (RCTs), to improve outcomes. A recent systematic review of hemodialysis RCTs found that, among 10,713 outcome measures, the most common were surrogates such as phosphate, dialysis adequacy, anemia, inflammatory markers, and calcium. Patient-centered outcomes such as mortality, cardiovascular disease, and quality of life were reported very infrequently.

Recent initiatives promoting a focus on patient-centered outcomes and more active patient and caregiver involvement in the planning and conduct of clinical trials may result in more clinically relevant RCTs and broader participation from patients representing the diversity of the ESRD population. For example, the "Standardized Outcomes in Nephrology" (SONG) initiative established fatigue, cardiovascular disease, vascular access and mortality as the core outcomes that are critically important to all stakeholders. Other initiatives by national organizations in the US, Canada and Australia have also emphasized the importance of patient-centered outcomes such as enhanced quality of life.

"The ESRD population is diverse and complex, making it difficult to test interventions within the framework of a traditional RCT design that has resulted in unexpectedly low event rates and high drop-out and cross-over rates, rendering results internally invalid and yielding inconclusive results", explains Professor Csaba P. Kovesdy, author of a review entitled Clinical trials in end-stage renal disease--priorities and challenges that was published today in NDT. "The recent emergence of various RCT designs could aid in making ESRD clinical trials more successful."

Pragmatic clinical trials (PCTs) have been introduced as a means of enhancing the external validity of clinical trials, by implementing broad enrolment criteria, clinically relevant comparators, evaluation of interventions within clinical practice, and the testing of practical, meaningful outcomes. The broad utilization of electronic health records (EHRs), the standardized application of multiple medical and technical interventions within the framework of routine clinical practice, and the clustering of patients within dialysis units using uniform clinical practices make PCTs particularly feasible in the hemodialysis population. In addition to PCTs, there are other emerging RCT designs that could result in more successful testing of interventions in ESRD, such as adaptive platform designs.

"The application of such novel RCT designs could result in benefits including reduced trial cost, the examination of a broader, more representative population, and the testing of a higher number and more clinically relevant interventions, which is really needed", concludes Professor Kovesdy.

Alport syndrome (AS) is a hereditary type IV collagen disease that leads to progressive proteinuria, renal fibrosis, and kidney failure. Depending on the mutated gene and the pattern of inheritance, there are three types of AS. Mutations in COL4A5 cause severe disease in males and a disease of variable severity (but usually much less severe) in females. Mutations in COL4A3 and COL4A4 are the cause of the autosomal forms of AS. Homozygous or compound heterozygous mutations in COL4A3 or COL4A4 are the cause of autosomal recessive AS (ARAS), while a single mutation in either of these genes causes autosomal dominant AS (ADAS).

Having only one mutation in COL4A3 or COL4A4 can cause a phenotype that ranges from nothing (i.e. some parents of children with ARAS) to haematuria alone or to proteinuria and subsequent renal failure on top of haematuria. Over the past several years it has become increasingly apparent that more patients reach end-stage kidney disease (ESKD) due to ADAS than due to classical X-linked AS or ARAS, even though this progression occurs at a much older age. The seminal determinant of disease progression in AS logically seems to be the amount of damage in the glomerular basement membrane (GBM).

A surrogate pathological marker may be tubulointerstitial fibrosis, which has been recognized as the key feature in progressive renal damage leading to ESKD. The glomerular disease and the podocyte stress response lead to the secretion and distribution of profibrotic chemokines and cytokines, which are the main causes of
interstitial fibrosis and tubular atrophy. Progression from haematuria to microalbuminuria and progression from microalbuminuria to overt proteinuria represent very important steps in the course of AS. As for many renal diseases, the primary endpoint for AS clinical trials is or will be the decline in GFR.

"But similarly to other renal diseases, this is probably too late an endpoint to make a significant impact on the course of the disease", explains Professor Roser Torra, Barcelona/Spain, main author of the review published in NDT today. "Theoretically, treatment prior to the appearance of renal fibrosis offers more promising long-term renal outcomes. GBM aspect and degree of fibrosis on renal biopsy as well as proteinuria could be excellent endpoints for clinical trials."

At present, there is no curative treatment for AS, so all males with X-linked disease and all males and females with ARAS, as well as a certain percentage of patients with ADAS, will ultimately show progression to ESKD. The only recommended treatment nowadays for this disease is RAAS (renin-angiotensin-aldosterone system) blockade. Currently RAAS is being tested in children even before the onset of proteinuria.

Currently there is an ongoing trial using bardoxolone and another using anti miRNA21 is expected to start soon. Other drugs under study for AS are paricalcitol, lipid-lowering agents, epidermal growth factor receptor inhibitors, chaperones, stem-cell based therapies, inhibitors of STAT3, etc.

"A specific disease-modifying therapy for AS remains an unmet need, but I am sure this will change, because AS has become a very attractive disease for pharmaceutical companies to target", emphasizes Professor Torra and gives five reasons:

(1) it is an excellent model of chronic kidney disease (CKD) with proteinuria and fibrosis that may be extrapolated to other more common causes of CKD;

(2) any drug approved for this disease will have an orphan drug designation with its consequent benefits, such as shortened approval timeline, financial incentives, and a period of market exclusivity;

(3) the number of patients to be treated will be substantial, AS being the second more frequent inherited kidney disease after ADPKD;

(4) patients are young and have very few comorbidities, which facilitates clinical trials;

(5) there is no approved treatment for AS

[1] Roser Torra. New therapeutic options for Alport syndrome. NDT 2019. June 13 [epub]

Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular disease (CVD). Accordingly, cardiovascular mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. In addition, it has been documented that LDL accumulating in the vascular wall is prone to be post-translationally modified; e.g. by oxidation or carbamylation, which is particularly relevant to patients with CKD.

Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy with a great body of evidence from several large clinical trials. Statin therapy reduces cardiovascular events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is rather weak. Moreover, reduced kidney function may represent a risk factor for statin-related adverse outcomes such as myopathy.

The inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) represents a novel lipid-lowering tool directly modulating hepatic LDL metabolism. PCSK9 protein reduces the expression of LDL-receptor (LDLR) on the surface of liver cells and, thereby, decreases cellular uptake of LDL and thus its clearance from the circulation. Currently, the monoclonal antibodies evolocumab and alirocumab are approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects.

Moreover, in large clinical outcome trials, both antibodies have been proven to lower cardiovascular events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function--i.e. the population at the highest cardiovascular risk--have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome has to be determined.

"In particular, in patients with advanced CKD, the high annual costs of therapy with PCSK9 inhibitors have to be balanced against weak evidence for a benefit", explains Thimoteus Speer, corresponding author of the review PCSK9 in kidney disease [1]. "Specific studies in CKD patients are mandatory to prove the efficacy and safety of PCSK9 inhibitors and to determine their ability to improve outcomes in these patients."

Hypercholesterolemia is a major risk factor for cardiovascular disease. Statins are the most widely used cholesterol-lowering drugs. However, despite treatment with statins, many patients with elevated cholesterol levels will still develop cardiovascular disease.

Currently it is apparent that not only cholesterol but also the immune system plays an important role in the development of atherosclerosis, but how cholesterol and the immune system interact is still unravelled.

A recent study from the Netherlands now provides a novel potential explanation for this residual cardiovascular risk, related to persistent activation of the immune system in patients with hypercholesterolemia who are treated with statins.

Siroon Bekkering, Radboud university medical center, Nijmegen, with colleagues from Amsterdam and Rotterdam investigated the activity of part of the immune system in individuals with and without high cholesterol levels. It appeared that specific immune cells in the blood ('monocytes') were more activated in patients with high cholesterol levels than in individuals with normal cholesterol levels; these cells produced more inflammatory molecules that are important in the development of cardiovascular disease. Subsequently, the patients with high cholesterol were treated with statins to lower their cholesterol levels and the same measurements were repeated three months later. Importantly, despite cholesterol lowering, the hyperactivity of the immune cells did not decrease at all. Niels Riksen, professor of internal medicine from the Radboud university medical center, and coordinator of the project states that "we thus observed that these immune cells appear to 'remember' the high cholesterol, they once were exposed to. The finding that monocytes can remember previous exposures has only recently been discovered, and has been termed 'trained immunity', and this is the first study to demonstrate this in patients." According to Riksen it would be interesting to investigate now how long this memory lasts and also whether the hyperactivity of the monocytes can be reduced by other drug types, such as anti-inflammatory drug.

Researchers from the University of Oxford, along with partners from five institutions around the world, have identified the human antibodies that prevent the malaria parasite from entering blood cells, which may be key to creating a highly effective malaria vaccination. The results of the study were published today in the journal Cell.

"Following an infectious mosquito bite, the malaria parasite goes first to the human liver, and then moves into the blood. Here it replicates ten-fold every 48 hours inside red blood cells - it is this blood-stage of the infection that leads to illness and can be fatal," explains study author Simon Draper, Professor of Vaccinology and Translational Medicine at the Nuffield Department of Medicine, University of Oxford. "The malaria parasite has a protein called RH5, which must bind to a human protein on red blood cells called basigin in order to infect them. In this study, we were able to demonstrate which human antibodies effectively block RH5 from binding with basigin, thus preventing the parasite from spreading through the blood."

The study was done as part of a clinical trial in Oxford of the first vaccine that targets the RH5 malaria protein. Until now, however, it was not clearly understood which specific antibodies could be generated by vaccination of a human volunteer and would effectively prevent RH5 from binding to red blood cells. "When someone is vaccinated, they make many different types of antibodies against the same RH5 target," explains co-author and researcher Dr Daniel Alanine. "This study is key to understanding which specific antibodies are actually effective against malaria, and which are not."

Another key finding of the study is the identification of an exciting new antibody, which works by slowing down the speed in which RH5 binds to red blood cells. "The parasite can still invade, but this antibody slows down the invasion," says study co-author Matthew Higgins, Professor of Molecular Parasitology at the Department of Biochemistry, University of Oxford. "This gives the antibodies that do block RH5 more time to act, helping them become more effective. This is an exciting finding because it shows that antibodies which do not prevent the parasite from getting into red blood cells might still be useful, by making the protective antibodies more potent."

There remains an urgent need to develop an effective malaria vaccine. Despite the increasing use of bed nets, insecticides and drugs in malaria-endemic regions, malaria still kills approximately 430,000 people each year. Scientists have yet been unsuccessful at creating a vaccine that works against the malaria parasite in the blood. The current vaccine based on RH5 has so far shown real promise, and continues to be trialled in the UK and Africa.

