Month: October 2021

Categories : Diseases, Syndromes and ConditionsTags :

Tamoxifen Found to be Ineffective in Fungal Meningitis Trial

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Photomicrograph of a sample extracted from a lesion that revealed the presence of Cryptococcus neoformans. Credit: CDC

In a disappointing outcome, a clinical trial has shown that tamoxifen, a promising candidate to improve survival for a deadly form of fungal meningitis, is ineffective. The trial was conducted by University of Oxford researchers and published in eLife.

The study finds that adding tamoxifen, a breast cancer drug, to standard antifungal treatment was no faster in clearing fungal infection from the spinal fluid of people with meningitis. More patients who received tamoxifen had evidence of heart conduction disturbances, rates of severe side effects were similar.

Cryptococcal meningitis is a leading cause of death in people with HIV, but also affects those without HIV, regardless of whether they are immunocompromised. Most infections are caused by a fungus called Cryptococcus neoformans (C. neoformans) and occur in low-income tropical settings. The gold-standard treatment is a combination of three drugs: flucytosine and amphotericin B initially, followed by fluconazole. Yet, even on this gold-standard therapy, a third of patients die within 10 weeks of being diagnosed. Moreover, the drug flucytosine is severely restricted by availability and cost, meaning it is rarely used where the disease burden is highest.

Co-first author Nguyen Thi Thuy Ngan, Clinician at the Oxford University Clinical Research Unit (OUCRU): ‘Tamoxifen has shown antifungal activity against various yeasts in the lab; we subsequently showed that it acts synergistically with amphotericin against two-thirds of clinical Cryptococcus isolates from our archive. As a well-understood, off-patent, cheap and widely available medicine, it was a promising candidate for treating cryptococcal meningitis.’

Co-first author Nhat Thanh Hoang Le, Biostatistician at OUCRU, added: ‘We designed a randomised trial to determine whether using these drugs in combination could improve the speed of clearance of Cryptococcus from patients with meningitis with and without HIV.’

The trial involved 50 patients, 40 with HIV. Of the patients, 24 were assigned to receive a standard anti-fungal treatment of amphotericin B and fluconazole plus tamoxifen, and 26 received the standard anti-fungal treatment only. Researchers measured the Early Fungicidal Activity (EFA) for both groups – how quickly C. neoformans amounts declined in a patient’s spinal fluid in the two weeks following treatment.

Based on their prior work, the team were hoping for better EFA for patients receiving tamoxifen, but there was no detectable difference in EFA.

The only observed difference was increased heart toxicity in the tamoxifen group. Lab studies had shown that a tamoxifen dose five to 10 times higher than that used routinely in breast cancer would be needed to have an antifungal effect. However, high doses of tamoxifen cause QT prolongation, which can cause cardiac arrest. While there was one sudden death in the tamoxifen group in this study, this occurred after the period of tamoxifen administration and it was not associated with an abnormal heart rhythm.

Senior author Professor Jeremy Day, Professor of Infectious Diseases, Oxford University, said: “Despite its apparent anti-cryptococcal effect and synergy with other drugs, tamoxifen does not increase the rate of clearance of yeast from spinal fluid in people with meningitis and is unlikely to result in clinical benefit.

“Our results show the importance of small-scale trials such as this for rapidly evaluating repurposable drugs and preventing the time and cost of a larger clinical study that is likely to fail. However, sadly this does mean that we urgently still need new, specific anti-cryptococcal drugs to be developed, and we also need to ensure that existing, available treatments are made accessible and affordable.”

Source: Oxford University

Categories : Neurodegenerative DiseasesTags :

Deaths from Parkinson’s on the Rise

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Photo by Kindel Media on Pexels

Over the last two decades, the death rate from Parkinson’s disease has risen about 63% in the US, and the death rate was twice as high in men as in women, with a higher death rate in White people than other racial/ethnic groups.

“We know that people are living longer and the general population is getting older, but that doesn’t fully explain the increase we saw in the death rate in people with Parkinson’s,” study author Wei Bao, MD, PhD, who conducted the research at the University of Iowa in Iowa City. “Understanding why more people are dying from this disease is critical if we are going to reverse the trend.”

The study, published in Neurology, looked at a national death registry that included 479 059 people who died of Parkinson’s from 1999–2019.

