Day: 01/19/2023

In the search for therapies for solid tumors, companies are turning to a novel target: claudin-6

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On target column illo cancer drug targets

On Target is a recurring feature from STAT that dives deep into the most promising drug targets in oncology. This column is adapted from the new STAT Report: Targeting cancer: the new frontier of immunotherapy and precision oncology.

Targeted immunotherapies like CAR-T have been remarkably successful in combating blood cancers like chronic lymphocytic leukemia. But malignancies that involve solid tumors have proved far more challenging for these new technologies. As yet, there has been no engineered cell therapy for solid tumors, which make up the overwhelming majority of cancers and include breast, lung, pancreatic, ovarian and prostate cancers.

One of the biggest roadblocks has been finding the right molecular targets. These therapies work by killing any cell that carries a designated marker, so scientists need to find a molecular target that exists on cancer cells but is not present in healthy tissues –  especially life-sustaining tissues like the heart or the brain.

Scientists have found few targets that fit this bill, but recently, a protein called claudin-6 or CLDN6 has been drawing the interest of researchers as one potential guide for immunotherapies. Several biotech and pharma companies have begun developing bispecific antibodies — engineered antibodies that can bind to two different antigens — or CAR-T cell therapies targeting CLDN6. BioNTech, whose founders helped discover the protein as a possible cancer antigen, is one of the most notable.

Researchers working with BioNTech presented data from a clinical trial of a CAR-T therapy targeting CLDN6 at the American Association of Cancer Research meeting in New Orleans in 2022. The trial showed that, with an immunologic boost from an mRNA vaccine, the therapy could shrink some solid tumors. BioNTech code-named the combination of the vaccine and therapy BNT211, and it remains one of the first examples of early efficacy from CAR-T cells in solid tumors, something that the cancer immunotherapy field has long struggled to achieve.

That data also helped put CLDN6 more firmly on the map as a target, said Martin Lehr, the CEO of Context Therapeutics, a biotech that is also developing drugs targeting CLDN6. “For me as an oncology drug developer, the BioNTech data was really exciting. It creates opportunities for companies like us,” he said.

The discovery

In the 1990s, Özlem Türeci and her husband, Uğur Şahin, the co-founders of BioNTech, were mulling over how to find a viable target for solid tumors. Ideally, they knew, it would be a protein that wasn’t present in healthy tissues but was highly expressed on cancer cells. That gave them an idea. Cancer cells sometimes turn on embryonic genes, or genes that are only turned on during fetal development and then silenced after birth.

“We knew cancer cells like to activate embryonic genes because they make use of proliferation,” Türeci said.

So, if Türeci and her colleagues could find activated embryonic genes in cancer cells, that might yield a useful therapeutic target. In their search, “We got this set of interesting targets,” Türeci said. “One of them was claudin-6.”

Türeci and Şahin went on to found a company called Ganymede that was focused on building antibodies to CLDN6 and other targets, including one in the same protein group, claudin 18.2. Astellas Pharma acquired that company, along with its claudin assets, but it wasn’t the end of Türeci and Şahin’s interest in CLDN6. Later, after they created BioNTech, they turned back to CLDN6 and created more therapies targeting the protein, including BNT211, the CAR-T and mRNA vaccine combination.

The biology

CLDN6 is a member of the claudin family of proteins, involved with regulating cell permeability and adhesion and helping maintain the structure and shape of cells. While scientists know that CLDN6 is present during the development of a fetus, its exact function is not entirely clear. The protein helps cancer cells spread, Türeci said,  “but we can’t explain fully how it promotes transformation of a cancer cell, for example. We do not know in-depth how CLDN6 functions. To understand this in-depth, it really is a project of a lifetime.”

Horrific Simulation: Nuclear War Would Kill Five Billion People

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Unbelievable devastation.

Getty Images/Futurism

For the better part of the last century, one question has dogged humanity: what would happen after a nuclear war?

Climate scientists devised a terrifying simulation to find answers, published in the Nature Food journal this week, and the results are nothing short of apocalyptic.

The waves of terror would be almost impossible to comprehend. Death at ground zero for miles around. Famine. Radiation. Climate destruction. It’s all there, and all as horrific as imaginable.

As the researchers at Rutgers noted in their study, it wouldn’t even necessarily take two global superpowers to lead to mass death.

If any nuclear-armed country were to attack another with a nuclear weapon — the scientists used the lengthy geopolitical dispute between India and Pakistan over the Kashmir region as an example — not only would they kill countless people at and around the site of their target, but the soot from the detonations would cause such devastation to the global climate that upwards of five billion people would be at risk of death. For perspective, that’s more than half the global population.

While this all sounds very “Biblical plague,” the Rutgers climate science simulation is grounded in atmospheric science. The soot from the blast and the leftover burning could be enough to partially or completely encircle the planet, the study found, which would in turn result in further global cooling and harm agriculture so harshly that there would be a reduction in food production from anywhere between 7 and 90 percent, depending on the size of the nuclear conflict.

A India-Pakistan-sized war would blast between five and 47 million tons of soot into the atmosphere. If the US and Russia were to have it out, it would release 150 million tons of soot, cutting the global food supply by 90 percent. That level of famine would lead to death at an incredible scale within the first three to four years after a war, and would add to the death toll of the blasts and their aftermaths as well.

