Cedars-Sinai investigators have discovered why some injured kidneys heal while others develop scarring that can lead to kidney failure. Their findings, detailed in a paper published in the peer-reviewed journal Science, could lead to the development of noninvasive tests to detect kidney scarring and, eventually, new therapies to reverse the condition.
“The key to this discovery was our ability to directly compare injured kidney cells that successfully regenerated with those that did not,” said Sanjeev Kumar, MD, PhD, a nephrologist-scientist in the Board of Governors Regenerative Medicine Institute and the Department of Medicine at Cedars-Sinai and senior author of the study.
“Injured cells activate a protein called SOX9 to regenerate themselves. When they have healed, the cells silence this protein. Cells that aren’t able to regenerate leave SOX9 active, and this leads to a type of scarring called fibrosis. But when we deactivate SOX9 in a timely fashion, the scarring literally goes away.”
The kidneys can be injured by diabetes and high blood pressure, serious infections such as COVID-19, and overuse of antibiotics and non-steroidal anti-inflammatory pain medications, said Kumar, who is also part of the Department of Biomedical Sciences at Cedars-Sinai.
The SOX9 protein plays a major role in organ development but is not active in healthy adult kidneys.
In previous work at another institution, Kumar and team found that when kidneys are injured, the surviving cells reactivate SOX9 as part of the healing process.
In this study, Kumar and fellow investigators studied kidney damage in laboratory mice.
They labeled individual cells at the point of injury, then followed how the cells’ progeny evolved over time.
“At Day 10, some cells’ descendants were fully healed while others were not,” Kumar said.
“The cell lineage that healed had switched off SOX9 expression, while the unhealed lineage, in a continuing attempt to fully regenerate, maintained SOX9 activity. It’s like a sensor that switches on when cells want to regenerate, and off when they are restored, and we are the first to identify this.”
Further, investigators discovered that cells that were unable to regenerate began recruiting proteins called Wnts, another key player in organ development. Over time, this accumulation of Wnts triggered scarring. And they found that deactivating SOX9 a week after injury promoted kidney recovery.
Investigators observed the same process in patient databases from collaborating institutions in Switzerland and Belgium.
“We could see that by Day 7, human patients with transplanted kidneys that were slow to begin working also activated SOX9,” Kumar said.
“And in our collaborators’ database, we were able to distinguish that patients who had sustained SOX9 activation had lower kidney function and more scarring than those who did not. Human kidneys with cells that maintained SOX9 were also enriched with Wnts and showed increased fibrosis.”
These discoveries provide targets for drug development, as well as for noninvasive biomarker discovery permitting diagnosis of kidney fibrosis through the urine, Kumar said.
Currently, the only available test for kidney fibrosis is a biopsy, which carries many risks.
“Elucidating the mechanisms of scarless healing versus fibrosis has eluded investigators for decades and has implications beyond the kidney, including for certain cancers,” said Paul Noble, MD, chair of the Department of Medicine and director of the Women’s Guild Lung Institute at Cedars-Sinai and a co-author of the study.
There’s a comeback of sexually transmitted infections (STIs) in South Africa and around the world. The Gauteng Department of Health recently reported an increase of newly acquired STIs, in particular gonorrhoea and chlamydia. This spike in cases call for management guidelines and awareness programmes to be reviewed, reports Ufrieda Ho.
A rise in reported cases of sexually transmitted infections in Gauteng in 2023 is a wake-up call that control and management strategies are not keeping pace with the growing disease burden in South Africa’s most populous province.
“The Gauteng information confirms the rise in STIs that we are seeing in South Africa and across the world, including in the United States and Canada,” said Dr Nomathemba Chandiwana, a director and principal scientist at Ezintsha Research Centre at Wits University. She is also a co-author of the 2022 guidelines on the management of sexually transmitted infections produced by the Southern Africa HIV Clinicians Society.
Chandiwana said any increase in STIs should raise alarms because it means “we simply don’t have control over the things we thought we had under control”.
The World Health Organization (WHO) in 2022 noted that countries reported low coverage for preventive, testing and treatment services related to STIs, because of Covid-19 lockdown restrictions. The WHO confirmed that this had led to a “resurgence of STIs and the emergence of non-classical STIs [such as Shigella sonnei, hepatitis A, Neisseria meningitidis, Zika and Ebola] globally”. It also reported that currently more than 1 million new STIs are acquired around the world each day “posing a significant global health challenge”.