After adjusting for age, researchers found that the number of people who died from the disease increased from 5.4 per 100,000 people in 1999 to 8.8 per 100 000 people in 2019. The average annual increase was 2.4%.

Mortality increased significantly across all age groups, both sexes, various racial and ethnic groups and different urban-rural classifications. However, death rates were twice as high in men as in women. According to Dr Bao, a possible explanation for this sex difference is that oestrogen, which leads to higher dopamine levels in parts of the brain that control motor responses, may protect women from developing Parkinson’s.

White people were more likely to die from Parkinson’s than other racial and ethnic groups. In 2019, the death rate for White people was 9.7 per 100 000, followed by Hispanic people, at 6.5 per 100 000, and non-Hispanic Black people, at 4.7 per 100 000. In previous studies, compared to White people, Black and Hispanic people are less likely to see an outpatient neurologist, due to socioeconomic barriers, suggesting that White people may have a higher chance of receiving a Parkinson’s diagnosis.

“It’s important to continue to evaluate long-term trends in Parkinson’s death rates,” Dr Bao said. “This can inform future research that may help pinpoint why more people are dying of the disease. Also, updating vital statistics about Parkinson’s death rates may be used for priority setting and financing of health care and policy.”

A limitation of the study is that only one underlying cause of death was recorded on each death certificate, so only people who were recorded as having died of Parkinson’s were included in the study. This may not accurately reflect the prevalence of the disease as a cause of death.

Source: American Academy of Neurology

Categories : Cardiovascular Disease COVIDTags :

Large Study Finds Statins Ineffective, Possibly Worsen COVID

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Source: Unsplash

Though small studies have suggested that statins, which lower low-density lipoprotein (LDL), may also reduce COVID severity or mortality, findings from a large study suggest that it has no effect and may even worsen the disease.

In the effort to fight COVID, researchers have attempted to find existing medications that might have an effect on the outcome of the disease, and statins were one readily available candidate that appeared to have some effect. However, a new study published in the journal PLOS ONE suggests they may not be suitable.

“Despite the apparent beneficial effect of statins on the outcomes of various infectious diseases, our study revealed that their specific use to treat COVID is probably not merited,” said senior study author Petros Karakousis, MD, professor of medicine at the Johns Hopkins University School of Medicine. “Compared with earlier research, we looked at a larger and more widely varied inpatient population, and had better criteria for defining disease severity, thereby enabling our results to be more relevant for predicting the impact of statins on COVID outcomes in hospitalised patients.”

In the study, researchers reviewed the records of 4447 hospitalised patients, ages 18 years or older, who had been diagnosed with SARS-CoV-2 infection between March 1 and June 30, 2020. Of these, 594 (13%) were receiving statins at admission, with most statin users being men (57%) and older (ages 52–78 compared with ages 29–62) than the non-statin users. The highest percentage of statin users were black (47%), had hypertension (74%) or diabetes (53%), and were more likely to take medications for lowering blood pressure – along with statins to reduce their LDL cholesterol.

After accounting for confounding factors, statin use was found to have no significant effect on COVID mortality. However, they did find that patients hospitalised with COVID and taking statins had an 18% increased risk for having a more severe form of the disease.

“One plausible explanation for this finding is that statins increase cellular production of angiotensin-converting enzyme 2 [ACE2], the receptor on a cell’s surface through which SARS-CoV-2 gains entry,” said Prof Karakousis. “Therefore, statins may lower a cell’s resistance to infection and in turn, increase the odds that the patient will have a more severe case of COVID.”

Prof Karakousis said future studies should attempt to better define the relationship between statin use and COVID, noting that all previous ones were retrospective and had factors that could not be eliminated, such as many statin users being overweight.

The only way to definitively determine if statins have any benefit for patients with COVID is to conduct a randomised, placebo-controlled clinical trial.

Source: Johns Hopkins Medicine

Categories : CancerTags :

Nut Consumption Linked to Long-term Breast Cancer Survival

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Photo by Pavel Kalenik on Unsplash

In a study of breast cancer survivors, the consumption of nuts was linked with reduced risks of breast cancer recurrence or death.