While these horrific scenarios are absolutely nightmarish, the researchers did note a few caveats. First, that the simulation required lots of simplifications and presumptions about how global food supply chains would react during nuclear winter. And second, even in worst-case scenarios, there are regions that could fare better than others, with Australia seeming to fare the best on their devastation-prediction maps.

“The first time I showed my son the map,” Lily Xia, the Rutgers climate scientist who led the research, said in a Nature new release, “the first reaction he had is ‘let’s move to Australia.'”

Nonetheless, the findings from this simulation are jarring and should be taken as seriously as a heart attack.

“A large percent of the people will be starving,” Xia warned. “It’s really bad.”

Given these stark possibilities, it’s very hard to argue.

New Study Shows Where You Should Hide to Survive a Nuclear Attack

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“People should stay away from these locations and immediately take shelter.”

The Day After

In the event of a nuclear blast, let’s face it: you’re probably screwed. Fortunately, the good researchers at the University of Nicosia decided to simulate a nuclear bomb explosion to see how it would affect people taking shelter indoors, and while the results may be grim, their findings just might increase your odds of surviving.

For the study, published this week in the journal Physics of Fluids, the researchers focused on a 750 kiloton nuclear warhead detonated almost two miles above ground, delivered by an intercontinental ballistic missile.

Anyone caught in the over half a mile in radius fireball wouldn’t stand a chance, dying instantly. Not much to look into there, but it’s the ensuing shockwave that extends beyond the initial blast where things get interesting. It’s called the moderate damage zone (MDZ), and here your odds are better, but not by a whole lot.

In just ten seconds, a pressurized shockwave would extend nearly 3 miles in radius, bringing with it roaring winds that, together, would topple less resilient structures and likely kill anyone unlucky enough to be caught outside. On the other hand, concrete structures and otherwise sturdy structures might take a few licks but would mostly remain standing.

Heady Winds

Logically, your odds of survival would be better inside a sturdy building, but it’s not as straightforward as that.

“Before our study, the danger to people inside a concrete-reinforced building that withstands the blast wave was unclear,” explained study coauthor Dimitris Drikakis in a press release. “Our study shows that high airspeeds remain a considerable hazard and can still result in severe injuries or even fatalities.”

Those vicious winds will invade through windows and doors and become even stronger as they storm through corridors and narrow spaces, and likely so suddenly that you couldn’t react. In a worst case scenario, those wind speeds can power up to over 400 miles per hour in the first ten seconds. If that or deadly debris doesn’t kill you, the winds could still throw you around helplessly if you don’t get to ground, turning your shelter into a particularly cruel bouncy castle.

However, those are the absolute worst case conditions, and luckily, there are some spots where you could avoid the brunt of the winds. And no, it’s not the fridge.

“The most dangerous critical indoor locations to avoid are the windows, the corridors, and the doors,” said fellow co-author Ioannis Kokkinakis.

“People should stay away from these locations and immediately take shelter,” he added. “Even in the front room facing the explosion, one can be safe from the high airspeeds if positioned at the corners of the wall facing the blast.”

Of course, you would still have to deal with the radioactive fallout, infernal fires sweeping the landscape, and near-total breakdown of social services. But hey, it’s a starting point.

MRI-Guided RT Reduced Acute Toxic Effects in Men With Localized Prostate Cancer

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Compared with CT guidance, MRI strategy led to better patient-reported urinary and bowel outcomes

A photo of a mature man laying on a table awaiting stereotactic body radiotherapy

Stereotactic body radiotherapy (SBRT) guided by MRI for localized prostate cancer resulted in fewer toxicities and an improvement in quality of life compared with CT guidance, according to the randomized phase III MIRAGE trialopens in a new tab or window.

At 3-month follow-up, incidence of acute grade 2 or higher genitourinary toxic effects was 24.4% with MRI-guided SBRT versus 43.4% with CT guidance (P=0.01), while incidence of acute grade 2 or higher gastrointestinal toxic effects was 0% versus 10.5%, respectively (P=0.003), reported Amar U. Kishan, MD, of the University of California Los Angeles, and colleagues.

Moreover, a significantly smaller proportion of patients had a 15-point or greater increase in International Prostate Symptom Score (IPSS) at 1 month with MRI guidance (6.8% vs 19.4%, P=0.01), though this was not the case at 3 months (4.1% vs 1.4%, P=0.30), they noted in JAMA Oncologyopens in a new tab or window.

Among the 154 patients in the study, MRI guidance also resulted in a significantly smaller decrease in Expanded Prostate Cancer Index Composite-26 (EPIC-26) bowel domain subscores at 1 month (4.1-point vs 18.2-point decrement, P<0.001), and there was a significantly larger proportion of patients treated with CT guidance with a clinically relevant (≥12-point) decrease in EPIC-26 bowel domain scores (50% vs 25%, P=0.001) at 1 month.

The team also observed a numerically greater increase in EPIC-26 sexual domain scores that favored MRI guidance at 3 months.