Since the middle of 2023, the WHO has pushed for low-cost point of care tests to be more readily available in low and middle income countries, saying this would improve screening and diagnosis, data collection and make STI services more effective. South Africa has not made such tests accessible, still relying on a syndromic approach, which is clinical diagnosis made by assessing a patient’s symptoms and other visible signs.
New public health threats
Chandiwana said a review of STI treatment and management guidelines is necessary because the rising numbers pose significant new public health threats. Of particular concern, she said, is that having STIs pushes up a person’s risk to contract HIV, which is “a chronic and serious disease” as well as developing other long term or irreversible medical risks, including reproductive complications.
Earlier in February, the Gauteng Department of Health reported that the incidence of Male Urethritis Syndrome (MUS) in men aged 15 to 49 in the province had increased from 12% in 2020 to 15% in 2023. The department did not provide actual figures for the comparison, which is also somewhat complicated by the fact that in 2020 there were strict COVID-19 lockdowns and restrictions in place.
The department’s information from 2023 showed that 167 109 males aged 15 to 49 visited health facilities across the province from April to December. Of these patients, 67 400 (40% of the 167 109) were treated for MUS.
The diagnosis of MUS is an indicator of newly acquired STIs, in particular gonorrhoea and chlamydia, which according to the Gauteng Department of Health are the most prevalent STIs in South Africa.
Chandiwana said diagnosis of MUS in men and pelvic inflammatory disease (PID) among women, are made by assessing symptoms of pain, discomfort and genital discharge and sores. Conventionally, it’s treated with broad range antibiotics.
She explained South Africa’s guidelines to treatment and management is to make clinical decisions based on a patient’s symptoms and signs. “While this standard approach has worked, we are calling for a move to targeted diagnosis and targeted treatment. It’s because you want to know which STI someone has and to treat them for that particular disease,” said Chandiwana.
Different STIs can also result in different complications. Syphilis for instance, she said, can result in women giving birth to children who are deaf or blind or raises the risks for infertility. (Spotlight previously reported on congenital syphilis in South Africa in more depth here.)
“We also have STIs that are present but not visible, so asymptomatic STIs, including HPV (human papillomavirus), which is the leading cause of cervical cancer in black women in South Africa,” Chandiwana said.
“Of course it’s complicated in a public healthcare system where we might not have lab services everywhere, and where there may be lab testing there is a long turnaround for results,” she added.
What to do
It means a multi-pronged approach is still necessary. This she said, has to include a shift from blaming and policing people’s sexual behaviour. Her comments are in response to Gauteng MEC for health and wellness Nomantu Nkomo-Ralehoko’s remarks in the same Gauteng Department of Health press release in which the MEC drew a link between a higher number of women coming forward to be initiated on Pre-Exposure Prophylaxis (PrEP) – an antiretroviral drug prescribed for HIV-negative people to stop HIV infection – and the higher recorded number of STIs. The MEC is quoted saying: “We believe that the high uptake of PrEP among women has led this group to having unprotected sex resulting in high incidence of MUS. The studies have reported that STI incidence is also high among young women receiving PrEP.”
Chandiwana dismissed the conclusion of a causal relationship. “PrEP is a very important tool because it’s something people can take to prevent HIV. But before we had PrEP it was not like people were using condoms – people were using nothing. So I disagree, the uptake of PrEP is not directly involved with the increase of STIs,” she said.
What’s needed instead, she said, is to ask why people are not using condoms more often and why South Africa is not creating STI friendly services that include differentiated care for key populations such as sex workers, men who have sex with men, or people who inject drugs. There should also be more peer navigators, services that are quick, efficient and confidential as well as investment and development of rapid testing kits, she added.
Preliminary findings from the Sixth South African National HIV Prevalence, Incidence, and Behaviour survey released by the Human Sciences Research Council in November indicated that condom use had dropped substantially among young people from 2017 to 2022. It did prompt MEC Nkomo-Ralehoko to call for more uptake of PrEP. “We would like to encourage more males to get initiated on PrEP to protect themselves against STI. Additionally, both men and women who are on PrEP should use condoms to protect themselves against STIs, HIV and unwanted pregnancies,” she was quoted in the press release.