Researchers examined data for 3449 breast cancer survivors from the Shanghai Breast Cancer Survival Study who completed a dietary assessment five years after diagnosis. Of the participants, there were 374 deaths during a median follow-up of 8.27 years after the dietary assessment. Among 3274 survivors who did not have a previous recurrence at the time of their dietary assessment, 209 developed breast cancer-specific events, including recurrence, metastasis, or breast cancer mortality.

There was a dose-response pattern in the relationship between nut consumption and risk of breast cancer recurrence or death, with those consuming the highest amounts having the lowest risks. Also, the association was stronger for survivors who had earlier stages of breast cancer than for those who had later stages.

The findings were published in the International Journal of Cancer.

Source: Wiley

Categories : CancerTags :

In Metastatic Colon Cancer, Youth is no Advantage

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Colon cancer cells. Source: National Cancer Institute on Unsplash

Even though young patients with metastatic colorectal cancer tend to be more fit and receive more intensive treatment than older patients, both groups survive for roughly the same amount of time, according to a new study by Dana-Farber Cancer Institute investigators.

The findings, published in the Journal of the National Cancer Institute, come as colorectal cancer rates in young people are rising. The researchers said the results are somewhat surprising, as younger patients, who usually have fewer complicating health factors, might be expected to survive longer than older patients.

“As a group, younger patients are more physically active and have higher performance status and are better able to perform the activities of daily living than older patients. They also tend to be treated with higher doses of therapy and have less severe side effects,” said study senior author Kimmie Ng, MD, MPH, director of the Young-Onset Colorectal Cancer Center at Dana-Farber. “This is the first study to compare survival in younger versus older patients participating in a clinical trial of treatment for metastatic colorectal cancer.”

The study drew on clinical trial data which tested a combination of chemotherapy and biologic therapy in patients with metastatic colorectal cancer, comparing patients under 50 with those over 50.

“We found no significant difference in overall survival between the two groups,” said Dana-Farber’s Marla Lipsyc-Sharf, MD, the first author of the study. The median survival for patients with young-onset colorectal cancer was 27.07 months vs. 26.12 months for the older-onset group. Progression-free survival – how long patients lived before the cancer worsened – was also similar for the two groups: 10.87 months for the younger patients vs. 10.55 for the older ones.

Confounding expectations even further, patients under age 35 had the shortest median overall survival of any age group: 21.95 months vs 26.12 months in older-onset patients. Because the study included relatively few patients younger than 35, the difference is not considered statistically significant, researchers noted, but it aligns with previous research suggesting that very young patients have worse outcomes.

Cases are markedly on the rise: between 2000 and 2013, incidence of the disease in people under age 50 increased approximately 22%, even as overall incidence of colorectal cancer has declined. Yet despite a wellspring of new research, no definitive cause for the increase has been found.

“If current trends hold, colorectal cancer is projected to be the second leading cancer and leading cause of cancer death in patients ages 20–49 by the year 2040,” Lipsyc-Sharf stated. “It is important to understand survival in this population in order to develop tailored treatments.”

That younger patients fare no better than older ones despite more favourable factors could suggest that colorectal cancer is more aggressive at an earlier age. But there is no conclusive evidence that that is the case.

“Research has yet to identify consistent molecular differences in the colorectal cancer cells of younger patients and older patients,” Dr Lipsyc-Sharf noted. Current studies also are exploring whether differences in the intestinal microbiome of younger and older patients might explain the increased incidence of early-onset colorectal cancer.

Source: Dana Farber Cancer Institute

Categories : COVIDTags :

COVID Test Sensitivity Changes with Circadian Rhythm

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Source: Fusion Medical Animation on Unsplash

A new study suggests that the sensitivity of tests for SARS-CoV-2 vary throughout the day according to the body’s circadian rhythm, which could have implications for how the disease is managed.

Carl Johnson, Cornelius Vanderbilt Professor of Biological Sciences, wondered how the virus might act differently depending on the time of day and the body’s circadian rhythms, and collaborated with colleagues to determine if the percentage of people testing positive for COVID varies based on time of day. They found that people were up to two times as likely to have an accurate positive test result if they tested in the middle of the day compared to at night. Their findings were published in the Journal of Biological Rhythms.

The data support the hypothesis that COVID acts differently in the body based on our natural circadian rhythm, which has also been implied by studies of other viral and bacterial infections. COVID virus shedding, when infected cells release infectious virus particles into the blood and mucus, appears to be more active around midday due to modulation of the immune system by our biological clock.