“Our results demonstrated that the aggressive margin reduction afforded by MRI guidance allowed a substantial reduction in acute physician-scored toxic effects as well as multiple patient-reported outcome metrics,” Kishan and team wrote. “Longer-term follow-up is necessary to determine whether differences in late urinary or bowel toxic effects will occur and to evaluate differences in sexual outcomes.”

In explaining the rationale behind the study, Kishan and colleagues noted that MRI guidance offers a number of advantages over CT guidance, specifically the ability to reduce planning margins and provide a more focused treatment, thereby reducing the toxic effects of treatment to nearby organs and tissue.

However, “given the increased resources needed for MRI-guided radiotherapy, it is imperative to establish that it offers a tangible benefit for patients,” they added.

In a commentary accompanying the studyopens in a new tab or window, Shankar Siva, PhD, MBBS, of Peter MacCallum Cancer Centre in Melbourne, and colleagues wrote that the MIRAGE trial “demonstrated an undoubted clinical advantage by implementing exciting new technology.”

However, they also noted that the data offer “interesting insights” into the ways in which physicians evaluate toxicity compared with how patients report adverse events.

“The physician-scored data show that the likelihood of developing toxicity is lower in the MRI group during the first 90 days following radiotherapy. However, this is where the PROs [patient-reported outcomes] data offer some different insights. Although MRI-based SBRT offered an advantage in some PRO subdomains, this difference was predominantly observed in the first month and largely resolved by the time of the 3-month follow-ups,” they wrote.

“These findings lead us to ask how we, as a community, should value these improvements in early acute toxicity from a patient and payer perspective,” they added.

Siva and colleagues further noted that Kishan’s group estimated that the cost differential for the MRI-guided strategy was approximately $1,500, and thus “until a comprehensive cost-effectiveness analysis is completed, it is difficult for the community to estimate the value of potentially transient improvements in toxicity.”

For this study, Kishan and team included men with histologically confirmed, clinically localized prostate cancer (median age 71 years) from a single center from May 2020 to October 2021. Patients were randomized 1:1 to SBRT with CT guidance or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions.

Be Alert For Ectopic Pregnancy After Self-Managed Abortion

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It’s “important that clinicians know what’s normal after medication abortion,” expert says

A computer rendering of an ectopic pregnancy

Clinicians in the emergency department (ED) and primary care settings should be prepared to spot complications of self-managed abortion, according to a case report.

A patient who had attempted self-managed abortion presented to the ED with a ruptured ectopic pregnancy that went undetected, reported Isabel Beshar, MD, of Stanford University in California, and colleagues.

They explained in a correspondence to the New England Journal of Medicineopens in a new tab or window that the 22-year-old patient was just over 5 weeks pregnant when she presented to the ED with severe abdominal pain 6 days after taking the abortion medications mifepristone (Mifeprex) and misoprostol. The patient had no prior births.

ED physicians initially performed a pelvic ultrasound, which showed that the patient had an empty uterus and small-volume intra-abdominal bleeding. Because of the patient’s history of medication abortion, clinicians presumed that the pregnancy was terminated and that the patient’s condition was due to a hemorrhagic cyst rupture.

But another 6 days later, the patient returned to the ED with even more pain. A diagnostic laparoscopy revealed that the patient had a ruptured right tubal ectopic pregnancy that was removed without further complications.

Many states have restricted abortion since the Supreme Court ruling on Dobbs v. Jackson Women’s Health Organizationopens in a new tab or window, with at least 13 states banning most of the procedures entirelyopens in a new tab or window. Increased abortion restrictions are pushing many patients to self-managed abortion, Beshar told MedPage Today.

Initial evidence shows that self-managed abortion, defined as any action taken to end a pregnancy outside of the formal healthcare system and including the use of abortion medications, has become more common since the Dobbs decision. Daily requests to Aid Access — an online abortion pill provider — jumped from an average of 80 requests a day before the Supreme Court ruling to more than 200 after the decisionopens in a new tab or window came down last Juneopens in a new tab or window, a recent study found.

“Looking ahead, more people will opt to manage their pregnancies outside of the formal medical system,” Beshar said in an email. “The healthcare system has not yet adjusted to this paradigm shift, and this case reflects the current uncertainty around management.”

Beshar added that some people in states that restrict abortion care may not feel comfortable revealing their decision to self-manage, due to “legitimate fear of criminalization.” She said that providers should consider obtaining an ultrasound and assess beta human chorionic gonadotropin (hCG) levels for women presenting with a history of medication abortion, or even those with a positive pregnancy test and pain. “Above all, providers should maintain patient confidentiality and trust,” she added.

Beshar and colleagues stated in the report that clinicians should have increased concerns of ectopic pregnancy in patients with a recent medical abortion who:

  • Do not have prior confirmation of intrauterine pregnancy
  • Do not have a previous ectopic pregnancy or tubal surgery
  • Do not have an intrauterine device
  • Do not have an ultrasound showing abdominal free fluid

Daniel Grossman, MD, director of the University of California San Francisco (UCSF) Advancing New Standards in Reproductive Health, was not involved with this case report, but told MedPage Today that as patients present for follow-up care in EDs and primary care settings after attempting to end their pregnancies, it’s “important that clinicians know what’s normal after medication abortion.”