Role of medical male circumcision
Meanwhile, the NGO Right to Care is promoting voluntary medical male circumcision as another strategy to combat the rise in STI cases. “Uncircumcised men are more susceptible to STIs than men who are circumcised, especially STIs that cause ulcers or wounds,” said Dr Nelson Igaba, senior technical specialist for voluntary medical male circumcision at the NGO.
He described the Gauteng statistics as “worrying” and said it should be read as a prompt for more men to opt for circumcision. The NGO will connect men to their nearest public facility to have the procedure done for free. (They can be contacted at 082 808 6152.)
Dr Tendesayi Kufa-Chakezha, a senior epidemiologist at the Centre for HIV and STIs at the National Institute of Communicable Diseases (NICD), also homes in on the need for more awareness building.
“As a country we are not talking about STIs enough, among ourselves or with our children. More healthcare workers are needed and more training can be made available. We also need a massive campaign to educate communities on the causes of STI syndromes, symptoms, where to get treatment, types of treatments, complications and to go back to facilities if they don’t get better.”
Kufa-Chakezha said South Africa’s STI treatment guidelines do conform with existing WHO guidelines. She said the NICD regularly collects information and specimens from health facilities, which allows them to determine the most common causes associated with the symptoms that are most commonly seen. The NICD uses these findings to inform the country’s STI management and treatment strategies that are based on diagnosis and treatment of the most prevalent STIs.
“If as a country we are not able to get more people with or without STI symptoms screened and treated, we will continue to have people acquiring STIs, developing symptoms associated with them, becoming ill and developing complications from them,” she added.
A new intervention for men with urinary problems trialled across GP practices has shown a sustained reduction in symptoms. Findings from the University of Bristol-led Treating Urinary Symptoms in Men in Primary Healthcare (TRIUMPH) study, involving over 1000 participants and 30 GP practices, have been published in the BMJ. The study was funded by the National Institute for Health and Care Research (NIHR).
The severity and prevalence of lower urinary tract symptoms [LUTS] in men increases with age (up to 30% in men over 65 years), with greater numbers likely to be affected as the population ages. Symptoms can have a substantial impact on quality of life but can also influenced by lifestyle factors.
Current therapies recommended by NICE (National Institute for Health and Care Excellence) include bladder training, controlling fluid intake and lifestyle advice. However, there is a lack of evidence on their effectiveness, and provision by GP practices varies.
Bristol Medical School researchers sought to trial whether a new intervention, comprising a healthcare professional consultation and an information booklet providing conservative and lifestyle guidance, could be more effective than usual care.
Study findings
The team recruited 1077 adult men, each suffering with troublesome urinary tract symptoms between June 2018 and August 2019. Participants were split with 524 in the intervention arm and 553 in the usual care arm. Participants in the intervention arm were directed to relevant sections of the booklet by general practice nurses/healthcare assistants or research nurses following urinary symptom assessment, with subsequent contacts over 12 weeks to ask how the participant was managing.
Overall, the study’s findings showed a range of troublesome urinary tract symptoms improved over 12 months in a population of men with moderate symptom severity, using a standardised booklet and manualised approach to symptom management. Analyses of symptoms in each trial arm found the intervention achieved a greater reduction in symptoms than usual care, and that the difference was maintained in the longer term
Consultant Urologist, Professor Marcus Drake, the study’s Chief Investigator, said: “The assessment of male lower urinary tract symptoms and use of conservative treatments in primary care are inconsistent. Until now, there was limited evidence that conservative treatments are effective, despite their recommendation in national guidelines. The TRIUMPH study aimed to address this need in primary care.
“Implementation of this intervention as management in primary care, has the potential to improve care and reduce drug prescriptions. Our study also found the intervention can be delivered by practice nurses or healthcare assistants rather than GPs.”
Dr Jon Rees, GP Partner at Tyntesfield Medical Group, and Chair of the Primary Care Urology Society, added: “In primary care we have often traditionally relied upon pharmaceutical management for men with bothersome urinary symptoms – the TRIUMPH study emphasises the importance of discussing conservative measures with all of these patients – for some men, this will be all that is required, for others these measures can act as an adjunct to any medication prescribed.