"We know the key to stopping malaria is a strong immune response, and so every antibody counts," says Draper. "What we must do next is use these findings to develop an improved RH5 vaccine that induces more of the effective antibodies and less of the non-effective ones - this will ultimately make a better vaccine, and hopefully lead to an effective means of preventing malaria."

One of the most successful interventions in reducing infectious disease worldwide, vaccination still has limited effectiveness in protecting one group of patients - newborn infants. Now a study based at the Ragon Institute of MGH, MIT and Harvard has determined how a pregnant woman's vaccine-induced immunity is transferred to her child, which has implications for the development of more effective maternal vaccines. The report will be published in the June 27 issue of Cell and is receiving early online release.

"Newborns arrive into the world on the first day of life with brand-new immune systems that, like the children themselves, need to learn to cope with both helpful and harmful microbes in their environment," says Galit Alter, PhD, of the Ragon Institute and the Massachusetts General Hospital (MGH) Department of Medicine, co-senior author of the Cell paper. "To help the newborn immune system learn to discriminate between friend and foe, mothers transfer antibodies to their infants via the placenta. The rules by which the placenta performs this absolutely essential function have been unknown but, if decoded, could hold the key to generating more powerful vaccines to protect these most precious patients."

While maternal antibodies against some diseases such as measles can be transferred from mother to infant, providing some protection until the child is old enough for individual vaccination, antibodies to other serious diseases like polio are less efficiently transferred. To investigate the mechanisms by which antibodies are transferred from mother to child, Alter and her team - including co-senior author Laura Riley, MD, formerly with the MGH Department of Obstetrics and Gynecology and now the chair of Obstetrics and Gynecology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center - used a novel tool called system serology to compare the quantity and quality of antibodies against pertussis in blood samples from mothers and from the umbilical cords that carry blood, nutrients and immune factors from the placenta to the infant.

Their investigation revealed that the placenta preferentially sifts out and delivers to the infant antibodies that activate natural killer (NK) cells, key elements of the innate immune system. While several important immune cells are too immature in newborns to provide effective protection, NK cells are among the most abundant and functional immune cells during the first days of life. The team found a similar preference for placental transfer of NK-activating antibodies against influenza and respiratory syncytial virus, a common disease of childhood, and also identified antibody features that appear to regulate placental selection, features that could possibly be built into next-generation vaccines with improved mother-to-child antibody transfer.

Co-senior author Riley says, "We will now have the opportunity to create better maternal vaccines and deliver them at the ideal time during pregnancy to maximally protect newborns when they are most vulnerable." She and Alter will be actively investigating additional aspects of maternal:infant immunity to pave the way for developing improved maternal vaccines.

In a clinical trial of 220 people with "wet" age-related macular degeneration, Johns Hopkins Medicine researchers, collaborators from many sites across the country, and Genentech in South San Francisco have added to evidence that using a new implant technology that continuously delivers medication into the eyes is safe and effective in helping maintain vision and reduces the need for injections in the eyes.

The investigators note that research is needed on larger groups of patients before the implant can be approved for commercial availability and use.

"Current treatment programs require frequent visits to the doctor, commonly every four to six weeks, for injections of medication. Missed appointments, which are common, can lead to an irreversible decline in vision, " says Peter Campochiaro, M.D., the George S. and Dolores D. Eccles Professor in Ophthalmology at the Wilmer Eye Institute at Johns Hopkins. "This study shows that the implant is safe and effective, and may only require a clinic visit and refill every six months."

The research findings were published online April 1 in the journal Ophthalmology.

According to the National Eye Institute, some 8 million adults over age 50 in the United States have age-related macular degeneration (AMD), a progressive condition marked by the loss of central vision and permanent damage to cells in the light-sensitive retina. The advanced, or so-called wet, form of AMD is a major cause of blindness in 1.75 million elderly Americans. In these people, a buildup of debris in the retina triggers the overproduction of a growth factor called vascular endothelial growth factor (VEGF), which stimulates overgrowth of blood vessels that leak, causing swelling and -- if untreated -- scarring of the retina. Like pouring water on electrical wires, the process interferes with the neural network that enables sight, causing vision to blur.

Although no therapies are available to cure the condition, several drugs suppress VEGF and slow the disease progression when injected directly into the eye. The treatments, Campochiaro notes, help preserve central vision but only temporarily, partly because the drugs' effect is not long lasting. Even monthly injections may show relatively rapid swings in the level of retina swelling due to stopping and then restarting of leakage from blood vessels.

In an effort to keep drug levels more steady, investigators have been testing the value of a port delivery system, a reservoir that is implanted in patients' eyes through a small incision and slowly releases medication over time.

When the reservoir is implanted, physicians can replenish the medication without removing the reservoir.

To test the technology's effectiveness and safety, researchers recruited 220 patients with wet-form AMD from 49 sites across the U.S. over a two-year period from Sept. 29, 2015, to Sept. 5, 2017. The mean age of patients was 73.8, with a range of 50 to 92 years, and 64.1% were female. The majority of patients were white (97.7%); 0.9% were American Indian and 0.5% were African American.

Each patient had the implant in one eye and was tracked with measurements of vision, fluid in the retina, safety and side effects each month for nine to 38 months after implantation.