Symptoms such as severe abdominal pain days after a termination can be a red flag for clinicians that patients may need follow-up care, including hCG tests to confirm termination, Grossman said.

“We always have to be alert to someone having an ectopic pregnancy if they have not had a prior confirmation of intrauterine pregnancy,” he added. Grossman encouraged providers to ask patients who present with abnormal symptoms if they’ve had a prior ultrasound to confirm their pregnancy.

Ectopic pregnancy is a “rare, but very serious complication” of pregnancy that is not limited to patients seeking abortion care, Grossman said. The incidence of ectopic pregnancy among patients seeking abortion care is very low, approximately 0.07 per 1,000, Beshar’s group noted. But they added that despite the low risk, ruptured ectopic pregnancy remains an important cause of pregnancy-related morbidity and mortality that clinicians should be aware about.

“While self-managed abortion has been shown to be safe and effective, it does not include some of the same safety checks for rare, but potentially serious, complications such as ectopic pregnancy,” Beshar said. “Healthcare providers caring for people after a self-managed abortion should keep in mind these small risks.”

Buprenorphine-naloxone, buprenorphine, and methadone throughout pregnancy in maternal opioid use disorder

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Abstract

Introduction

Current WHO guidelines recommend using methadone or buprenorphine as maintenance treatments for maternal opioid use disorder. However, buprenorphine-naloxone, with a lower abuse risk than buprenorphine monotherapy or methadone, offers a potentially beneficial alternative, but scientific evidence on its effects on pregnancies, fetuses, and newborns is scarce. This paper compares the outcomes of the pregnancies, deliveries, and newborns of women on buprenorphine-naloxone, buprenorphine, or methadone maintenance treatments. According to the hypothesis, as a maintenance treatment, buprenorphine-naloxone does not have more adverse effects than buprenorphine, whereas methadone is more complicated.

Material and methods

In this population-based study, 172 pregnant women on medical-assisted treatments were followed-up at Helsinki University Women’s Hospital (Finland). Women receiving the same opioid maintenance treatment from conception to delivery and their newborns were included. Consequently, 67 mother–child dyads met the final inclusion criteria. They were divided into three groups based on their opioid pharmacotherapy. The outcomes were compared among the groups and, where applicable, with the Finnish population.

Results

The buprenorphine-naloxone and buprenorphine groups showed similar outcomes and did not significantly differ from each other in terms of maternal health during pregnancies, deliveries, or newborns. Illicit drug use during the pregnancy was common in all groups, but in the methadone group it was most common (p = 0.001). Most neonates (96%) were born full-term with good Apgar scores. They were of relatively small birth size, with those in the methadone group tending to be the smallest. Of the neonates 63% needed pharmacological treatment for neonatal opioid withdrawal syndrome. The need was lower in the buprenorphine-based groups than in the methadone group (p = 0.029).

Conclusions

Buprenorphine-naloxone seems to be as safe for pharmacotherapy for maternal opioid use disorder as buprenorphine monotherapy for both mother and newborn. Hence it could be a choice for oral opioid maintenance treatment during pregnancy, but larger studies are needed before changing the official recommendations. Women on methadone treatment carry multifactorial risks and require particularly cautious follow up. Furthermore, illicit drug use is common in all treatment groups and needs to be considered for all patients with opioid use disorder.

DISCUSSION

In the present paper, we demonstrate that OMT with buprenorphine-naloxone appears to be as safe during pregnancy as buprenorphine monotherapy for both mother and newborn. Women on methadone OMT carry marked risks and require particularly cautious follow up. Illicit drug use is common in all OMT groups despite seemingly committed patients.

Studies on relatively new OMT, such as buprenorphine-naloxone, are urgently needed.3, 13, 16–18 However, research on drug abuse issues is challenging because of recruitment problems, social stigma, dropouts, compliance issues, and confounding factors. In this study, we aimed at investigating OMT groups that were as pure as possible by including only mothers, who used the same OMT throughout the pregnancy, and their newborns. Aiming at the purity of the study groups leads to limited size of the study population. Although the basic population in the current population-based region is large (1.7 million), the number of women fulfilling the final inclusion criteria was small, and therefore the study may not have been powerful enough to discover all clinically significant factors. Hence, even though our population was larger than in many previous reports, specifically with buprenorphine-naloxone studies,13, 17 it was still small. Furthermore, the care of pregnant women with OUD is organized differently in different countries, which also may influence the results. Therefore, larger multicenter studies are needed before more precise conclusions are drawn.

The patient groups were relatively homogeneous and committed to OMT and follow up. The pregnancy monitoring, the deliveries, and neonatal care were performed in standardized circumstances. Several potential confounding factors were ruled out with the study design, which is a strength.