“Many men will prefer to avoid long-term medication, so an understanding of the potential benefits of the interventions used in the study is a vital part of the toolkit for any clinician managing these patients.”
Professor Matthew Ridd, at University of Bristol, said: “This is a ‘bread-and-butter’ problem seen by GPs every day and it is great to now have evidence for something other than tablets. It has the additional advantage that it can be done by a practice nurse, freeing up GP time.”
A new Japanese ecological study revealed that participation rates for Specific Health Checkups (SHC participation rates) had significant negative effects on standardised incidence rates (SIRs) of treated end-stage kidney disease (ESKD) and prevalence of chronic kidney disease (CKD). The findings support the importance of increasing SHC participation rates at the population level and encouraging people to undergo regular health checkups.
These factors were all relative to each of Japan’s administrative regions, known as prefectures. The findings were reported in Clinical and Experimental Nephrology.
“Japan has one of the highest incidence and prevalence rates of treated ESKD and substantial regional variation in the incidence of treated ESKD despite a uniform health care and insurance system and low ethnic and racial diversity,” said Dr Wakasugi, the corresponding author of the study. “Large variations have been observed by prefecture in participation rates for SHC, an annual health screening program introduced by Japan’s Ministry of Health, Labour and Welfare since 2008 to identify individuals requiring specific health guidance to reduce the number of people having or at risk for, metabolic syndrome.”
Using five sources of nationwide open data, the study revealed that SHC participation rates had significant direct negative effects on prefecture-specific standardised incidence rates (SIRs) and the prefecture-specific prevalence of CKD. Furthermore, through SHC participation rates, the ratio of nephrology specialists had a significant indirect negative effect on prefecture-specific SIRs, suggesting that a higher prefecture-specific ratio of nephrology specialists was associated with lower prefecture-specific SIRs. The structural equation modelling model explained 14% of the variance in prefecture-specific SIRs, indicating that prefecture-specific SHC participation rates can partially explain regional variation in prefecture-specific SIRs of treated ESKD.
“Our findings concord with the Neyagawa Health Checkups and Health Care in Kokuho Database study, which showed that men who did not attend health checkups and did not undergo a kidney test using dipstick urinalysis and/or serum creatinine measurement at medical facilities were at significantly higher risk of treated ESKD than those who attended checkups, especially among those aged ≥ 75 years,” said Dr Wakasugi. “Our findings provide evidence to support the importance of increasing SHC participation rates from a population-level perspective and encouraging people to undergo health checkups.”
A study published in the Journal of Internal Medicine indicates that SARS-CoV-2 infection may worsen lower urinary tract symptoms (LUTS) in men. The study researchers found that a enlarged prostate as a result of COVID was involved.
The study included 17 986 men receiving medication for LUTS within the public healthcare system of Hong Kong in 2021–2022, half of whom had SARS-CoV-2 infection. The group with SARS-CoV-2 had significantly higher rates of retention of urine (4.55% versus 0.86%); blood in the urine (1.36% versus 0.41%); clinical urinary tract infection (4.31% versus 1.49%); bacteria in the urine (9.02% versus 1.97%); and addition of 5-alpha reductase inhibitors, which are drugs prescribed for enlarged prostate. (0.50% versus 0.02%). These urological manifestations occurred regardless of COVID severity.
The findings might relate to the presence of certain proteins targeted by SARS-CoV-2 that are known to be expressed in the prostate.
“We are excited to be the first to report the effects of COVID on complications of benign prostatic hyperplasia – or enlarged prostate – and also demonstrate the alarming extent of its urological effects,” said corresponding author Alex Qinyang Liu, MD, of Prince of Wales Hospital, in Hong Kong.
Mount Sinai investigators have developed a new approach for treating invasive bladder cancer without the need for surgical removal of the bladder, they report in their study published in Nature Medicine. At present, cystectomy (removal of the bladder) is currently a standard approach when cancer has invaded the muscle layer of the bladder.
In a phase 2 clinical trial that was the first of its kind, doctors found that some patients could be treated with a combination of chemotherapy and immunotherapy without the need to remove their bladder. Radical cystectomy can be curative in muscle-invasive bladder cancer, but the procedure is a life-changing operation due to the need for urinary diversion and is associated with a 90 day mortality risk of up to 6–8%.