Researchers filled the reservoir with 10 milligrams per milliliter of medication in 58 patients, 40 milligrams per milliliter of medication in 62 patients, and 100 milligrams per milliliter of medication in 59 patients. For comparison, they followed a control group of 41 patients who received the traditional treatment of a monthly injection of 0.5 milligram of medication.

During each visit, ophthalmologists assessed the severity of retinal swelling, the patient's eyesight and development of new macular bleeding to assess the need for reservoir refills.

On average, patients who were implanted with the reservoir filled with 100 milligrams per millimeter of medication did not require a refill until 15 months after implantation, and about 80% of patients with this dosage went beyond six months before needing a refill.

Researchers also say there was a significant average improvement in the eyesight of patients with 100 milligrams per millimeter of medication. At the starting point, the average vision for the patients was being able to see, standing 20 feet from an eye chart, what an average person can see 40 feet away from the eye chart. After nine months of treatment, these patients could see an average of five more letters -- at 20 feet away from the eye chart, they could see what an average person can see 32 feet away.

In comparison, patients with the reservoir of 10 milligrams per millimeter of medication and 40 milligrams per millimeter of medication could see 3.2 and 0.5 fewer eye chart letters respectively compared to baseline, and the average times to first implant refill were 8.7 months and 13 months respectively. Patients treated with traditional monthly injection could see an average of 3.9 more letters than during their initial appointment during the study.

Besides improving eyesight, the technology was safe for patients. Eleven of the first 22 patients experienced some bleeding into the eye after implantation, leading to a change in the implant procedure, after which only seven of 157 experienced bleeding.

Studies are planned with a larger group of patients receiving implants with a reservoir holding the 100 milligram per milliliter dosage. Campochiaro says the cost of the implant is not yet known, but over time, it is likely to be less than that of monthly injections, which currently is about $2,000 per injection.

Campochiaro says other treatments that provide sustained suppression of VEGF, such as gene therapy, are also being tested in clinical trials, and results will be available by the end of the year.

The New England Journal of Medicine recently published the primary endpoint of the NRG Oncology clinical trial NRG-GOG 0258, which showed that carboplatin and paclitaxel chemotherapy preceded by radiotherapy with concurrent cisplatin, or combined modality therapy, did not significantly increase recurrence-free survival for women with stage 3-4A endometrial cancer when compared to chemotherapy with carboplatin and paclitaxel alone. These results were also presented in abstract form at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

"This combined modality approach to locally advanced endometrial carcinoma has been previously studied, however, earlier trials never compared the regimen to chemotherapy given alone. The results of NRG-GOG 0258 indicate that the combined modality regimen did not result in an improvement in recurrence-free survival, and that chemotherapy alone remains the standard of care for stage III uterine cancer. Our data are compatible with findings from prior studies that the completion of chemotherapy is key to preventing distant relapse," stated Daniela Matei, MD, of the Division of Gynecologic Oncology at Northwestern University and the lead author of the NRG-GOG 0258 manuscript.

The phase 3 trial randomly assigned 736 eligible patients to one of two possible treatment study arms. 346 women received the combined modality treatment, which included cisplatin and volume-directed radiation followed by 4 cycles of carboplatin and paclitaxel, over a median of 21 weeks, whereas 361 women received chemotherapy alone in 6 cycles over a median of 17 weeks. While the primary endpoint was to determine if the combined modality arm increased recurrence-free survival, patients were also observed for secondary endpoints that included overall survival, acute and chronic toxicities, and quality of life. At this time, the overall survival data are not mature and this secondary endpoint will be reported at a later date.

At 60 months, 59% (95% CI 53%-65%) and 58% (95% CI 53%-64%) of patients were alive, recurrence-free on combined modality and chemotherapy only arms, respectively (hazard ratio was 0.9; 90% CI 0.74 to 1.10). Combined modality treatment reduced the 5-year incidence of vaginal (2% vs. 7%, HR = 0.36, 95% CI 0.16 to 0.82), pelvic and para-aortic lymph node recurrences compared to chemotherapy alone (11% vs. 20%, HR=0.43, 95% CI 0.28 to 0.66), but distant recurrences were more common with combined modality treatment (27% vs. 21%, HR 1.36, 95% CI 1 to 1.86). Grade 3-5 adverse events were reported in 202 (58%) and 227 (63%) patients in the combined modality and chemotherapy alone arm, respectively.

New research has identified a novel approach to staving off the detrimental effects of aging, according to a study from Washington University School of Medicine in St. Louis.

The study suggests that a protein that is abundant in the blood of young mice plays a vital role in keeping mice healthy. With age, levels of this protein decline in mice and people, while health problems such as insulin resistance, weight gain, cognitive decline and vision loss increase. Supplementing older mice with the protein obtained from younger mice appears to slow this decline in health and extend the life spans of older mice by about 16 percent.

The study is published June 13 in the journal Cell Metabolism.

The circulating protein is an enzyme called eNAMPT, which is known to orchestrate a key step in the process cells use to make energy. With age, the body's cells become less and less efficient at producing this fuel -- called NAD -- which is required to keep the body healthy. Washington University researchers have shown that supplementing eNAMPT in older mice with that of younger mice appears to be one route to boosting NAD fuel production and keeping aging at bay.