The concomitant illicit drug use is a potential confounding factor. Although we had assumed some illicit drug use, its magnitude during pregnancy was unexpectedly high.19, 20 Moreover, the actual use may have been even higher because the data are based on the patients’ own reports and voluntary urine tests, when the fear of child protection services involvement may have hindered truthful reporting. The role of the OMT dosage reduction in illicit drug use also remains uncertain. On the one hand, it did not seem to solely explain the high rate of illicit drug use, as 56% of the women with reduced doses did not use illicit drugs, but on the other hand, 44% did. In any case, the OMT dosing role needs to be clarified in future studies, not only because of the possible effects on illicit drug use, but also because constant dosing has been suggested to be more beneficial for both mother and fetus than decreasing doses.2

The most-used illicit drugs are in line with the previous literature,21, 22 except that cocaine was rarely used. Furthermore, mothers from buprenorphine-based groups may have additionally used illicit buprenorphine, which is difficult to detect in the tests (as the tests are anyway positive for buprenorphine as the OMT). Of note, the reason for preferring buprenorphine-naloxone as OMT and performing the present study, is this parenteral abuse potential of oral buprenorphine.

The illicit drug use was concerning in the research cohort. The methadone group was most complicated, not only with their most frequent illicit drug use, but also because of the overall situation. Their backgrounds were more severe, and they had more previous OMT periods as well as psychiatric comorbidities and medications. Furthermore, they suffered more from substance-use-related somatic diseases and experiences of violence. They also tended to start their visits to the maternity outpatient clinic later. Hence, their risk profiles were highly complex and may have, in a multifactorial way, affected the well-being, health and other outcomes of the women and their fetuses. Therefore, the interpretation of the methadone group requires caution because the outcomes may be caused by their overall complex situation rather than the methadone medication alone.

Smoking was common in all OMT groups, which is in accordance with previous publications.21, 22 Alcohol use, in turn, was far more moderate and of the same level as in the Norwegian study.19 We believe that this may be at least close to the truth. Although the alcohol consumption was based on women’s own reports, they had reported illicit drug use in higher numbers. Hence, one could assume that they would also report alcohol use, especially as in Finland, alcohol is legal whereas non-prescribed drugs and cannabis are not.

Maternal pregnancy complications and relatively common somatic diseases were as prevalent as in the general population. As expected, psychiatric comorbidities were more common,22, 23 as were certain generally rare somatic conditions that are likely to be associated with the history of injection drug use and associated lifestyle,24, 25 such as amputations, fasciotomy, endocarditis, thrombosis, pulmonary embolism and HCV. Considering heavy smoking, it was a slight surprise that placental abruption was not more common.26 The deliveries were also mostly uneventful. These patients, like all mothers in Finland, received free-of-charge high-quality maternal care, as indicated by the relatively low frequency of cesarean sections and low perinatal mortality (3.7/1000 neonates in Finland, 0 in the final study population14). The thorough follow up and planned labor modes may have resulted in these relatively safe pregnancies and deliveries.

The neonates were mainly born full-term, in good condition and without major defects. Hence, earlier single investigations suggesting higher risk for prematurity in OMT pregnancies,2 lower Apgar scores with buprenorphine-naloxone than with buprenorphine treatment,18 and increased risk for congenital defects27 were not supported by our research. In our original study population was one stillbirth, which was most likely explained by maternal injecting amphetamine use followed by septicemia rather than OMT, and the case was excluded from the final analysis. An assumption stating that it is unlikely to have a causal link between OMT substances and birth abnormalities2, 27 is supported by this paper. However, one must keep in mind the limited power of the reported studies, including ours.

Over half of the infants needed pharmacological treatment for NOWS. The need was lower in the buprenorphine-based groups than in the methadone group, which is in line with the clinical experience and the literature (maternal buprenorphine associated with less severe NOWS).8, 28, 29 Of note, even though the average daily dose of buprenorphine during the pregnancy was higher in the buprenorphine-naloxone group than in the buprenorphine-monotherapy group, the former infants did not suffer more from NOWS than the latter.

The neonates in all groups were born relatively small, although mostly within normal range. This is in line with previous literature7, 8, 13, 22 and could, at least partly, be explained by tobacco exposure.30 However, other risk factors, such as alcohol31 and polysubstance use, poor nutrition, as well as OMT medication8, 32 are also possible explanations. Additionally, because of limited human safety data,12 the role of naloxone needs further confirmation. Several studies, including ours, show similar outcomes with buprenorphine-naloxone and other forms of OMT,13 indicating that naloxone causes no additional harm. Nevertheless, solid scientific evidence is needed. Furthermore, the long-term clinical, developmental, and social effects of OMT on both mother and child require evaluation in future studies.

CONCLUSION

In this study, buprenorphine-naloxone maintenance treatment seems equal to buprenorphine monotherapy for mother and newborn. Future studies with larger data are needed to confirm the results. With lower parenteral abuse risk than with buprenorphine, buprenorphine-naloxone could be considered as useful medication for OMT during pregnancy. Women on methadone OMT have a more severe substance abuse problem with marked overall risk profile, so they require particularly cautious follow up. Furthermore, the ongoing illicit drug use is worryingly common even among committed patients. Hence, routine drug screening for women and neonates should be available, and NOWS needs to be diagnosed, if the mother is on OMT or any suspicion of fetal drug exposure exists.