“Treatment for muscle-invasive bladder cancer is in need of major improvements from both a quality-of-life and an effectiveness standpoint,” said Matthew Galsky, MD, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, a part of the Tisch Cancer Center at Mount Sinai. “If additional research confirms our findings, this may lead to a new paradigm in the treatment of muscle-invasive bladder cancer.”
The 76 patients received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Approximately 43% (33 patients) achieved a complete response (no detectable cancer) when treated with this combination of chemotherapy and immunotherapy. Patients with a clinical complete response were offered the opportunity to proceed with additional immunotherapy, without surgical removal of the bladder. Among patients opting to proceed without surgical removal of the bladder, about 70% had no evidence of recurrent cancer after two years.
The most common adverse events were fatigue, anaemia, neutropenia and nausea. Somatic alterations in pre-specified genes or increased tumour mutational burden did not improve the positive predictive value of complete response.
Based on the results of this trial, two follow-up studies were launched to build on this approach; one is ongoing, and another will open in the next six months.
A global study looking at the benefits of cranberry products has determined that cranberry juice, and its supplements, reduce the risk of repeat symptomatic UTIs in women by more than a quarter. The study researchers, from Flinders University and The Children’s Hospital at Westmead, also found that was reduced in children by more than half, and in people susceptible to UTI following medical interventions by about 53%.
Cranberry juice and healthcare supplements that commonly include the fruit, such as capsules and tablets, have long been promoted as a readily available solution to ward off the infection but the most recent review in 2012, with evidence from 24 trials, showed no benefit from the products.
The medical scientists behind this updated review published in Cochrane Reviews aimed to update these findings, as by looking at 50 more recent trials that included almost 9000 participants.
“This incredible result didn’t really surprise us, as we’re taught that when there’s more and better evidence, the truth will ultimately come out. UTIs are horrible and very common; about a third of women will experience one, as will many elderly people and also people with bladder issues from spinal cord injury or other conditions,” says the study lead author Dr Gabrielle Williams.
“Even back in 1973, my mum was told to try cranberry juice to prevent her horrible and frequent UTIs, and for her it’s been a saviour. Despite me niggling in her ear about evidence, she’s continued to take it daily, first as the nasty sour juice and in recent years, the easy to swallow capsules. As soon as she stops, wham the symptoms are back. As usual, it turns out that mum was right! Cranberry products can help some women prevent UTIs.”
Flinders University epidemiologist Dr Jacqueline Stephens, a co-author of the study, says if the UTI persists untreated it can move to the kidneys and cause pain and more complications, including sepsis in very severe cases, so prevention is the most effective way to reduce risks.
“Most UTIs are effectively, and pretty quickly, treated with antibiotics, sometimes as little as one dose can cure the problem. Unfortunately, in some people UTIs keep coming back. Without being sure if or how it works, some healthcare providers began suggesting it to their patients. It was a harmless, easy option at the time. Even centuries ago, Native Americans reportedly ate cranberries for bladder problems, leading somewhat more recently, to laboratory scientists exploring what it was in cranberries that helped and how it might work.”
“The studies we looked at included a range of methods to determine the benefits of cranberry products. The vast majority compared cranberry products with a placebo or no treatment for UTI and determined drinking cranberries as a juice or taking capsules reduced the number of UTIs in women with recurrent cases, in children and in people susceptible to UTi’s following medical interventions such as bladder radiotherapy.”
“It’s also important to consider that few people reported any side effects with the most common being tummy pain based on the results. We also did not find enough information to determine if cranberry products are more or less effective compared with antibiotics or probiotics in preventing further UTIs.”
The data also doesn’t show any benefit for elderly people, pregnant women or in people with bladder emptying problems.
The study’s senior author, Professor Jonathan Craig, says the real benefits of cranberry products became clear when the researchers expanded the scope of the review to include the most recently available clinical data.
“This is a review of the totality of the evidence and as new evidence emerges, new findings might occur. In this case, the new evidence shows a very positive finding that cranberry juice can prevent UTI in susceptible people,” says Professor Craig.