"We have found a totally new pathway toward healthy aging," said senior author Shin-ichiro Imai, MD, PhD, a professor of developmental biology. "That we can take eNAMPT from the blood of young mice and give it to older mice and see that the older mice show marked improvements in health -- including increased physical activity and better sleep -- is remarkable."

Imai has long studied aging, using mice as stand-ins for people. Unlike other studies focused on transfusing whole blood from young mice to old mice, Imai's group increased levels of a single blood component, eNAMPT, and showed its far-reaching effects, including improved insulin production, sleep quality, function of photoreceptors in the eye, and cognitive function in performance on memory tests, as well as increased running on a wheel. Imai's group also has shown other ways to boost NAD levels in tissues throughout the body. Most notably, the researchers have studied the effects of giving oral doses of a molecule called NMN, the chemical eNAMPT produces. NMN is being tested in human clinical trials.

"We think the body has so many redundant systems to maintain proper NAD levels because it is so important," Imai said. "Our work and others' suggest it governs how long we live and how healthy we remain as we age. Since we know that NAD inevitably declines with age, whether in worms, fruit flies, mice or people, many researchers are interested in finding anti-aging interventions that might maintain NAD levels as we get older."

Imai's research has shown that the hypothalamus is a major control center for aging throughout the body, and it is directed in large part by eNAMPT, which is released into the blood from fat tissue. The hypothalamus governs vital processes such as body temperature, thirst, sleep, circadian rhythms and hormone levels. The researchers have shown that the hypothalamus manufactures NAD using eNAMPT that makes its way to the brain through the bloodstream after being released from fat tissue. They also showed that this eNAMPT is carried in small particles called extracellular vesicles. As levels of eNAMPT in the blood decline, the hypothalamus loses its ability to function properly, decreasing life span.

In an intriguing finding, Imai and first author Mitsukuni Yoshida, a doctoral student in Imai's lab, showed that levels of eNAMPT in the blood were highly correlated with the number of days the mice lived. More eNAMPT meant a longer life span, and less meant a shorter one.

The researchers also showed increased life span with delivering eNAMPT to normal old mice. All mice that received saline solution as a control had died before day 881, about 2.4 years. Of the mice that received eNAMPT, one is still alive as of this writing, surpassing 1,029 days, or about 2.8 years.

"We could predict, with surprising accuracy, how long mice would live based on their levels of circulating eNAMPT," Imai said. "We don't know yet if this association is present in people, but it does suggest that eNAMPT levels should be studied further to see if it could be used as a potential biomarker of aging."

The study also found sex differences in levels of eNAMPT, with female mice consistently showing higher levels of the enzyme.

"We were surprised by the dramatic differences between the old mice that received the eNAMPT of young mice and old mice that received saline as a control," Imai said. "These are old mice with no special genetic modifications, and when supplemented with eNAMPT, their wheel-running behaviors, sleep patterns and physical appearance -- thicker, shinier fur, for example -- resemble that of young mice."

Imai and his colleagues, including co-author Rajendra Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences, noted that eNAMPT also is carried in extracellular vesicles in humans. As such, future studies should be done to investigate whether low levels are associated with disease in aging people and whether supplementing eNAMPT in extracellular vesicles could serve as an anti-aging intervention in older people, they said.

The promise of new treatments for sickle cell disease, a group of inherited red blood cell disorders, has never been so great, but it will only be realized if there is constant investment in health policies such as programs for screening newborns, especially in sub-Saharan Africa, where most cases occur.

This point is made in a comprehensive review of the main research findings regarding sickle disease published in Nature Reviews Disease Primers and signed by experts affiliated with institutions in the United States, United Kingdom, Ghana and Brazil.

Sickle cell disease is caused by a mutation in the gene that helps make hemoglobin, the oxygen transport protein in red blood cells. Red blood cells containing normal hemoglobin are disc-shaped, but cells with this mutation are sickle-shaped. Sickle cell anemia is the most severe disorder in the group of related diseases. Another medically important hemoglobin-related disorder is thalassemia, a hereditary form of chronic anemia with different degrees of severity.

"Major progress has been achieved in diagnosis and treatment in recent years, and there will be more, but the number of people with sickle cell disease is growing in poor countries. It's important above all to focus on Africa and Asia, as well as Brazil, where funding of the public health system is not just not increasing but appears to be falling, so that all this progress is endangered in Brazil," said Fernando Ferreira Costa, a full professor and researcher at the Hematology and Hemotherapy Center (Blood Center) of the University of Campinas (UNICAMP) in São Paulo State, Brazil.

Costa, the only Brazilian among the authors of the study, was referring to the existence of publicly funded blood centers and support from SUS, the national health service, for PNTN, a nationwide neonatal screening program, which administers, among other diagnostic modalities, the heel prick test, which is designed to detect hemoglobinopathies and six other diseases in newborns. Costa also stressed the importance of the free supply by the SUS of hydroxycarbamide (also known as hydroxyurea), the main drug used to treat sickle cell anemia, and the blood transfusions required by many patients.

"A lot of progress has been made in Brazil, which has successfully established centers of excellence. Diagnosis, treatment and research have all developed significantly in recent decades," he told.

Costa is the principal investigator for the Thematic Project "Red blood cell disorders: pathophysiology and new therapeutic approaches" funded by Paulo Research Foundation - FAPESP.