Source: obgyn.onlinelibrary.wiley.com

Cognitive behavior therapy vs. control conditions, other psychotherapies, pharmacotherapies and combined treatment for depression: a comprehensive meta-analysis including 409 trials with 52,702 patients

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Abstract

Cognitive behavior therapy (CBT) is by far the most examined type of psychological treatment for depression and is recommended in most treatment guide­lines. However, no recent meta-analysis has integrated the results of randomized trials examining its effects, and its efficacy in comparison with other psychotherapies, pharmacotherapies and combined treatment for depression remains uncertain. We searched PubMed, PsycINFO, Embase and the Cochrane Library to identify studies on CBT, and separated included trials into several subsets to conduct random-effects meta-analyses. We included 409 trials (518 comparisons) with 52,702 patients, thus conducting the largest meta-analysis ever of a specific type of psychotherapy for a mental disorder. The quality of the trials was found to have increased significantly over time (with increasing numbers of trials with low risk of bias, less waitlist control groups, and larger sample sizes). CBT had moderate to large effects compared to control conditions such as care as usual and waitlist (g=0.79; 95% CI: 0.70-0.89), which remained similar in sensitivity analyses and were still significant at 6-12 month follow-up. There was no reduction of the effect size of CBT according to the publication year (<2001 vs. 2001-2010 vs. >2011). CBT was significantly more effective than other psychotherapies, but the difference was small (g=0.06; 95% CI: 0-0.12) and became non-significant in most sensitivity analyses. The effects of CBT did not differ significantly from those of pharmacotherapies at the short term, but were significantly larger at 6-12 month follow-up (g=0.34; 95% CI: 0.09-0.58), although the number of trials was small, and the difference was not significant in all sensitivity analyses. Combined treatment was more effective than pharmacotherapies alone at the short (g=0.51; 95% CI: 0.19-0.84) and long term (g=0.32; 95% CI: 0.09-0.55), but it was not more effective than CBT alone at either time point. CBT was also effective as unguided self-help intervention (g=0.45; 95% CI: 0.31-0.60), in institutional settings (g=0.65; 95% CI: 0.21-1.08), and in children and adolescents (g=0.41; 95% CI: 0.25-0.57). We can conclude that the efficacy of CBT in depression is documented across different formats, ages, target groups, and settings. However, the superiority of CBT over other psychotherapies for depression does not emerge clearly from this meta-analysis. CBT appears to be as effective as pharmacotherapies at the short term, but more effective at the longer term.

DISCUSSION

This is the largest meta-analysis ever of a specific type of psychotherapy for a mental disorder, including 409 RCTs (518 comparisons) with 52,702 patients. CBT was found to be effective in depression when compared to control conditions such as usual care and waitlist, with a moderate to large effect size (g=0.79). This effect was robust in several sensitivity analyses, although it was somewhat smaller for studies with low risk of bias (g=0.60) and after adjustment for publication bias (g=0.47). CBT was still significantly effective at 6-9 month (g=0.74) and 10-12 month (g=0.49) follow-up, and this was confirmed in most sensitivity analyses.

A total of 42% of patients receiving CBT responded to treatment, while the response rate was only 19% in control groups, with a NNT of 4.7 in favor of CBT. The remission rate was 36% in patients receiving CBT, compared to 15% in control conditions, with a NNT of 3.6.

Comparative trials suggest that CBT is significantly more effective than other psychotherapies, but the difference is small (g=0.06) and does not remain significant in most sensitivity analyses. The effects of CBT are comparable to those of pharmacotherapies at the short term, but CBT is significantly more effective at 6 to 12 months (g=0.34). Combined treatment is significantly more effective than pharmacotherapy alone, at the short (g=0.51) and the longer term (g=0.32), but combined treatment is not more effective than CBT alone at either time point.

Most trials examine CBT in an individual, group or guided self-help format, and we previously showed that there are no significant differences between these formats12. In the current meta-analysis, we could also include a set of trials of unguided self-help CBT, and found that this was also effective, with a small to moderate effect size (g=0.45). CBT was also found to be effective in inpatient settings (g=0.65), as well as in children and adolescents (g=0.41).

Research on CBT has evolved over time. The quality of studies has improved, which can be seen from the increasing number of trials with low risk of bias, the decrease in the use of waitlist control groups, and the increase in sample sizes of included studies. The number of treatment sessions has significantly decreased over the years. In a meta-regression analysis, we could not confirm that the effect size of CBT has decreased over time, as was suggested in an earlier study37.

The findings of this study should be considered in the light of some limitations. First, heterogeneity was high in many analyses, and subgroup and meta-regression analyses could not identify all sources of this heterogeneity, suggesting that there are differences between trials that cannot be explained by the extracted characteristics. Second, risk of bias was high in many of the included trials, and the effect sizes of the trials with low risk of bias were significantly lower in some of the analyses. Fortunately, the number of studies was so large that we could examine outcomes in subsets of trials with low risk of bias. Finally, we found indications of publication bias in many analyses, although several findings remained robust after correcting for this bias.