“We have shown the efficacy of cranberry products for the treatment of UTIs using all the evidence published on this topic since the mid-nineties. The earlier versions of this review didn’t have enough evidence to determine efficacy and subsequent clinical trials showed varied results, but in this updated review the volume of data has shown this new finding.”
The study authors conclude that while cranberry products do help prevent UTIs in women with frequent recurrence, more studies are needed to further clarify who with UTI would benefit most from cranberry products.
Delirium is common among women with urinary tract infections (UTIs) – especially those who have experienced menopause. In mouse models, researchers have been able to prevent symptoms of the condition by administering oestrogen. Their study was published in the peer-reviewed journal Scientific Reports.
“There has been a resurgence of interest in hormone replacement therapy, and this study, which builds on our previous work, shows that it may be a tool to mitigate delirium,” said Shouri Lahiri, MD, director of the Neurosciences Critical Care Unit and Neurocritical Care Research at Cedars-Sinai and senior author of the study. “I think it is a major step toward a clinical trial of oestrogen in human patients with UTIs.”
Lahiri said that delirium is a common problem in older women with UTIs.
“Even as a medical student, you know that if an older woman comes to the hospital and she’s confused, one of the first things you check is whether the patient has a UTI,” Lahiri said.
In previous studies, Lahiri’s team found a connection between delirium and an immune-regulating protein called interleukin 6 (IL-6). Events such as lung injury or UTI cause IL-6 to travel through the blood to the brain, causing symptoms such as disorientation and confusion. Oestrogen is a known suppressor of IL-6, so the investigators designed experiments to test its effects on UTI-induced delirium.
The researchers compared pre- and postmenopausal mice with UTIs and observed their behaviour in several types of specialised environments. They found that the mice in which menopause had been induced exhibited symptoms of delirium, such as anxiousness and confusion, while the others did not.
When they treated the mice with oestrogen, levels of IL-6 in the blood and delirium-like behaviour were greatly reduced. The behavioural differences were not related to UTI severity, as bacterial levels in the urine weren’t markedly different between the two groups, Lahiri said.
The investigators also looked at the direct effects of oestrogen on neurons, using what Lahiri called a “UTI in a dish.”
“We exposed individual neurons to an IL-6 inflammation cocktail to create UTI-like injury,” Lahiri said. “But when we added oestrogen to the cocktail, it mitigated the injury. So, we showed that there are at least two ways that oestrogen helps reduce symptoms of delirium. It reduces IL-6 levels in the blood and protects the neurons directly.”
Just how oestrogen acts to protect neurons is still unexplained. And before conducting a clinical trial, researchers need to identify which patients with UTIs are most likely to experience delirium and at what point oestrogen treatment might be most effective.
“Currently, it is common practice to treat UTI-induced delirium using antibiotics, even though there are no clinical trials that indicate this practice is effective and it is not supported by clinical practice guidelines,” said Nancy Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “This work is an important step in determining whether modulating immune response via oestrogen replacement or other means is a more effective treatment.”
The team is also working to understand the different effects of delirium on females versus males, which was not a topic of this study. Effective treatment of delirium could be of long-term importance, Lahiri said, because it is a known risk factor for long-term cognitive impairments, such as Alzheimer’s disease and related dementia.
An international study published in JAMA comparing new and older treatments against complicated urinary tract infections has found that a new drug combination of cefepime and enmetazobactam to be more effective, especially against drug-resistant strains.
Researchers in the ALLIUM Phase 3 clinical trial showed that a combination of the drugs cefepime and enmetazobactam was more effective in treating both complicated urinary tract infections (UTIs) and acute pyelonephritis (AP), a bacterial infection causing kidney inflammation, than the standard combination of piperacillin and tazobactam. UTIs are considered complicated when they are associated with risk factors such as fevers, sepsis, urinary obstruction or catheters, that increase the danger of failing antibiotic therapy.
“This new antibiotic was superior to the standard-of-care therapy,” said Professor Keith Kaye at Rutgers Robert Wood Johnson Medical School, the study’s lead author. “It represents an exciting option for treatment.”