The Nature Reviews article highlights a decision by the US Food and Drug Administration (FDA) to rate the development of new treatments for sickle cell disease (SCD) as a top priority, facilitating investment by the pharmaceutical industry. As a result, many drugs targeting one or more of the mechanisms that contribute to SCD are currently being tested in humans.

"The prospects for new treatments for SCD have never looked better," the authors conclude.

Hereditary mutation

Sickle cell anemia is the most severe and prevalent form of SCD. Sickle-shaped red blood cells are deformed and become rigid, with a tendency to polymerize - form groups that stick to the inner lining of blood vessels (endothelium) - impairing or even blocking the flow of blood.

In addition to causing unpredictable pain episodes, blood vessel blockage greatly increases the risk of heart attack, stroke, chronic kidney disease and pulmonary embolism, among other complications. "It's a chronic disease requiring medications and control for life," Costa said.

Hydroxycarbamide is the medication currently used to prevent this type of blockage (vaso-occlusion). The drug boosts the production of a protein called fetal hemoglobin, which hinders the polymerization of defective hemoglobin and mitigates the risk of vaso-occlusion.

In recent years, researchers at UNICAMP's Blood Center have discovered other uses for the drug, such as preventing some of the complications that result from hemolysis, the rupture of red blood cells and the release of hemoglobin into the blood stream, which potentially leads to chronic inflammation (read more at: http://agencia.fapesp.br/22007 http://agencia.fapesp.br/research-identifies-drug-capable-of-preventing-complications-from-hemolysis/22007/).

The only treatment capable of curing sickle cell anemia, however, is a bone marrow transplant. In Brazil, the procedure has been covered by the SUS only since 2015. Many bone marrow transplants in patients with sickle cell anemia in Brazil, always involving compatible siblings, have been performed by the Center for Cell-Based Therapy (CTC), hosted by the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP). The CTC is a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP.

The article notes that gene therapy has been considered promising as a treatment for SCD since the mid-1990s, but clinical trials have only recently begun, seeking FDA approval for a procedure using lentiviral vectors, which involves inserting genes engineered to reduce sickling into hematopoietic stem cells. The initial results have been promising.

Other approaches, such as CRISPR/Cas9 gene editing, which can replace a specific DNA region, are also considered promising for the treatment of SCD. This technique is currently used only in mice and cultured human cells.

Many ethical issues must be resolved before such techniques can be used in humans, the authors write: "Long-term follow-up trials will be needed to confirm their safety and sustainability, and the accessibility of gene therapy in high-burden, low-income areas needs to be addressed".

As noted by the article, the burden of SCD is heavier on poor countries. In high- and middle-income countries, the clinical course of SCD has substantially changed since the 1970s in both children and adults. The survival of children with sickle cell anemia is similar to that of healthy children in the United States and the United Kingdom. In Africa, however, mortality rates range from 50% to 90% for children under 5 years of age with the disease. Adults with SCD in high-income countries can now expect to live well into their sixties.

Inequality of SCD distribution and care

The Brazilian Health Ministry estimates that between 30,000 and 50,000 people have some form of SCD in the country. Worldwide, 300,000-400,000 babies are estimated to be born with one of the genetic mutations each year, with 230,000 in sub-Saharan Africa alone.

Thanks partly to the PNTN national newborn screening program, Brazil has reliable epidemiological data and can take action before the symptoms of SCD appear. The heel prick test was officially implemented by the federal government in 2001, although it had already been in use for some time in certain parts of the country.

In fact, coverage is still highly unequal. In 2016, all hospitals in the state of Minas Gerais performed the heel prick test, while only approximately half did so in the state of Amapá, according to Costa.

Screening has enabled the authorities to estimate survival rates and the main causes of death among people with SCD. It is also the basis for the provision of prophylaxis, especially vaccination and the administration of penicillin before age 5 to avoid infections, which are the main cause of death.

Ensuring universal coverage is key because the distribution of SCD is so uneven. Sickle cell anemia is more common in the North and Northeast than in other regions of Brazil because the mutation that causes the disease is more prevalent among people of African ancestry, of whom there are many in those regions.

On the other hand, thalassemia, especially the most severe form, is more common among people of Mediterranean ancestry, such as the many descendants of Italian immigrants in the South and Southeast regions.

The article shows that in areas without screening programs for newborns, the initial diagnosis of SCD occurs at approximately 21 months of age. For many individuals, the first sign of sickle cell anemia is a fatal infection or an acute splenic sequestration crisis, when sickled red blood cells become trapped in the spleen in large numbers, causing a sudden enlargement of the organ that can be life-threatening. Early diagnosis and penicillin prophylaxis reduces mortality in the first five years from 25% to less than 3%, according to the article.

The problem is that accurate estimates of the number of sickle cell anemia patients are difficult to obtain, even with good healthcare systems and in countries with universal screening programs such as Brazil.

"Fortunately, the collection of epidemiological data is steadily improving. Geospatial and other sophisticated methods could produce fairly reliable estimates of the number of people with sickle cell anemia worldwide," Frédéric B. Piel, a researcher at Imperial College London and one of the authors of the article, told.

"These projects depend on large collaborative networks for data collection and processing, and the ability to analyze big data, all of which requires substantial amounts of funding."