We can conclude that CBT is effective in the treatment of depression with a moderate to large effect size, and that its effect is still significant up to 12 months. The superiority of CBT over other psychotherapies does not emerge clearly from this meta-analysis. CBT appears to be as effective as pharmacotherapies at the short term, but more effective at the longer term. Combined treatment appears to be superior to pharmacotherapy alone but not to CBT alone. The efficacy of CBT in depression is documented across different delivery formats, ages, target groups, and settings.

Source: onlinelibrary.wiley.com

How to spot a cyberbot – five tips to keep your device safe

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Illustration of insecure network, world wide computer controlled by a botnet master
Malware is designed to hide in your device

You may know nothing about it, but your phone – or your laptop or tablet – could be taken over by someone else who has found their way in through a back door. They could have infected your device with malware to make it a “bot” or a “zombie” and be using it – perhaps with hundreds of other unwitting victims’ phones – to launch a cyberattack.

Bot is short for robot. But cyberbots don’t look like the robots of science fiction such as R2-D2. They are software applications that perform repetitive tasks they have been programmed to do. They only become malicious when a human operator (a “botmaster”) uses it to infect other devices.

The botmaster controls their zombies via a command and control server (C&C) Author provided

Botmasters use thousands of zombies to form a network (“botnets”), unknown to their owners. The botnet lies dormant until the number of infected computers reaches a critical mass. This is when the botmaster initiates an attack. An attack could involve hundreds of thousands of bots, which target a single or very small number of victims.

This type of attack is called a distributed denial-of-service (DDoS) attack. Its aim is to overwhelm the resources of a website or service with network data traffic.

Attacks are measured by how many connection requests (for example website/browser connections) and by how much data they can generate per second. Usually a lone bot can only generate a few Mbps of traffic. The power of a botnet is in its numbers.

Are bots illegal?

Not entirely. Anyone can buy a botnet. “Botnets-for-hire” services start from $23.99 (£19.70) monthly from private vendors. The largest botnets tend to be sold by reference. These services are sold so you can test your personal or company service against such attacks. However, it wouldn’t take much effort to launch an illegal attack on someone you disagree with later on.

Other legitimate uses of bots include chatting online to customers with automated responses as well as collecting and aggregating data, such as digital marketing. Bots can also be used for online transactions.

Botnet malware is designed to work undetected. It acts like a sleeper agent, keeping a low profile on your system once it’s installed. However, there are some simple ways to check if you think you might be part of a botnet.

Antivirus protection

Computer operating systems (such as Windows) come with antivirus protection installed by default, which offers the first line of defence. Antivirus software uses signature analysis. When a security company detects malware, it will make a unique signature for the malware and add it to a database.

But not all malware is known.

More advanced types of antivirus detection solutions include “heuristic” and “behaviour” techniques. Heuristic detection scans algorithm code for suspect segments. Behaviour detection tracks programs to check if they’re doing something they should not (such as Microsoft Word trying to change antivirus rules). Most antivirus packages have these features to a greater or lesser degree but compare different products side by side to side to see if they meet your needs.

Use a firewall

Computers are more vulnerable when connected to the internet. Ports, input devices with an assigned number that run on your computer, are one of the parts that become more exposed. These ports allow your computer to send and receive data.

A firewall will block specific data or ports to keep you safe. But bots are harder to detect if the botmaster uses encrypted channels (the firewall can’t read encrypted data like Hypertext Transfer Protocol Secure (https) data).

Investing in a new broadband router rather than using the one your broadband provider sends can help, especially if it features advanced network-based firewalls, web security/URL filtering, flow detection and intrusion detection and prevention systems.

Behaviour and decisions

Ignoring system and software updates leaves you vulnerable to security threats. Your computer data should also be backed up on a regular basis.

Don’t use administrator accountsfor regular computer access for both home and business use. Create a separate user account even for your personal laptop, without admin privileges. It is much easier for attackers to introduce malware via a phishing attack or gain those credentials by using impersonation when you are logged into an administrator account. Think twice before downloading new apps and only install programs that are digitally verified by a trusted company.

Many attacks, such as ransomware, only work when people lack awareness. So keep up to date with the latest information about techniques cybercriminals use.

Use an alternative domain name service

Usually your internet provider handles this automatically for you (linking website addresses to network addresses and vice versa). But botnets often use domain name services to distribute malware and issue commands.

Young hacker in the dark breaks the access to steal information and infect computers and systems.
Botmasters need to infect thousands of devices to create their network of zombies.

You can manually check patterns of known botnet attacks from sites such as OpenDNS against your computer records.

What if I think I have a botnet infection?

Signs your device is a zombie include websites opening slowly, the device running slower than usual or behaving oddly such as app windows opening unexpectedly.

Have a look at what programs are running. On Windows for example, open Task Manager to do a brief survey to see if anything looks suspicious. For example, is a web browser running despite the fact you have not opened any websites?

For more information look at guides to viewing Windows computer processes. Other tools include Netlimiter for Windows and Little Snitch for Mac.

When there have been news reports of a botnet attack, you might want to take a look at reputable botnet status sites which offer free checks to see if your network has an infected computer.

If your computer has a botnet infection it either needs to be removed by antivirus software. Some types of malware with features like rootkit functionality are notoriously hard to remove. In this case your computer’s data (including the operating system) should be deleted and restored. Another reason to back your computer up on a regular basis – anything not backed up will be lost.