“Taking a COVID test at the optimal time of day improves test sensitivity and will help us to be accurate in diagnosing people who may be infected but asymptomatic,” Prof Johnson said. Their results indicate that viral load is lower after 8 pm. If people choose to get tested at that time, there could be a higher chance of a false-negative result. False negatives can be harmful to the community and for the patient, who might not seek additional care due to their negative test result.

A difference in COVID viral shedding throughout the day would help inform treatment for the disease. As Johnson and his co-authors report, the peak shedding in the afternoon, when patients are more likely to interact with others or seek medical care, could play a role in increasing the spread of the virus in hospitals and the wider community.

Further research is needed to confirm the diurnal nature of SARS-CoV-2. Experimentally testing COVID patients to see if individuals shed the virus differently throughout the day would have important public health implications, Prof Johnson said.

Source: Vanderbilt University

Categories : VaccinesTags :

Vaccine to Prevent Hookworm Infection Could be a ‘Gamechanger’

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Photo by Bill Oxford on Unsplash

There’s been a significant breakthrough in the development of a vaccine to prevent hookworm infection – a parasite which causes serious disease in tens of millions of people globally.

Mouse trials of the vaccine candidate in mice indicate that it is more than twice as effective than current alternatives. The results were published in Vaccines.

Professor Istvan Toth from UQ’s School of Chemistry and Molecular Biology said the easy oral administration would be a gamechanger for developing countries.

“Our vaccine candidate can be orally self-administered, bypassing the need for trained medical staff, and means there’s no requirement for special storage, enabling it to reach large, isolated populations,” Professor Toth said, noting that costs can be significantly reduced.

A serious healthcare challenge
About 500 million people worldwide are infected with hookworm, which lives within the human intestine, feeding on the host’s blood, digested through a special set of enzymes.

It’s often found in regions with poor water quality, sanitation, and hygiene – greatly impacting on the physical and cognitive development of children and increasing the risk of mortality and miscarriage.

UQ’s trials in mice showed significant improvements on an alternative vaccine candidate which only achieved a 30 to 50 per cent reduction in the number of worms.

“The UQ-developed vaccine resulted in an impressive 94% worm reduction in mice,” Professor Toth said, noting that besides being easier to deliver, it “triggers a staggeringly good immune response.”

Hookworms lose their appetite
Paper co-author Dr Mariusz Skwarczynski said the hookworm’s digestion enzyme (APR 1) was the target.

“When the function of these enzymes is blocked, the parasite starves,” Dr Skwarczynski said.

“Our vaccine produces antibodies against the hookworm enzymes responsible for the digestion of blood – they simply stop being able to eat properly.”

The researchers plan to continue working on and refining the vaccine candidate in preclinical development settings, to ensure its safety and efficacy, before beginning human clinical trials.

Source: University of Queensland

Categories : AgeingTags :

A New Mechanism Explains Hair Loss in Men and Women

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Bald man
Photo by Brett Sayles on Pexels

Studies of balding male mice have uncovered a possible cause of hair loss in men and women as well. The findings, published in Nature Aging, provide new insight into how hair and tissues age.

The study shows as hair stem cells age, they lose the adhesion that keeps them lodged inside the hair follicle. As their adhesiveness wanes, the stem cells escape from their location, called the bulge, into the dermis. Once outside their delicate microenvironment, they generally can’t survive.

“The result is fewer and fewer stem cells in the hair follicle to produce hair,” said lead author Rui Yi, the Paul E. Steiner Research Professor of Pathology at Northwestern University Feinberg School of Medicine. “This results in thinning hair and ultimately baldness during ageing.”

This finding could be applicable to older men and women with thinning hair as mice and humans share hair and stem cell similarities, Prof Yi said.

By labelling individual stem cells with a fluorescent marker, the researchers were able, for the first time, to track hair follicle ageing in real time in live animals. Scientists also discovered two key genes responsible for enhancing adhesiveness of the stem cells. They are now trying to reinstate these genes to see if that will reverse hair loss.

During follicles’ normal cycles of life and death, a large number of stem cells remain permanently lodged in the stem cell compartment of hair follicles to keep producing hair follicle cells.

“We believe this stem cell escape mechanism has never been reported before, because nobody could track the aging process in live animals,” Yi said.