Among all major cancers, pancreatic cancer has the highest rate of death - 93 percent of patients die within five years of diagnosis.

Treating the disease is difficult not only because the tumors spread quickly, but because of a muscle-wasting condition called cachexia that affects at least 80 percent of people with pancreatic cancer. However, a team of researchers from the OU College of Medicine has published a groundbreaking research study that reveals how cachexia is triggered, setting the stage for further studies on how to prevent it. The research was recently featured in the journal Gastroenterology, the leading publication in GI tract disease.

"Pancreatic cancer is a very tough disease, and novel therapies like treating cachexia are the only way we're going to make progress because the traditional approach of trying to destroy the tumor isn't enough," said Courtney Houchen, M.D., a senior author on the study.

Although cachexia can occur in several types of cancers, it is especially prevalent in pancreatic cancer. Patients with cachexia experience a dramatic loss of muscle mass, usually accompanied by loss of appetite, weight loss and fatigue. Because cachexia takes such a toll on patients with pancreatic cancer, many cannot withstand surgery and they respond poorly to chemotherapy and radiation.

OU College of Medicine researchers set out to learn more about why cachexia occurs, in order to give patients the best chance at fighting pancreatic cancer. The team focused on a protein called ZIP4, which they already knew is excessive in pancreatic cancer. In the new study, researchers discovered that ZIP4 is at the center of a communication that occurs between pancreatic cancer cells and muscle cells. During that communication, ZIP4 prompts the cancer cells to release two specific types of molecules and even sparks the opening of a pathway for their journey to the muscles. ZIP4 also does the equivalent of hailing a cab for the molecules - called an exosome -- which ferries them to the muscle cells, where they prompt cachexia to begin.

"We think this discovery is significant because of its potential to be translated into a therapy for patients. If we can find a way to inhibit ZIP4, we hope to intervene much earlier with cachexia and help more patients become able to undergo surgery, when they previously would have been too weak. That also means they would respond better to chemotherapy and radiation, which would also increase the survival rate," said Min Li, Ph.D., another lead author on the study, who holds the Virginia Kerley Cade Endowed Chair in Cancer Treatment.

The OU College of Medicine research team, which includes both scientists and medical doctors from the Department of Medicine, leverages that collaboration for a quicker conversion of a laboratory finding into a patient treatment. Their next steps are to further study ZIP4 and to search for a way to hinder its role in triggering cachexia.

"The way we have traditionally looked at cancer is that if you can just kill the cancer cells, then people will get better. But that's not realistic - we have to address complications like cachexia to help people survive," Houchen said. "Now we have the opportunity to look at potential targets for overcoming cachexia, which may then improve the treatment of pancreatic cancer and its devastating consequences."

SAN ANTONIO - Recently unemployed people with undiagnosed obstructive sleep apnea have a higher risk of having lost a job multiple times, according to preliminary results from a new study.

Results show that individuals with undiagnosed obstructive sleep apnea were more likely to have experienced multiple involuntary job losses. Compared to participants who did not have sleep apnea, those with moderate-to-severe sleep apnea were more than twice as likely to have a history of multiple job layoffs or firings.

"These results suggest that undetected obstructive sleep apnea could have long-term, negative effects on vocational functioning," said principal investigator Patricia Haynes, Ph.D., an associate professor in the Department of Health Promotion Sciences at the University of Arizona in Tucson.

Nearly 30 million adults in the U.S. have obstructive sleep apnea, a chronic disease that involves the repeated collapse of the upper airway during sleep. Common warning signs include snoring, choking or gasping during sleep. Untreated sleep apnea can cause excessive daytime sleepiness, fatigue, and impairments in cognitive functioning.

This analysis of data from the ongoing, prospective Assessing Daily Activity Patterns through occupational Transitions (ADAPT) study involved 261 participants with an average age of 41 years; 58% were women. Seventy-three percent received hourly wages rather than a salary, and about 45% of participants had a history of multiple job losses. Breathing during sleep was evaluated with a home sleep apnea test, which revealed that 42% percent had at least mild sleep apnea.

After a propensity score analysis, 39 matched pairs (78 participants) remained for the logistic regression model. Results were controlled for potential confounders such as age, sex, race, and job payment type.

The authors noted that one limitation of the study was the inability to include body mass index in the analysis.

Depression is a common and serious problem for older adults. Some 15 to 20 percent of people aged 65 and older who live independently deal with symptoms of major depressive disorder. For residents of nursing homes, the rates of depression may be as high as 50 percent.

For some people, medication is an effective part of treatment for depression. However, when considering whether to prescribe antidepressant medication for older adults, healthcare providers must weigh the safety risks these medications pose against the often modest benefits they can provide compared to other options.

For example, tools like the American Geriatrics Society (AGS) Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults recommended that healthcare providers avoid prescribing certain antidepressant medications to older adults who have a history of falls or fractures. These include selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). That's because these medications may actually increase the risk of falls and fractures.

Understanding these and other risks associated with "potentially inappropriate medications" is key to building better care for us all as we age. That's why a team of researchers recently reviewed and analyzed studies to learn more specifically about the harmful effects of antidepressants for treating major depressive disorder in adults 65 years of age or older. Their study was published in the Journal of the American Geriatrics Society.

The systematic review was performed at the University of Connecticut Evidence-based Practice Center (EPC). The researchers reviewed studies that examined how many older adults experienced a harmful event during the study.