Prof Kaye added this drug combination also fights an often-dangerous category of bacterial illnesses caused by pathogens known as extended spectrum beta-lactamase (ESBL) infections, named for an enzyme the bacteria produce. ESBL-producing bacteria can’t be killed effectively by many of the antibiotics conventionally used to treat infections, such as penicillins and cephalosporins.
“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and we found this new combination to be highly effective,” Prof Kaye said.
The trial was conducted at 90 sites in Europe, North and Central America, South America and South Africa from September 2018 to November 2019. More than 1000 patients participated in the study. Some 79% of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9% of those receiving the conventional treatment of piperacillin and tazobactam.
Of the 20% of patients from the overall group belonging to the subset of those with ESBL infections, 73% receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51% on the standard therapy.
The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been fast-tracked for approval by the U.S. Food and Drug Administration (FDA).
Credit: Darryl Leja / National-Human-Genome Research Institute / National Institutes of Health
Diagnoses of early, curable stages of prostate cancer are being missed because national guidelines and media health campaigns in the UK focus on urinary symptoms despite a lack of scientific evidence, according to University of Cambridge researchers.
Prostate cancer is the most common type of cancer in men. And while 78% of men diagnosed with this cancer survive for over ten years, this proportion has barely changed over the past decade in the UK, largely because the disease is detected at a relatively late stage. In England, for example, nearly half of all prostate cancers are picked up at stage three of four (stage four being the latest stage).
Despite no evidence of a link between urinary symptoms and prostate cancer, national guidelines, health advice and public health campaigns continue to promote this link. In a review published in BMC Medicine, Cambridge researchers argue that not only is this unhelpful, but it may even deter men from coming forward for early testing and detection of a potentially treatable cancer.
“When most people think of the symptoms of prostate cancer, they think of problems with peeing or needing to pee more frequently, particularly during the night,” said Vincent Gnanapragasam, Professor of Urology at the University of Cambridge. “This misperception has lasted for decades, despite very little evidence, and it’s potentially preventing us picking up cases at an early stage.”
Prostate enlargement can cause the urinary problems often included in public health messaging, but evidence suggests that this is rarely due to malignant prostate tumours. Rather, research suggests that the prostate is smaller in cases of prostate cancer. A recent study – the UK PROTECT trial – even went as far as to say that a lack of urinary symptoms may in fact be an indicator of a higher likelihood of cancer.
Screening programmes are one way that cancers are often detected at an early stage, but in the case of prostate cancer, some argue that such programmes risk overwhelming health services and leading to men being treated for relatively benign disease.
Testing for prostate cancer involves a blood test that looks for a protein known as a prostate-specific antigen (PSA) that is made only by the prostate gland; however, it is not always accurate. PSA density is significantly more accurate than PSA alone in predicting a positive biopsy and is used in everyday clinical practice.
The researchers point to evidence that there is a misconception that prostate cancer is always symptomatic: a previous study found that 86% of the public associated prostate cancer with symptoms, but only 1% were aware that it could be asymptomatic.
“We urgently need to recognise that the information currently given to the public risks giving men a false sense of security if they don’t have any urinary symptoms,” said Prof Gnanapragasam.
“We need to emphasise that prostate cancer can be a silent or asymptomatic disease, particularly in its curable stages. Waiting out for urinary symptoms may mean missing opportunities to catch the disease when it’s treatable.
“Men shouldn’t be afraid to speak to their GP about getting tested, and about the value of a PSA test, especially if they have a history of prostate cancer in their family or have other risk factors such as being of Black or mixed Black ethnicity.”
The researchers say they are not advocating for an immediate screening programme, and acknowledge that changes in messaging could mean more men approaching their GPs for a PSA test, potentially resulting in unnecessary investigations and treatment. However, they argue that there are ways to reduce the risk of this happening. These include the use of algorithms to assess an individual’s risk and whether they need to be referred to a specialist, and for those who are referred, MRI scans could help rule out ‘indolent’ (mild) disease or negative findings, reducing the risks of an unnecessary biopsy.
“We’re calling on organisations such as the NHS, as well as patient charities and the media, to review the current public messaging,” said Prof Gnanapragasam.
“If men were aware that just because they have no symptoms doesn’t necessarily mean they are cancer free, then more might take up offers for tests. This could mean more tumours identified at an earlier stage and reduce the numbers of men experiencing late presentation with incurable disease.”