Though scientists knew hair follicles become miniaturised during aging, how it happened was unclear. Many thought it was due to cell death or the inability of cells to divide as they age.

“We discovered, at least in part, it is due to hair follicle stem cells migrating away from their niche,” Prof Yi said. “Cell death also occurs during our observation. So, our discovery doesn’t dispute existing theories but provides a new mechanism.”

Source: Northwestern University

Categories : COVIDTags :

Lateral Flow Tests now Approved for Travellers to England

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Fully vaccinated passengers arriving in England and most under 18s arriving from non red-list countries (which now includes South Africa) can use a lateral flow test (LFT) on or before day 2 of their arrival in England, the UK government has announced.

LFTs must be taken as soon as possible on the day of arrival in England or at the latest before the end of a passenger’s second day and can now be purchased from the list of private providers on GOV.UK from as little as £22 – significantly cheaper than PCR tests.

LFTs for international travel must be purchased from a private provider as NHS Test and Trace lateral flow tests cannot be used for international travel. Passengers who have already bought a PCR to use for travel do not need to buy another test as PCRs can still be used.

Passengers have to take a photo of their lateral flow test and booking reference supplied by the private provider, then send it back to them to verify the result. Failure to do so could result in a fine of £1000 (R20 000). It is also possible for passengers to book a test at some airport testing centres. People using PCR tests for travel will have their test reported by the company they purchase the test from.

Anyone who tests positive will need to isolate and take a confirmatory PCR test, at no additional cost to the traveller, which can be genomically sequenced to help identify new variants. PCR tests can be accessed free of charge by ordering in the usual way through NHS Test and Trace – via nhs.uk/coronavirus or by calling 119.  Test providers will be expected to advise people to self-isolate and direct people towards the NHS Test and Trace booking page.

In addition, all travellers must complete a passenger locator form beforehand, including providing a test booking reference number supplied by a testing provider.

However, these new rules apply only to those arriving in England: anyone travelling on to Ireland, Northern Ireland, Scotland, Wales, the Channel Islands or the Isle of Man within 10 days after arrival in England have to follow the rules for testing and quarantine in those places.

Those passengers who are not fully vaccinated with an authorised vaccine returning from a non-red list destination must still take a pre-departure test (antigen/PCR), a PCR test on day 2 and day 8 test and complete 10 days’ self-isolation (with the option of doing Test to Release on day 5).

Source: UK Government

Categories : Diseases, Syndromes and ConditionsTags :

A Genetic Risk Score to Identify Alchol-related Cirrhosis

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Photo by Pavel Danilyuk on Pexels

In a world first, researchers have developed a genetic risk score (GRS) test able to identify patients at high-risk of developing alcohol-related cirrhosis.

Cirrhosis results in approximately 300 000 deaths each year world-wide. In their study, the researchers found that a high GRS from the test of excessive alcohol consumers resulted in a three-fold increase in cirrhosis risk. Having diabetes together with a high GRS increased the cirrhosis risk among drinkers more than 10-fold.

Joint senior author of the study, Clinical Associate Professor Devanshi Seth, said that only a minority of high-risk drinkers – approximately 10 to 15%– actually end up developing alcohol-induced cirrhosis. To date, however, there had been no way to identify those at-risk individuals.

“Our GRS test lets us identify at-risk individuals at an early stage enabling the application of focused interventions. Evidence suggests that even just informing excessive drinkers that they have an increased cirrhosis risk may motivate them to reduce their alcohol intake, helping prevent serious disease,” said Clinical Associate Professor Seth.

The lead author of the study, Dr John Whitfield from QIMR Berghofer Medical Research Institute, said that the test had been developed by examining samples from patients with and without alcohol-related cirrhosis, but who all had a history of heavy alcohol consumption.

“This was classified as men consuming more than 80 grams (8 standard drinks) of alcohol daily and women more than 50 grams daily, both for a time period of ten or more years.”

“Risk scores were computed by the analysis of up to eight gene variations and three clinical risk factors (including type 2 diabetes) associated with alcohol-related cirrhosis,” Dr Whitfield said.

“We’ve shown that a GRS based on only three genetic risk variants plus diabetes status can be extremely meaningful in determining overall cirrhosis risk. Our test will allow for early and personalised management of high-risk patients,” said Clinical Associate Professor Seth.

Source: Centenary Institute