The researchers looked at patients 65 years of age or older who are prescribed serotonin and norepinephrine reuptake inhibitors (SNRIs) to treat the acute phase of major depressive disorder (the earliest stage of the condition, when the goal is to address the symptoms associated with an episode of depression). They found that taking SNRIs led to a greater number of harmful events compared to people who took a placebo (a harmless sugar pill that has no effect on health and is prescribed to some study participants to help with comparing their results to results from people who were treated with actual medication). Older adults who took SSRIs experienced about the same number of harmful events as did people who took a placebo.

The researchers said that taking either SSRIs or SNRIs led to a greater number of people leaving the study due to harmful events of the drugs compared to placebos. They also noted that the drug duloxetine, an SSRI, increased the risk of falls.

"Some of the antidepressants have not been studied in older patients with major depression, and studies don't often describe specific side effects. Future research in this field is critical to better inform how the safety profiles of different antidepressants compare in older adults," said study co-author Diana M. Sobieraj, Pharm.D., FCCP, BCPS, Assistant Professor, University of Connecticut School of Pharmacy.

Scientists have created a laser-based platform that can quickly and noninvasively screen large quantities of blood in patients with melanoma to detect circulating tumor cells (CTCs) - a precursor to deadly metastases. The new system accurately sniffed out hard-to-detect CTCs in 27 of 28 patients with the cancer in as little as 10 seconds and was 1,000 times more sensitive than existing assays (detecting one CTC per liter of blood). Although more work is needed, the test could help identify patients at risk of metastasis and guide the use of laser therapies to kill melanoma cells. Researchers have attempted to assess CTCs to determine the risk of metastasis in patients, but existing assays can only examine small amounts of blood, which sometimes do not capture any CTCs. Seeking a solution, Ekaterina Galanzha and colleagues created a system called the Cytophone that uses laser pulses and focused ultrasound to noninvasively peer under the skin of patients with melanoma, revealing pigmented CTCs that pass through veins in the arm. Galanzha et al. applied their technology to 28 light-skinned patients with melanoma and 19 healthy volunteers and found that it identified CTCs in 27 (96%) of the patients between 10 seconds and 60 minutes without generating false positives in the controls. Importantly, the system's laser could destroy the detected CTCs, resulting in a large drop in CTC numbers. It also uncovered circulating blood clots - the second leading cause of death in cancer patients. The Cytophone was able to account for other variables such as patient skin pigmentation and movement, but future studies should investigate and expand on the range of skin tones for which the technology could be used.

East Hanover, NJ. June 12, 2019. A New Jersey team

of researchers has reported the successful, long-term relief of chronic refractory shoulder pain in a wheelchair user with spinal cord injury (SCI) following a single injection of autologous, micro-fragmented adipose tissue into the affected shoulder joint. The article, "Autologous micro-fragmented adipose tissue as a treatment for chronic shoulder pain in a wheelchair using individual with spinal cord injury: a case report" (doi: 10.1038/s41394-019-0186-8) was epublished ahead of print on May 13, 2019 by Spinal Cord Series and Cases. This is the first reported use of this intervention for shoulder pain in an individual with spinal cord injury who has failed to improve with conservative care, such as physical therapy and pharmacological agents.

The authors are Chris Cherian, MD, of Rutgers New Jersey Medical School, Gerard Malanga, MD, of the New Jersey Regenerative Institute and Kessler Institute for Rehabilitation, Trevor Dyson-Hudson, MD, and Nathan Hogaboom, PhD, of Kessler Foundation, and Michael A. Pollack, MD, of Montclair Radiology.

Courtesy of the publisher, this Editors' Choice article is Open Access through June 30: https://www.nature.com/articles/s41394-019-0186-8

Chronic shoulder pain is a common cause of functional decline among wheelchair users with SCI who rely on their upper limbs for mobility and everyday activities of daily living. When pain persists despite conservative management, current options for individuals with SCI have significant drawbacks. Corticosteroid injections offer only temporary relief and surgical interventions often require prolonged periods of recovery and have poor outcomes, which can add to the burden of disability.

This individual, a 54-year-old man with a ten-year history of T10 complete SCI, had a history of chronic shoulder pain that was unresponsive to conservative treatment, including repeated corticosteroid injections that provided only short-term pain relief of 3 months. Ultrasound and MRI examinations of the shoulder revealed a rotator cuff tear and degenerative changes of the acromioclavicular joint. The participant's own fat was harvested and processed using the Lipogems® system to yield a sample of autologous, micro-fragmented adipose tissue that was injected into the shoulder joint under ultrasound guidance. He experienced relief of pain and improvement in performing activities of daily living. At 12-month follow-up, he remained pain free and maintained his functional improvements, with 50% healing of the rotator cuff tear on MRI.

Treatment of intractable shoulder pain with autologous micro-fragmented adipose tissue warrants further investigation as a potential alternative to surgery in wheelchair users with spinal cord injury.

This report is part of a pilot study at Kessler Foundation funded by the Derfner Foundation. The team also recently received a grant from the New Jersey Commission on Spinal Cord Research to conduct a randomized, controlled trial to investigate the safety and efficacy of micro-fragmented adipose tissue for refractory shoulder pain in wheelchair users with SCI.