How to Live Longer and Better

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As of today, no drugs, supplements or potions have been shown to extend your life, in spite of the fact that the internet is full of an incredible number of fraudulent life-extension products that provide no benefits while they steal your money. However, we do have overwhelming evidence that several healthful lifestyle habits can extend how long you live and improve your quality of life in your later years. These lifestyle factors have been associated with freedom from type-2 diabetes, heart and respiratory diseases, cancers, and other diseases that can make your life miserable.

A study of 116,043 European men and women, followed for 15 years, found that of 16 different lifestyle profiles, four were associated with the greatest disease-free life years (JAMA Intern Med, published online April 6, 2020):
• absence of obesity (BMI < 25),
• never smoked,
• exercised regularly, and
• drank no more than a moderate amount of alcohol.

Longevity and Quality of Life
In North America, the average man lives to age 76, and the average woman to age 81. Harvard researchers found that adopting five healthy habits could extend life expectancy by 14 years for women and by 12 years for men (Circulation, 2018;345:345):
• eating a diet high in plants and low in fats,
• exercising at a moderate to vigorous level for several hours a week,
• maintaining a healthy body weight,
• not smoking, and
• consuming no more than one alcoholic drink a day for women and two for men.

The team of Harvard researchers followed that study with another that found that by following a healthful lifestyle, women can extend their disease-free life expectancy after age 50 by 10 years, and men can add about eight more years (BMJ, Jan 8, 2020). Women who followed four out of five of the healthful lifestyle factors lived on average 34 more years without those diseases after age 50 compared to 24 years for women who said they did not follow any of the healthy habits. Men who reported fulfilling four or five of the lifestyle habits lived on average 31 more years free of disease after age 50 while those who adopted none of them lived on average 23 more years after age 50.

Longevity is determined by both genes and lifestyle, but genes are estimated to contribute only about seven percent, so lifestyle is much more important. Living with a person who practices a healthful lifestyle increases your chances of practicing a healthful lifestyle (Genetics, November 1, 2018;210(3):1109-1124), and parents’ healthful lifestyles can change their genes so that they pass on more healthful genes to their children (Epigenomics, Jun, 2011;3(3):267–277). This process is called epigenetic modification. Mothers who live to their 90s with a healthy lifestyle are far more likely to have healthy daughters who live to their 90s (Age and Ageing, Nov, 2018;47(6):853–860).

Alcohol Does Not Have Health Benefits
The authors of the European study found that those who took in 1-21 drinks a week had the most disease-free years. Next came non-drinkers, and as expected, those who took in more than 22 drinks per week suffered the most disease. However, other recent studies on alcohol consumption show that alcohol at any dose does not benefit health. One review of 45 studies found that the studies that associated moderate drinking with reduced heart attack rates were flawed (Journal of Studies on Alcohol and Drugs, May 2017;78(3):375-386). Studies designed to show that alcohol prevents heart attacks must have a control group of nondrinkers, but many members of the control groups were former drinkers who had given up alcohol because they were alcoholics, had heart, liver or kidney diseases, were diabetic, or had some other disease or condition that forced them to give up alcohol. When these unhealthy people are removed from the non-drinking control groups, the corrected studies show that even moderate drinking can shorten your life. Alcohol causes inflammation and oxidative stress that damages cells and increases risk for disease. There may be a threshold at which alcohol causes disease, but alcohol at any dose increases cancer risk and does not help to prevent heart attacks.

My Recommendations
Here are the major components of a healthful lifestyle:
• Diet: You should be eating primarily a plant-based diet with lots of vegetables, fruits, whole grains, beans, nuts and other seeds. Your main drink should be water; avoid fluids with calories, including fruit juices and adding sugar or cream to coffee or tea. I recommend that you avoid mammal meat, processed meats, fried foods and sugar-added foods. Restrict refined carbohydrates, particularly if weight control is an issue for you. That means everything that is made from flour or other refined grains such as bread, pretzels, bagels, spaghetti, macaroni, white rice, most cold breakfast cereals, and so forth.
• Exercise: Try to exercise for at least a half hour every day, and an hour is better. All exercise is beneficial, but increasing intensity at least once a week will help you even more. Resistance exercise to strengthen your muscles has been shown to help prevent heart disease and strengthen bones.
• Avoid smoke: Recent data show that you can shorten your life by breathing other people’s smoke (second-hand smoke) or even living in an environment where people have smoked previously (third-hand smoke).
• Avoid or restrict alcohol: Most doctors agree that men who take more than two drinks a day and women who take more than one drink a day, or have any pattern of binge drinking, are at increased risk for disease and premature death. I believe that no amount of alcohol has health benefits.
• Avoid overweight: The fat that kills is in your belly and around organs. Fat elsewhere is far less dangerous. Research shows that skinny people can be at high risk for heart attacks, diabetes and premature death if they store most of their fat in their belly (Annals of Internal Medicine, November 10, 2015), and the people who are at highest risk for premature death are those who have big bellies and small buttocks (J Bone Miner Res, July 2019;34(7):1264-1274). Your doctor can order a sonogram of your liver to see if you store too much fat there.